Skip to main content
  • ASM
    • Antimicrobial Agents and Chemotheraphy
    • Applied and Environmental Mircobiology
    • Clinical Microbiology Reviews
    • Clinical and Vaccine Immunology
    • EcoSal Plus
    • Eukaryotic Cell
    • Infection and Immunity
    • Journal of Bacteriology
    • Journal of Clinical Microbiology
    • Journal of Microbiology & Biology Education
    • Journal of Virology
    • mBio
    • Microbiology and Molecular Biology Reviews
    • Microbiology Resource Announcements
    • Microbiology Spectrum
    • Molecular and Cellular Biology
    • mSphere
    • mSystems
  • Log in
  • My alerts
  • My Cart

Main menu

  • Home
  • Articles
    • Current Issue
    • Accepted Manuscripts
    • Archive
    • Minireviews
    • JB Special Collection
    • JB Classic Spotlights
  • For Authors
    • Submit a Manuscript
    • Scope
    • Editorial Policy
    • Submission, Review, & Publication Processes
    • Organization and Format
    • Errata, Author Corrections, Retractions
    • Illustrations and Tables
    • Nomenclature
    • Abbreviations and Conventions
    • Publication Fees
    • Ethics Resources and Policies
  • About the Journal
    • About JB
    • Editor in Chief
    • Editorial Board
    • For Reviewers
    • For the Media
    • For Librarians
    • For Advertisers
    • Alerts
    • RSS
    • FAQ
  • Subscribe
    • Members
    • Institutions
  • ASM
    • Antimicrobial Agents and Chemotheraphy
    • Applied and Environmental Mircobiology
    • Clinical Microbiology Reviews
    • Clinical and Vaccine Immunology
    • EcoSal Plus
    • Eukaryotic Cell
    • Infection and Immunity
    • Journal of Bacteriology
    • Journal of Clinical Microbiology
    • Journal of Microbiology & Biology Education
    • Journal of Virology
    • mBio
    • Microbiology and Molecular Biology Reviews
    • Microbiology Resource Announcements
    • Microbiology Spectrum
    • Molecular and Cellular Biology
    • mSphere
    • mSystems

User menu

  • Log in
  • My alerts
  • My Cart

Search

  • Advanced search
Journal of Bacteriology
publisher-logosite-logo

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Accepted Manuscripts
    • Archive
    • Minireviews
    • JB Special Collection
    • JB Classic Spotlights
  • For Authors
    • Submit a Manuscript
    • Scope
    • Editorial Policy
    • Submission, Review, & Publication Processes
    • Organization and Format
    • Errata, Author Corrections, Retractions
    • Illustrations and Tables
    • Nomenclature
    • Abbreviations and Conventions
    • Publication Fees
    • Ethics Resources and Policies
  • About the Journal
    • About JB
    • Editor in Chief
    • Editorial Board
    • For Reviewers
    • For the Media
    • For Librarians
    • For Advertisers
    • Alerts
    • RSS
    • FAQ
  • Subscribe
    • Members
    • Institutions
Minireview

Fifty Years after the Replicon Hypothesis: Cell-Specific Master Regulators as New Players in Chromosome Replication Control

Marcin Wolański, Dagmara Jakimowicz, Jolanta Zakrzewska-Czerwińska
Marcin Wolański
Faculty of Biotechnology, University of Wrocław, Wrocław, Poland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Dagmara Jakimowicz
Faculty of Biotechnology, University of Wrocław, Wrocław, PolandDepartment of Microbiology, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jolanta Zakrzewska-Czerwińska
Faculty of Biotechnology, University of Wrocław, Wrocław, PolandDepartment of Microbiology, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
DOI: 10.1128/JB.01706-14
  • Article
  • Figures & Data
  • Info & Metrics
  • PDF
Loading

ABSTRACT

Numerous free-living bacteria undergo complex differentiation in response to unfavorable environmental conditions or as part of their natural cell cycle. Developmental programs require the de novo expression of several sets of genes responsible for morphological, physiological, and metabolic changes, such as spore/endospore formation, the generation of flagella, and the synthesis of antibiotics. Notably, the frequency of chromosomal replication initiation events must also be adjusted with respect to the developmental stage in order to ensure that each nascent cell receives a single copy of the chromosomal DNA. In this review, we focus on the master transcriptional factors, Spo0A, CtrA, and AdpA, which coordinate developmental program and which were recently demonstrated to control chromosome replication. We summarize the current state of knowledge on the role of these developmental regulators in synchronizing the replication with cell differentiation in Bacillus subtilis, Caulobacter crescentus, and Streptomyces coelicolor, respectively.

INTRODUCTION

Faithful transmission of genetic material to daughter cells requires the precise regulation of chromosomal replication and its coordination with the cell cycle. In all three domains of life, chromosomal replication is mainly regulated at the initiation step, an important cell cycle checkpoint designed to guarantee that chromosomal replication occurs only once per cell division cycle. Over 50 years ago, Sydney Brenner, Francois Cuzin, and Francois Jacob proposed the replicon theory (1) explaining how chromosome replication in bacteria is coordinated with the cell cycle and cell division. The theory assumed the existence of only two key elements required for initiation of bacterial chromosome replication: the trans-acting element (a structural gene encoding an initiator) and the cis-acting element (replicator). According to their hypothesis, the initiator positively regulates replication initiation by interaction with the replicator. Twenty to 30 years later, the theory was experimentally proven not only for bacteria, phages, and plasmids but also for archaea and, to some extent, for eukaryotes. Over the last 20 years, researchers have made considerable progress in understanding the mechanisms of replication initiation, particularly the structures and functions of the key elements across the three domains of life.

In contrast to Eukaryota, bacterial chromosomes possess a single, unique replication origin, in which the DNA synthesis starts generating a single replication eye per chromosome (2, 3). Replication of the bacterial chromosome is initiated by the binding of the initiator protein called DnaA to specific 9-mer sequences (called DnaA boxes) within the oriC region (origin of chromosomal replication—the replicator) (originally described by the Kornberg group; see, e.g., references 4 and 5). The DnaA protein is composed of four functional domains that are responsible for self-oligomerization and interactions with other proteins (e.g., DnaB and HU), cofactors (ATP/ADP), and DNA (i.e., DnaA boxes) (see Table 1) (6–11). Bacterial oriC regions differ in size (from ∼200 to 1,000 bp), and their sequences are conserved only among closely related organisms. In addition to the repertoire of DnaA boxes, they usually include an AT-rich region with a DNA-unwinding element (DUE) and the binding sites for regulatory proteins. Through the sequential binding of high-, medium-, and low-affinity DnaA boxes, the DnaA protein forms a highly ordered nucleoprotein complex (orisome), which promotes separation of DNA strands at the DUE. Notably, only ATP-bound DnaA is able to unwind DNA. Furthermore, ATP-bound DnaA is also required for the binding of low-affinity DnaA boxes (e.g., those in Escherichia coli and Streptomyces) (12–15). The unwound region provides an entry site for the key replication enzymes helicase, primase, and DNA polymerase (Pol) III, the latter of which forms the replication fork (for a review, see reference 16).

View this table:
  • View inline
  • View popup
TABLE 1

DnaA—replication initiator proteina

Bacterial replication begins at a single oriC region, and the activity and availability of this region and the initiator protein have to be tightly regulated to ensure that chromosomal DNA is entirely replicated only once per cell cycle. Among several mechanisms involved in regulating replication initiation, the inactivation of DnaA-ATP by ATP hydrolysis is likely to be the most common in bacteria (10), whereas other mechanisms appear to be specific for particular bacteria. These include the sequestration of the hemimethylated oriC region seen in E. coli; the titration of DnaA proteins by clusters of DnaA boxes localized outside the oriC regions of E. coli, Bacillus subtilis, and Streptomyces coelicolor; the modulation of DnaA activity by different proteins, such as Hda homologues in E. coli and Caulobacter crescentus and SirA and YabA in B. subtilis; and the proteolytic degradation of DnaA by the Lon and ClpP proteases in C. crescentus (Table 2) (for reviews or details, see references 7, 10, 17, 18, 19, 20, 21, 22, and 23). Recently, master transcriptional regulators were demonstrated to be involved in controlling chromosome replication as well as other cellular processes. Examples of these are CtrA, Spo0A, and AdpA proteins, which, in C. crescentus, B. subtilis, and S. coelicolor, respectively, play crucial roles in coordination of replication with differentiation of these bacteria (Table 3).

View this table:
  • View inline
  • View popup
TABLE 2

Negative-regulatory mechanisms for DnaA-dependent replication initiation

View this table:
  • View inline
  • View popup
TABLE 3

Global transcription regulators

In bacteria that undergo differentiation, the regulatory networks that control replication initiation are likely to be intricate and require specific mechanisms that can synchronize chromosomal replication initiation with developmental processes, which involve functional specialization of specific cell types in response to environmental signals (e.g., nutrient limitations). In this review, we summarize the current state of knowledge regarding the checkpoints that couple replication to cell cycle progression. We focus on the master transcription factors, CtrA, Spo0A, and AdpA (Table 3), which control the morphological developments of C. crescentus, B. subtilis, and S. coelicolor, respectively, and discuss how these regulators temporally and spatially coordinate replication initiation with cell differentiation.

MASTER TRANSCRIPTION FACTORS CONTROL CELL CYCLE PROGRESSION IN BACTERIA THAT UNDERGO COMPLEX DEVELOPMENTAL CYCLES

Free-living bacteria develop specific strategies to survive unfavorable environmental conditions. Such adaptations may be achieved in certain bacteria through the acquisition of a complex life cycle that includes the formation of spores or dormant cells. A complex bacterial life cycle requires the specific coordination of cell division, chromosomal replication, segregation, and morphological differentiation (Fig. 1). Differentiation includes morphological changes that depend on the activation of numerous genes, such as those responsible for spore coat synthesis or flagellar assembly. Thus, complex developmental pathways require the presence of specific regulatory proteins capable of coordinating multiple processes, including chromosomal replication. This often arises via the specific spatial, temporal, and asymmetrical (depending on the cell type/cell compartment) regulation of gene expression and protein accumulation controlled by master regulators. Among the master regulators identified in Bacillus, Streptomyces, and Caulobacter, Spo0A, AdpA, and CtrA, respectively (see Table 3), have been shown to coordinate differentiation with the regulation of chromosomal replication.

FIG 1
  • Open in new tab
  • Download powerpoint
FIG 1

Chromosome distributions during the developmental life cycles of B. subtilis, S. coelicolor, and C. crescentus. Darker colors indicate intensive chromosomal replication or higher protein concentrations of the master regulators, Spo0A, AdpA, and CtrA.

Sporulation, which is a survival strategy in such diverse genera as Bacillus, Clostridium, Myxococcus, and Streptomyces, is triggered by nutrient limitation and/or high cell density (24–28). Spore formation may follow very diverse routes depending on the genus. During the sporulation of B. subtilis (Fig. 1), for example, formation of a single endospore starts with an asymmetric cell division that delimits a forespore, followed by engulfment of the forespore in a phagocytic-like process, the formation of a protective spore coat, and, subsequently, lysis of the mother cell to release the spore (reviewed in references 29, 30, and 31). In contrast, mycelial soil-inhabiting Streptomyces spp. form the chains of exospores (Fig. 1) (32). Here, the transition from vegetative growth to sporulation involves the differentiation of the branched network of vegetative hyphae into morphologically distinct aerial hyphae, which are further converted into chains of prespores via synchronized multiple-cell division (33). Thereafter, the spores mature via synthesis of a thick cell wall and eventually undergo dispersal. Unlike bacteria in which sporulation is an optional developmental pathway, the water-inhabiting Caulobacter sp. undergoes morphological differentiation as an intrinsic part of its natural cell cycle (34). Asymmetric division of a C. crescentus cell produces two daughter cells with different morphologies: a nonmotile stalked cell able to adhere to surfaces and a motile swarmer cell with a polar flagellum (Fig. 1). Only the stalked cell is able to divide; when the swarmer cell is provided with sufficient nutrients, it differentiates into a stalked cell (via ejection of the flagellum and formation of a stalk at the same pole) and undergoes division.

Normally, before initiation of sporulation of B. subtilis, ongoing chromosomal replication is terminated (Sda protein is a factor that prevents entry into sporulation when cells are initiating DNA replication [35]) and the newly replicated chromosomes are remodeled into an axial filament extending between the poles (36, 37). Asymmetrical positioning of the septum, which is typical of sporulation, traps the forespore chromosome within the closing septum and generates a transient asymmetry wherein the mother cell is diploid for two-thirds of the chromosomal genes. Completion of chromosome segregation requires active translocation of the chromosome through the closing septum (38).

Similarly to the situation in B. subtilis, the sporulation-related cell division of Streptomyces employs sporulation-specific control of the typical vegetative cell division machinery. During vegetative growth, occasional septa delimit adjacent elongated multinucleoid hyphal compartments; during sporulation, in contrast, the closely spaced sporulation septa form a ladder along the sporogenic multinucleoid compartment (39, 40) (Fig. 1). Formation of the long chains of spores is preceded by rapid extension of sporogenic hyphae accompanied by intensive chromosome replication, after which the ongoing rounds of replication are terminated and the chromosomes are condensed and precisely positioned between developing septa to form unigenomic spores (41, 42). In sporulating Streptomyces, therefore, cell division is tightly coordinated with the shutdown of chromosomal replication and the sporulation-specific segregation and organization of the chromosomes.

Precise synchronization of chromosomal replication with the cell cycle is also seen in C. crescentus (Fig. 1) (for recent reviews, see references 22 and 43). The newly replicated chromosome is moved to the nascent half of the cell immediately after initiation of replication in stalked cells (44), and after cell division, each daughter cell contains a single chromosome that is attached to the cell pole by a polarly localized replication origin region (45, 46). As noted above, chromosomal replication is blocked in swarmer cells until they transform into stalked cells. Septation is coordinated with replication initiation and the bipolar positioning of the two sister origin regions (47).

In B. subtilis, the sporulation “decision” depends on the master transcription factor, Spo0A (Table 3). A combination of signals associated with high population density and cell cycle progression accelerates a multicomponent phosphorelay cascade, resulting in the phosphorylation of Spo0A (48). Upon phosphorylation, Spo0A initiates the sporulation pathway by affecting the transcription of ∼500 genes (∼120 of which are directly controlled). The binding of Spo0A∼P to a specific DNA sequence called the Spo0A-box in promoter regions activates the genes involved in sporulation and represses many genes that had been expressed during vegetative growth (35, 49, 50). Spo0A∼P is responsible for activating mother cell/forespore-specific sigma factors (and other regulators) and genes whose products control asymmetric division (51–53) and sporulation-specific chromosomal segregation (36, 37). Interestingly, sporulation is triggered only when a high level of phosphorylated Spo0A is attained, whereas the intermediate levels of Spo0A∼P in the so-called “transition state” are associated with increased protease production, motility, competence for transformation, biofilm formation, and cannibalism, in a hierarchy of developmental decision-making (54).

Similarly to the case of B. subtilis, the sporulation of S. coelicolor (a model organism for developmental studies in Streptomyces) is governed by numerous transcriptional regulators, including sigma factors (55). The set of regulators responsible for controlling the erection of aerial hyphae is called Bld due to the “bald” colony phenotype caused by mutations in their encoding genes (“bald” colonies do not produce the outer fluffy layer—the aerial hyphae) (56, 57). The transition from fluffy white aerial hyphae to chains of gray spores requires the activation of regulatory proteins encoded by the whi genes (so named for the white appearance of mutant colonies) (58, 59). As the development of Streptomyces colonies is correlated with secondary metabolism and antibiotic production, mutations in bld genes can affect both morphological differentiation and the production of antibiotics (reviewed in reference 60). The product of the adpA gene (also known as bldH) (Table 3) plays a key coordinating role in regulating the morphological differentiation of Streptomyces. AdpA is a master transcription factor responsible for controlling several dozen genes (61, 62) whose encoded products are required for morphological development (e.g., SapB, a regulator of the aerial mycelium-promoting peptide, and SsgA, a protein involved in septum formation during sporulation [63]; reviewed by Higo et al. [64]). In silico analysis has identified AdpA-binding sequences in more than 150 intergenic regions of S. coelicolor (63).

As in sporulating bacteria, control of development in C. crescentus is associated with the spatiotemporal control of numerous genes (about 20% of all genes) (65). Many of these are controlled by CtrA (Table 3) and three other master regulators, GcrA (a DNA binding protein), DnaA, and CcrM (a DNA methylase), that are regulated at one or several levels (synthesis, activation, localization, degradation). Together, these four proteins precisely coordinate chromosomal replication and segregation with cell growth, cell division, and pole morphogenesis (22, 66, 67). CtrA recognizes and binds a specific DNA sequence (the CtrA box) to directly control the transcription of ∼100 genes within 55 operons affecting the expression of genes involved in flagellum assembly, holdfast synthesis, DNA methylation, and cell division (68). Activation of CtrA is controlled by its phosphorylation, in which a regulatory circuit of several polarly localized histidine kinases and phosphatases is involved (69, 70). Due to the polarity of C. crescentus predivisional cells, the swarmer cell inherits an active, phosphorylated form of CtrA whereas CtrA undergoes specific proteolysis in the stalked cell (71). When a swarmer cell transitions to a stalked cell, CtrA is inactivated and the gcrA gene, which encodes the stalked-cell-specific master regulator, is induced. GcrA affects the transcription of over 125 genes, including those encoding components of the DNA replication and chromosomal segregation machineries (72, 73). Upon initiation of cell division, clearance of GcrA is coincident with the gradual accumulation of CtrA (72).

In sum, the master regulators play crucial roles in the spatial and temporal regulation of sequential events during bacterial differentiation. Their abundance and activity are precisely controlled at different levels, including gene expression (at transcriptional and translational levels), proteolysis, and posttranslational modification (phosphorylation).

MASTER REGULATORS INHIBIT REPLICATION INITIATION DURING THE TRANSITION TO NONREPLICATING CELLS

Despite extensive studies on the mechanisms responsible for controlling the initiation of chromosomal replication (for reviews, see references 7, 9, and 10), we have begun only recently to understand how the master regulators coordinate differentiation with chromosomal replication. The initiation of chromosomal replication requires the ATP-bound form of DnaA (Table 1) and many other factors that organize and/or regulate initiation complex (orisome) formation, ensuring that DNA unwinding occurs once per cell cycle. AdpA, Spo0A, and CtrA (Table 3) have been identified as factors that coordinate replication with the cell cycle; they inhibit the initiation of chromosomal replication by binding to the cognate oriC region in S. coelicolor and B. subtilis (AdpA and Spo0A, respectively) and to the region called Cori in C. crescentus (CtrA) (15, 74–76). Compared with E. coli (14), the origin regions of B. subtilis, C. crescentus, and S. coelicolor are structurally more complex and relatively long (1,000 bp or longer) and contain multiple high-, moderate-, and low-affinity DnaA boxes (Fig. 2) (74, 77, 78). In the oriC regions of S. coelicolor and B. subtilis, the DnaA boxes are organized in two clusters (boxes 1 to 11 and boxes 13 to 19 in S. coelicolor and boxes separated by the dnaA gene in B. subtilis), both of which are required for autonomous replication (79, 80). In vitro observations indicate that upon binding of the DnaA protein, a loop is formed between the clusters; this mechanism may promote the in vivo unwinding of DNA at the DUE (81, 82). Interestingly, the oriC region of each three model organisms possesses multiple binding sites for their respective master regulators, AdpA, CtrA, and Spo0A, located near or partially overlapping the DnaA-binding sites that are indispensable for replication initiation (Fig. 2) (15, 74, 77, 79, 83). Moreover, the specific interactions between these master regulators and their oriC regions were confirmed by in vitro (electrophoretic mobility shift assay [EMSA], DNase I footprinting, or surface plasmon resonance) and in vivo (chromatin immunoprecipitation [ChIP]) assays in all three model organisms (15, 49, 68, 84). The interaction of master regulators with their targets presumably interferes with the formation of functional orisomes, thereby preventing replication initiation. Indeed, in vivo experiments demonstrated that B. subtilis, C. crescentus, and S. coelicolor with oriC regions lacking the Spo0A-, CtrA-, and AdpA-binding sequences, respectively, exhibited chromosome overreplication (15, 76, 85). The master regulators can probably displace DnaA from oriC (as shown for CtrA [77]) or prevent DnaA from oligomerizing at oriC and thus block the formation of a functional orisome by limiting DnaA access to the replication origin. Thus, the master regulators and initiator proteins presumably compete for binding to a particular part(s) of the oriC region to inhibit and promote, respectively, the initiation of replication. The balance of this “battle” depends on the cell cycle stage, since both elements are temporally and spatially regulated.

FIG 2
  • Open in new tab
  • Download powerpoint
FIG 2

Organization of the origin regions (oriC) from C. crescentus, B. subtilis, and S. coelicolor. Positions of the binding sites of master regulators CtrA, Spo0A, AdpA (red), and DnaA (black) are shown. Filled, stripped, empty, and dotted boxes (in that order) represent increasing deviations from the consensus sequence. Gray rectangles indicate AT-rich sequences; the oval DUE represents the DNA unwinding element; Ps represents the transcription start site from the strong hemE promoter. The DUE for C. crescentus and S. coelicolor origins has not been defined.

In C. crescentus, the levels of CtrA and DnaA oscillate during the cell cycle, peaking in swarmer and stalked cells, respectively (18). Replication initiation occurs in stalked cells or in the stalked compartment of late predivisional cells, whereas it is inhibited by the activated master regulator, CtrA∼P, in swarmer cells (84; for a review, see also reference 22). Interestingly, besides being involved in DnaA displacement from the origin of replication region (77), CtrA also negatively regulates the strong hemE promoter (located at the 5′ end of the origin; Fig. 2), the activity of which is essential for the initiation of DNA replication (86). It is assumed that transcription from this promoter allows formation of a RNA-DNA hybrid inside the origin of replication and thus promotes the melting of DNA strands. CtrA is spatiotemporally regulated by phosphorylation (by the CckA kinase [69]—where ChpT phosphotransferase is a direct donor of a phosphate group for CtrA [87]) and by proteolysis (by the ClpXP protease [88]—where the RcdA protein assists ClpXP-dependent CtrA degradation at the cell pole while another PopA recruits both RcdA and CtrA to the cell pole [89, 90]). The other protein, CpdR, in its unphosphorylated form binds to ClpXP and recruits this proteolytic complex to the cell pole, leading to CtrA degradation in stalked cells. CpdR is subject to phosphorylation by the CckA/ChpT proteins (91).

Moreover, the ctrA gene expression level is also spatiotemporally regulated, with maximum and minimum transcriptional activity seen in predivisional and swarmer cells, respectively (92). The transcription of ctrA starts from two promoters, P1 and P2, one of which (P1) is regulated by the orchestrated actions of three master proteins, CcrM, GcrA, and its own product, CtrA (Fig. 3). Interestingly, both promoter P1 and promoter P2 are subject, respectively, to negative and positive feedback control by CtrA∼P (92). CcrM inhibits transcription from P1, whereas GcrA activates transcription from P1 (72, 93). Recent studies showed that P1 activity could also be modulated (negatively) by another transcription factor, SciP, which is a CtrA antagonist responsible for repression of genes controlled by CtrA in the swarmer cell (94, 95). Thus, the presence of two promoters, whose activities are regulated in a sophisticated manner, allows C. crescentus to regulate precisely in time and space the level of CtrA during the cell cycle. CcrM and GcrA also temporally regulate the expression of dnaA during the cell cycle but with effects that are opposite their effects on the ctrA P1 promoter (72, 96). The DnaA protein of C. crescentus is subject to degradation in a cell cycle-dependent manner (first reported by Gorbatyuk and Marczynski [18]). Interestingly, Laub's group recently showed that the stability of DnaA under certain stress conditions is mainly controlled by the Lon protease, although they did not exclude a minor role (or a role under alternative conditions) for the ClpP protease (17). Additionally, DnaA activity in C. crescentus is negatively controlled by HdaA (Hda homologue from E. coli), as cells depleted of this protein often overinitiate DNA replication (21). The HdaA protein, in complex with the β-clamp, probably contributes to the RIDA (regulatory inactivation of DnaA) mechanism that stimulates the ATPase activity of DnaA protein and leads to initiator inactivation (97). Interestingly, DnaA directly stimulates gene expression of its negative regulator, HdaA (21). It is worth mentioning that, during the swarmer-cell-to-stalked-cell transition, DnaA accumulation (accompanied by CtrA degradation) leads to activation of gcrA transcription and subsequent CtrA expression induced by the GcrA cell cycle regulator (98). Interestingly, though there are also CcrM methylation sites within the C. crescentus origin, it seems that methylation of the origin does not play a role in regulating the initiation of chromosomal replication as it does with Dam methylase (99, 100).

FIG 3
  • Open in new tab
  • Download powerpoint
FIG 3

Master regulators coordinate the cell cycle with DNA replication. Examples of genes involved in cell cycle developmental processes and replication, which are regulated by Spo0A, CtrA, and AdpA proteins, respectively, are listed in boxes (for full lists of genes regulated by these transcription factors, see references 49, 50, 63, 68, and 118). The dotted line indicates an indirect multilevel interaction.

During sporulation of B. subtilis, binding of the activated master regulator, Spo0A∼P, to oriC prevents replication initiation, possibly by directly impeding the interaction of DnaA with oriC or by altering the ability of DnaA to form the orisome (76). In vitro experiments demonstrated that Spo0A prevents DnaA-dependent unwinding within the oriC region (74), while an in vivo analysis showed that growth and chromosomal replication were inhibited in a Spo0A-dependent manner in mother cells (101). Spo0A is regulated by multiple kinases via the multicomponent phosphorelay (48) where the Spo0B transferase is a direct donor of phosphate group for Spo0A (Fig. 3). The Spo0A activity is also temporally controlled on the transcriptional level by two promoters: a vegetative-state-related σA-recognized promoter (Pv) and a sporulation-related σH-recognized promoter (Ps) (102). The σA housekeeping sigma factor controls a weak Pv promoter, which provides a basal level of Spo0A that is required for efficient firing of a strong Ps promoter (Spo0A∼P and σH activated) during the transition to the stationary phase (103–105). spo0A transcription is autoregulated by Spo0A itself in a manner similar to (but more complex than) that seen with ctrA in C. crescentus. The spo0A regulatory region contains multiple binding sites for Spo0A∼P; one is responsible for repressing Pv during the transition to the stationary phase, while the others are responsible for repressing Ps during growth or activating Ps upon entry into sporulation. Moreover, the translation of Pv-originating mRNA is impeded by the presence of a secondary RNA structure, thereby decreasing the synthesis of Spo0A (103). This intricate mechanism for regulating spo0A ensures that high levels of Spo0A are appropriately available for the activation of key sporulation genes (50, 106). In contrast to the case in C. crescentus, the transcription of spo0A and dnaA in B. subtilis does not depend on methylation, as there are no dam, ccrM, or seqA homologues. Transcription of dnaA is also autoregulated, as binding of DnaA to the DnaA boxes within the promoter region represses the transcription of dnaA (107). The activity of B. subtilis DnaA is negatively regulated by SirA, YabA, DnaD, and monomeric Soj, which directly interact with DnaA to prevent its assembly on the oriC region (19, 20, 108–110). Additionally, DNA-bound Soj promotes replication initiation, presumably by stimulating DnaA protein helix assembly. As a ParA ortholog involved in chromosomal segregation, Soj enables the coordination of chromosomal replication and segregation in B. subtilis (109). Two other proteins, YabA and DnaD, have been also shown recently to inhibit DnaA helix formation during the initiation of replication, suggesting that oligomerization of the initiator protein is a strictly regulated step in B. subtilis (19). Additionally, the SirA sporulation protein negatively influences the activity of the DnaA protein by inhibiting the initiator binding to (or the removal of the initiator from) oriC (20). Expression of the sirA gene is positively regulated by the Spo0A regulator (49, 50). Conversely, the sporulation is blocked by DnaA-induced Sda protein when the replication is impaired. Sda acts by blocking one of the histidine kinases involved in activation of Spo0A (35, 111).

In contrast to the results from B. subtilis and C. crescentus, phosphorylation of the S. coelicolor master regulator, AdpA, has not been observed to date. Interestingly, AdpA competes with DnaA for binding of the oriC region, with ATP acting as a key regulator of the DNA-binding activities of both proteins (15). ATP is well known to strengthen the binding of DnaA proteins to DnaA boxes (particularly medium- and low-affinity boxes) and is also required for DNA unwinding. In contrast, the interaction between AdpA and oriC is profoundly weakened by ATP (15). The mechanism responsible for this phenomenon has not yet been elucidated. When AdpA reaches its highest level (which presages the emergence of aerial branches) and the ATP level is low, DnaA is not able to efficiently bind the oriC region and initiate replication (15, 112). Similarly to the cases of spo0A and ctrA, the expression of adpA is subject to regulation at different levels (Fig. 3). The abundance of the adpA transcript is modulated by AbsB/RNase III cleavage (113), and AdpA itself positively stimulates the transcription of adpA (63). Additionally, another transcriptional regulator, the BldD protein, encoded by one of the “bald” genes is involved in negative regulation of adpA transcription (114). Moreover, translation of adpA mRNA depends on the presence of a leucyl-tRNA (encoded by bldA) for a rarely used TTA codon (115, 116). Interestingly, the accumulation of this tRNA species coincides with aerial mycelium development (117). In a mutual feed-forward mechanism, AdpA directly activates bldA transcription (118). Thus, these mechanisms collectively ensure that AdpA protein levels peak at the proper time during colony development (Fig. 1 and 3). As in B. subtilis, the expression of S. coelicolor dnaA is negatively autoregulated, with two DnaA-binding sites located within the dnaA promoter region (119). Despite extensive studies, we have not yet identified any protein responsible for modulating S. coelicolor DnaA activity. Thus, DnaA activity is thought to be strictly dependent on its nucleotide-bound state, as the ATP-bound form of DnaA is required for DNA unwinding (our unpublished results) and the binding of low- and moderate-affinity DnaA boxes (15, 120).

The protein levels and activities of DnaA and the master regulators are subject to stringent and complex regulation during the cell cycle to ensure their effective and coordinated functioning (Fig. 3). Although the mechanistic principles of CtrA, Spo0A, and AdpA action may differ, since they originate from very diverse organisms, these proteins similarly regulate replication by binding oriC and negatively regulating initiation (Fig. 3). CtrA, Spo0A, and AdpA regulators are conserved in the alphaproteobacteria, endospore-forming bacilli, and Streptomyces, respectively, justifying adoption of C. crescentus, B. subtilis, and S. coelicolor as model organisms to study these regulators. In addition, although replication initiation has been extensively studied, we do not yet fully understand its regulation in microorganisms that undergo complex life cycles, and the participation of as-yet-unknown factors in this process cannot be excluded.

SUMMARY AND PERSPECTIVES

In all three domains of life, the synthesis of genetic material must be tightly regulated because under- or overreplication frequently leads to serious aberrations and/or genomic instability. In organisms that undergo complex life cycles, diverse checkpoint mechanisms have evolved to coordinate DNA replication with their sophisticated differentiation programs. Recent advances in cell biology have increased our understanding of how replication is regulated at the different steps of the cell cycle. Initiation of chromosomal replication is an essential checkpoint that seems to be common to all domains of life. In bacteria undergoing the transition to a dormant state, master transcription factors (e.g., Spo0A, CtrA, and AdpA) regulate the expression levels of dozens of genes involved in morphological differentiation and inhibit replication initiation by binding to the origin of replication. Analyses of oriC regions and their affinity toward the master regulators, DnaA, and other regulatory proteins suggest that the origin regions have evolved to coordinate chromosomal replication with the complex developmental cell cycles of certain bacteria. In the future, an improved understanding of replication regulation could facilitate the experimental control of bacterial replication, potentially allowing us to inhibit DNA replication in pathogens, optimize the production of valuable secondary metabolites (e.g., antibiotics), and/or generate synchronized cultures for various physiological and genetic studies.

ACKNOWLEDGMENTS

We are grateful to Keith Chater and Patrick Viollier for providing valuable comments on the manuscript.

This work was supported by the National Science Centre, Poland (Maestro, grant no. 2012/04/A/NZ1/00057).

FOOTNOTES

    • Accepted manuscript posted online 9 June 2014.
  • Address correspondence to Jolanta Zakrzewska-Czerwińska, jolanta.zakrzewska{at}uni.wroc.pl.
  • This article is dedicated to the memory of Walter Messer.

REFERENCES

  1. 1.↵
    1. Jacob F,
    2. Brenner S,
    3. Cuzin F
    . 1963. On the regulation of DNA replication in bacteria. Cold Spring Harbor Symp. Quant. Biol. 28:329–348. doi:10.1101/SQB.1963.028.01.048.
    OpenUrlAbstract/FREE Full Text
  2. 2.↵
    1. Kuzminov A
    . 2014. The precarious prokaryotic chromosome. J. Bacteriol. 196:1793–1806. doi:10.1128/JB.00022-14.
    OpenUrlAbstract/FREE Full Text
  3. 3.↵
    1. Leonard AC,
    2. Mechali M
    . 2013. DNA replication origins. Cold Spring Harb. Perspect. Biol. 5:a010116. doi:10.1101/cshperspect.a010116.
    OpenUrlAbstract/FREE Full Text
  4. 4.↵
    1. Fuller RS,
    2. Funnell BE,
    3. Kornberg A
    . 1984. The dnaA protein complex with the E. coli chromosomal replication origin (oriC) and other DNA sites. Cell 38:889–900. doi:10.1016/0092-8674(84)90284-8.
    OpenUrlCrossRefPubMedWeb of Science
  5. 5.↵
    1. Hwang DS,
    2. Kornberg A
    . 1992. Opening of the replication origin of Escherichia coli by DnaA protein with protein HU or IHF. J. Biol. Chem. 267:23083–23086.
    OpenUrlAbstract/FREE Full Text
  6. 6.↵
    1. Kaguni JM
    . 2006. DnaA: controlling the initiation of bacterial DNA replication and more. Annu. Rev. Microbiol. 60:351–375. doi:10.1146/annurev.micro.60.080805.142111.
    OpenUrlCrossRefPubMedWeb of Science
  7. 7.↵
    1. Katayama T,
    2. Ozaki S,
    3. Keyamura K,
    4. Fujimitsu K
    . 2010. Regulation of the replication cycle: conserved and diverse regulatory systems for DnaA and oriC. Nat. Rev. Microbiol. 8:163–170. doi:10.1038/nrmicro2314.
    OpenUrlCrossRefPubMedWeb of Science
  8. 8.↵
    1. Leonard AC,
    2. Grimwade JE
    . 2010. Regulating DnaA complex assembly: it is time to fill the gaps. Curr. Opin. Microbiol. 13:766–772. doi:10.1016/j.mib.2010.10.001.
    OpenUrlCrossRefPubMed
  9. 9.↵
    1. Messer W
    . 2002. The bacterial replication initiator DnaA. DnaA and oriC, the bacterial mode to initiate DNA replication. FEMS Microbiol. Rev. 26:355–374. doi:10.1111/j.1574-6976.2002.tb00620.x.
    OpenUrlCrossRefPubMedWeb of Science
  10. 10.↵
    1. Zakrzewska-Czerwińska J,
    2. Jakimowicz D,
    3. Zawilak-Pawlik A,
    4. Messer W
    . 2007. Regulation of the initiation of chromosomal replication in bacteria. FEMS Microbiol. Rev. 31:378–387. doi:10.1111/j.1574-6976.2007.00070.x.
    OpenUrlCrossRefPubMedWeb of Science
  11. 11.↵
    1. Messer W,
    2. Blaesing F,
    3. Majka J,
    4. Nardmann J,
    5. Schaper S,
    6. Schmidt A,
    7. Seitz H,
    8. Speck C,
    9. Tungler D,
    10. Wegrzyn G,
    11. Weigel C,
    12. Welzeck M,
    13. Zakrzewska-Czerwinska J
    . 1999. Functional domains of DnaA proteins. Biochimie 81:819–825. doi:10.1016/S0300-9084(99)00215-1.
    OpenUrlCrossRefPubMedWeb of Science
  12. 12.↵
    1. McGarry KC,
    2. Ryan VT,
    3. Grimwade JE,
    4. Leonard AC
    . 2004. Two discriminatory binding sites in the Escherichia coli replication origin are required for DNA strand opening by initiator DnaA-ATP. Proc. Natl. Acad. Sci. U. S. A. 101:2811–2816. doi:10.1073/pnas.0400340101.
    OpenUrlAbstract/FREE Full Text
  13. 13.↵
    1. Ozaki S,
    2. Noguchi Y,
    3. Hayashi Y,
    4. Miyazaki E,
    5. Katayama T
    . 2012. Differentiation of the DnaA-oriC subcomplex for DNA unwinding in a replication initiation complex. J. Biol. Chem. 287:37458–37471. doi:10.1074/jbc.M112.372052.
    OpenUrlAbstract/FREE Full Text
  14. 14.↵
    1. Rozgaja TA,
    2. Grimwade JE,
    3. Iqbal M,
    4. Czerwonka C,
    5. Vora M,
    6. Leonard AC
    . 2011. Two oppositely oriented arrays of low-affinity recognition sites in oriC guide progressive binding of DnaA during Escherichia coli pre-RC assembly. Mol. Microbiol. 82:475–488. doi:10.1111/j.1365-2958.2011.07827.x.
    OpenUrlCrossRefPubMed
  15. 15.↵
    1. Wolański M,
    2. Jakimowicz D,
    3. Zakrzewska-Czerwińska J
    . 2012. AdpA, key regulator for morphological differentiation regulates bacterial chromosome replication. Open Biol. 2:120097. doi:10.1098/rsob.120097.
    OpenUrlAbstract/FREE Full Text
  16. 16.↵
    1. Kaguni JM
    . 2011. Replication initiation at the Escherichia coli chromosomal origin. Curr. Opin. Chem. Biol. 15:606–613. doi:10.1016/j.cbpa.2011.07.016.
    OpenUrlCrossRefPubMed
  17. 17.↵
    1. Jonas K,
    2. Liu J,
    3. Chien P,
    4. Laub MT
    . 2013. Proteotoxic stress induces a cell-cycle arrest by stimulating Lon to degrade the replication initiator DnaA. Cell 154:623–636. doi:10.1016/j.cell.2013.06.034.
    OpenUrlCrossRefPubMedWeb of Science
  18. 18.↵
    1. Gorbatyuk B,
    2. Marczynski GT
    . 2005. Regulated degradation of chromosome replication proteins DnaA and CtrA in Caulobacter crescentus. Mol. Microbiol. 55:1233–1245. doi:10.1111/j.1365-2958.2004.04459.x.
    OpenUrlCrossRefPubMedWeb of Science
  19. 19.↵
    1. Scholefield G,
    2. Murray H
    . 2013. YabA and DnaD inhibit helix assembly of the DNA replication initiation protein DnaA. Mol. Microbiol. 90:147–159. doi:10.1111/mmi.12353.
    OpenUrlCrossRefPubMed
  20. 20.↵
    1. Rahn-Lee L,
    2. Merrikh H,
    3. Grossman AD,
    4. Losick R
    . 2011. The sporulation protein SirA inhibits the binding of DnaA to the origin of replication by contacting a patch of clustered amino acids. J. Bacteriol. 193:1302–1307. doi:10.1128/JB.01390-10.
    OpenUrlAbstract/FREE Full Text
  21. 21.↵
    1. Collier J,
    2. Shapiro L
    . 2009. Feedback control of DnaA-mediated replication initiation by replisome-associated HdaA protein in Caulobacter. J. Bacteriol. 191:5706–5716. doi:10.1128/JB.00525-09.
    OpenUrlAbstract/FREE Full Text
  22. 22.↵
    1. Collier J
    . 2012. Regulation of chromosomal replication in Caulobacter crescentus. Plasmid 67:76–87. doi:10.1016/j.plasmid.2011.12.007.
    OpenUrlCrossRefPubMed
  23. 23.↵
    1. Smulczyk-Krawczyszyn A,
    2. Jakimowicz D,
    3. Ruban-Osmialowska B,
    4. Zawilak-Pawlik A,
    5. Majka J,
    6. Chater K,
    7. Zakrzewska-Czerwinska J
    . 2006. Cluster of DnaA boxes involved in regulation of Streptomyces chromosome replication: from in silico to in vivo studies. J. Bacteriol. 188:6184–6194. doi:10.1128/JB.00528-06.
    OpenUrlAbstract/FREE Full Text
  24. 24.↵
    1. Grossman AD,
    2. Losick R
    . 1988. Extracellular control of spore formation in Bacillus subtilis. Proc. Natl. Acad. Sci. U. S. A. 85:4369–4373. doi:10.1073/pnas.85.12.4369.
    OpenUrlAbstract/FREE Full Text
  25. 25.↵
    1. Solomon JM,
    2. Lazazzera BA,
    3. Grossman AD
    . 1996. Purification and characterization of an extracellular peptide factor that affects two different developmental pathways in Bacillus subtilis. Genes Dev. 10:2014–2024. doi:10.1101/gad.10.16.2014.
    OpenUrlAbstract/FREE Full Text
  26. 26.↵
    1. Zusman DR,
    2. Scott AE,
    3. Yang Z,
    4. Kirby JR
    . 2007. Chemosensory pathways, motility and development in Myxococcus xanthus. Nat. Rev. Microbiol. 5:862–872. doi:10.1038/nrmicro1770.
    OpenUrlCrossRefPubMedWeb of Science
  27. 27.↵
    1. Chater KF
    . 2000. Developmental decisions during sporulation in the aerial mycelium in Streptomyces, p 33–48. In Brun YV, Shimkets LJ (ed), Prokaryotic development. American Society for Microbiology, Washington, DC.
  28. 28.↵
    1. Durre P,
    2. Hollergschwandner C
    . 2004. Initiation of endospore formation in Clostridium acetobutylicum. Anaerobe 10:69–74. doi:10.1016/j.anaerobe.2003.11.001.
    OpenUrlCrossRefPubMedWeb of Science
  29. 29.↵
    1. Errington J
    . 2003. Regulation of endospore formation in Bacillus subtilis. Nat. Rev. Microbiol. 1:117–126. doi:10.1038/nrmicro750.
    OpenUrlCrossRefPubMedWeb of Science
  30. 30.↵
    1. Piggot PJ,
    2. Hilbert DW
    . 2004. Sporulation of Bacillus subtilis. Curr. Opin. Microbiol. 7:579–586. doi:10.1016/j.mib.2004.10.001.
    OpenUrlCrossRefPubMedWeb of Science
  31. 31.↵
    1. Stragier P,
    2. Losick R
    . 1996. Molecular genetics of sporulation in Bacillus subtilis. Annu. Rev. Genet. 30:297–241. doi:10.1146/annurev.genet.30.1.297.
    OpenUrlCrossRefPubMedWeb of Science
  32. 32.↵
    1. Chater KF
    . 1998. Taking a genetic scalpel to the Streptomyces colony. Microbiology (Reading, England) 144:1465–1478. doi:10.1099/00221287-144-6-1465.
    OpenUrlCrossRefWeb of Science
  33. 33.↵
    1. Chater KF
    . 2011. Differentiation in Streptomyces: the properties and programming of diverse cell-types, 43–86. In Dyson P (ed), Streptomyces: molecular biology and biotechnology. Caister Academic Press, Norfolk, England.
  34. 34.↵
    1. Brun YV,
    2. Janakiraman R
    . 2000. The dimorphic life cycle of Caulobacter and stalked bacteria, p 297–317. In Brun YV, Shimkets LJ (ed), Prokaryotic development. American Society for Microbiology, Washington, DC.
  35. 35.↵
    1. Veening JW,
    2. Murray H,
    3. Errington J
    . 2009. A mechanism for cell cycle regulation of sporulation initiation in Bacillus subtilis. Genes Dev. 23:1959–1970. doi:10.1101/gad.528209.
    OpenUrlAbstract/FREE Full Text
  36. 36.↵
    1. Ben-Yehuda S,
    2. Rudner DZ,
    3. Losick R
    . 2003. RacA, a bacterial protein that anchors chromosomes to the cell poles. Science 299:532–536. doi:10.1126/science.1079914.
    OpenUrlAbstract/FREE Full Text
  37. 37.↵
    1. Ryter A,
    2. Schaeffer P,
    3. Ionesco H
    . 1966. Cytologic classification, by their blockage stage, of sporulation mutants of Bacillus subtilis Marburg. Ann. de l'Institut Pasteur (Paris) 110:305–315. (In French.)
    OpenUrl
  38. 38.↵
    1. Bath J,
    2. Wu LJ,
    3. Errington J,
    4. Wang JC
    . 2000. Role of Bacillus subtilis SpoIIIE in DNA transport across the mother cell-prespore division septum. Science 290:995–997. doi:10.1126/science.290.5493.995.
    OpenUrlAbstract/FREE Full Text
  39. 39.↵
    1. Grantcharova N,
    2. Lustig U,
    3. Flardh K
    . 2005. Dynamics of FtsZ assembly during sporulation in Streptomyces coelicolor A3(2). J. Bacteriol. 187:3227–3237. doi:10.1128/JB.187.9.3227-3237.2005.
    OpenUrlAbstract/FREE Full Text
  40. 40.↵
    1. Schwedock J,
    2. McCormick JR,
    3. Angert JR,
    4. Nodwell J,
    5. Losick R
    . 1997. Assembly of the cell division protein FtsZ into ladder-like structures in the aerial hyphae of Streptomyces coelicolor. Mol. Microbiol. 25:847–858. doi:10.1111/j.1365-2958.1997.mmi507.x.
    OpenUrlCrossRefPubMedWeb of Science
  41. 41.↵
    1. Jakimowicz D,
    2. Zydek P,
    3. Kois A,
    4. Zakrzewska-Czerwinska J,
    5. Chater KF
    . 2007. Alignment of multiple chromosomes along helical ParA scaffolding in sporulating Streptomyces hyphae. Mol. Microbiol. 65:625–641. doi:10.1111/j.1365-2958.2007.05815.x.
    OpenUrlCrossRefPubMedWeb of Science
  42. 42.↵
    1. Ruban-Ośmiałowska B,
    2. Jakimowicz D,
    3. Smulczyk-Krawczyszyn A,
    4. Chater KF,
    5. Zakrzewska-Czerwińska J
    . 2006. Replisome localization in vegetative and aerial hyphae of Streptomyces coelicolor. J. Bacteriol. 188:7311–7316. doi:10.1128/JB.00940-06.
    OpenUrlAbstract/FREE Full Text
  43. 43.↵
    1. Curtis PD,
    2. Brun YV
    . 2010. Getting in the loop: regulation of development in Caulobacter crescentus. Microbiol. Mol. Biol. Rev. 74:13–41. doi:10.1128/MMBR.00040-09.
    OpenUrlAbstract/FREE Full Text
  44. 44.↵
    1. Viollier PH,
    2. Thanbichler M,
    3. McGrath PT,
    4. West L,
    5. Meewan M,
    6. McAdams HH,
    7. Shapiro L
    . 2004. Rapid and sequential movement of individual chromosomal loci to specific subcellular locations during bacterial DNA replication. Proc. Natl. Acad. Sci. U. S. A. 101:9257–9262. doi:10.1073/pnas.0402606101.
    OpenUrlAbstract/FREE Full Text
  45. 45.↵
    1. Bowman GR,
    2. Comolli LR,
    3. Zhu J,
    4. Eckart M,
    5. Koenig M,
    6. Downing KH,
    7. Moerner WE,
    8. Earnest T,
    9. Shapiro L
    . 2008. A polymeric protein anchors the chromosomal origin/ParB complex at a bacterial cell pole. Cell 134:945–955. doi:10.1016/j.cell.2008.07.015.
    OpenUrlCrossRefPubMedWeb of Science
  46. 46.↵
    1. Ebersbach G,
    2. Briegel A,
    3. Jensen GJ,
    4. Jacobs-Wagner C
    . 2008. A self-associating protein critical for chromosome attachment, division, and polar organization in caulobacter. Cell 134:956–968. doi:10.1016/j.cell.2008.07.016.
    OpenUrlCrossRefPubMedWeb of Science
  47. 47.↵
    1. Thanbichler M,
    2. Shapiro L
    . 2006. Mipz, a spatial regulator coordinating chromosome segregation with cell division in Caulobacter. Cell 126:147–162. doi:10.1016/j.cell.2006.05.038.
    OpenUrlCrossRefPubMedWeb of Science
  48. 48.↵
    1. Burbulys D,
    2. Trach KA,
    3. Hoch JA
    . 1991. Initiation of sporulation in B. subtilis is controlled by a multicomponent phosphorelay. Cell 64:545–552. doi:10.1016/0092-8674(91)90238-T.
    OpenUrlCrossRefPubMedWeb of Science
  49. 49.↵
    1. Molle V,
    2. Fujita M,
    3. Jensen ST,
    4. Eichenberger P,
    5. González-Pastor JE,
    6. Liu JS,
    7. Losick R
    . 2003. The Spo0A regulon of Bacillus subtilis. Mol. Microbiol. 50:1683–1701. doi:10.1046/j.1365-2958.2003.03818.x.
    OpenUrlCrossRefPubMedWeb of Science
  50. 50.↵
    1. Fujita M,
    2. Gonzalez-Pastor JE,
    3. Losick R
    . 2005. High- and low-threshold genes in the Spo0A regulon of Bacillus subtilis. J. Bacteriol. 187:1357–1368. doi:10.1128/JB.187.4.1357-1368.2005.
    OpenUrlAbstract/FREE Full Text
  51. 51.↵
    1. Ben-Yehuda S,
    2. Losick R
    . 2002. Asymmetric cell division in B. subtilis involves a spiral-like intermediate of the cytokinetic protein FtsZ. Cell 109:257–266. doi:10.1016/S0092-8674(02)00698-0.
    OpenUrlCrossRefPubMedWeb of Science
  52. 52.↵
    1. Khvorova A,
    2. Zhang L,
    3. Higgins ML,
    4. Piggot PJ
    . 1998. The spoIIE locus is involved in the Spo0A-dependent switch in the location of FtsZ rings in Bacillus subtilis. J. Bacteriol. 180:1256–1260.
    OpenUrlAbstract/FREE Full Text
  53. 53.↵
    1. Levin PA,
    2. Losick R
    . 1996. Transcription factor Spo0A switches the localization of the cell division protein FtsZ from a medial to a bipolar pattern in Bacillus subtilis. Genes Dev. 10:478–488. doi:10.1101/gad.10.4.478.
    OpenUrlAbstract/FREE Full Text
  54. 54.↵
    1. Lopez D,
    2. Vlamakis H,
    3. Kolter R
    . 2009. Generation of multiple cell types in Bacillus subtilis. FEMS Microbiol. Rev. 33:152–163. doi:10.1111/j.1574-6976.2008.00148.x.
    OpenUrlCrossRefPubMedWeb of Science
  55. 55.↵
    1. Flärdh K,
    2. Buttner MJ
    . 2009. Streptomyces morphogenetics: dissecting differentiation in a filamentous bacterium. Nat. Rev. Microbiol. 7:36–49. doi:10.1038/nrmicro1968.
    OpenUrlCrossRefPubMedWeb of Science
  56. 56.↵
    1. Hopwood DA
    . 1967. Genetic analysis and genome structure in Streptomyces coelicolor. Bacteriol. Rev. 31:373–403.
    OpenUrlFREE Full Text
  57. 57.↵
    1. Merrick MJ
    . 1976. A morphological and genetic mapping study of bald colony mutants of Streptomyces coelicolor. J. Gen. Microbiol. 96:299–315. doi:10.1099/00221287-96-2-299.
    OpenUrlCrossRefPubMedWeb of Science
  58. 58.↵
    1. Chater KF
    . 1972. A morphological and genetic mapping study of white colony mutants of Streptomyces coelicolor. J. Gen. Microbiol. 72:9–28. doi:10.1099/00221287-72-1-9.
    OpenUrlCrossRefPubMedWeb of Science
  59. 59.↵
    1. Hopwood DA,
    2. Wildermuth H,
    3. Palmer HM
    . 1970. Mutants of Streptomyces coelicolor defective in sporulation. J. Gen. Microbiol. 61:397–408. doi:10.1099/00221287-61-3-397.
    OpenUrlCrossRefPubMedWeb of Science
  60. 60.↵
    1. Liu G,
    2. Chater KF,
    3. Chandra G,
    4. Niu G,
    5. Tan H
    . 2013. Molecular regulation of antibiotic biosynthesis in streptomyces. Microbiol. Mol. Biol. Rev. 77:112–143. doi:10.1128/MMBR.00054-12.
    OpenUrlAbstract/FREE Full Text
  61. 61.↵
    1. Horinouchi S
    . 2007. Mining and polishing of the treasure trove in the bacterial genus Streptomyces. Biosci. Biotechnol. Biochem. 71:283–299. doi:10.1271/bbb.60627.
    OpenUrlCrossRefPubMedWeb of Science
  62. 62.↵
    1. Ohnishi Y,
    2. Yamazaki H,
    3. Kato JY,
    4. Tomono A,
    5. Horinouchi S
    . 2005. AdpA, a central transcriptional regulator in the A-factor regulatory cascade that leads to morphological development and secondary metabolism in Streptomyces griseus. Biosci. Biotechnol. Biochem. 69:431–439. doi:10.1271/bbb.69.431.
    OpenUrlCrossRefPubMedWeb of Science
  63. 63.↵
    1. Wolanski M,
    2. Donczew R,
    3. Kois-Ostrowska A,
    4. Masiewicz P,
    5. Jakimowicz D,
    6. Zakrzewska-Czerwinska J
    . 2011. The level of AdpA directly affects expression of developmental genes in Streptomyces coelicolor. J. Bacteriol. 193:6358–6365. doi:10.1128/JB.05734-11.
    OpenUrlAbstract/FREE Full Text
  64. 64.↵
    1. Higo A,
    2. Hara H,
    3. Horinouchi S,
    4. Ohnishi Y
    . 2012. Genome-wide distribution of AdpA, a global regulator for secondary metabolism and morphological differentiation in Streptomyces, revealed the extent and complexity of the AdpA regulatory network. DNA Res. 19:259–274. doi:10.1093/dnares/dss010.
    OpenUrlCrossRefPubMedWeb of Science
  65. 65.↵
    1. Laub MT
    . 2000. Global analysis of the genetic network controlling a bacterial cell cycle. Science 290:2144–2148. doi:10.1126/science.290.5499.2144.
    OpenUrlAbstract/FREE Full Text
  66. 66.↵
    1. Jenal U
    . 2009. The role of proteolysis in the Caulobacter crescentus cell cycle and development. Res. Microbiol. 160:687–695. doi:10.1016/j.resmic.2009.09.006.
    OpenUrlCrossRefPubMedWeb of Science
  67. 67.↵
    1. McAdams HH,
    2. Shapiro L
    . 2011. The architecture and conservation pattern of whole-cell control circuitry. J. Mol. Biol. 409:28–35. doi:10.1016/j.jmb.2011.02.041.
    OpenUrlCrossRefPubMed
  68. 68.↵
    1. Laub MT,
    2. Chen SL,
    3. Shapiro L,
    4. McAdams HH
    . 2002. Genes directly controlled by CtrA, a master regulator of the Caulobacter cell cycle. Proc. Natl. Acad. Sci. U. S. A. 99:4632–4637. doi:10.1073/pnas.062065699.
    OpenUrlAbstract/FREE Full Text
  69. 69.↵
    1. Jacobs C,
    2. Domian IJ,
    3. Maddock JR,
    4. Shapiro L
    . 1999. Cell cycle-dependent polar localization of an essential bacterial histidine kinase that controls DNA replication and cell division. Cell 97:111–120. doi:10.1016/S0092-8674(00)80719-9.
    OpenUrlCrossRefPubMedWeb of Science
  70. 70.↵
    1. Tsokos CG,
    2. Laub MT
    . 2012. Polarity and cell fate asymmetry in Caulobacter crescentus. Curr. Opin. Microbiol. 15:744–750. doi:10.1016/j.mib.2012.10.011.
    OpenUrlCrossRefPubMed
  71. 71.↵
    1. Domian IJ,
    2. Quon KC,
    3. Shapiro L
    . 1997. Cell type-specific phosphorylation and proteolysis of a transcriptional regulator controls the G1-to-S transition in a bacterial cell cycle. Cell 90:415–424. doi:10.1016/S0092-8674(00)80502-4.
    OpenUrlCrossRefPubMedWeb of Science
  72. 72.↵
    1. Holtzendorff J,
    2. Hung D,
    3. Brende P,
    4. Reisenauer A,
    5. Viollier PH,
    6. McAdams HH,
    7. Shapiro L
    . 2004. Oscillating global regulators control the genetic circuit driving a bacterial cell cycle. Science 304:983–987. doi:10.1126/science.1095191.
    OpenUrlAbstract/FREE Full Text
  73. 73.↵
    1. Kirkpatrick CL,
    2. Viollier PH
    . 2012. Decoding Caulobacter development. FEMS Microbiol. Rev. 36:193–205. doi:10.1111/j.1574-6976.2011.00309.x.
    OpenUrlCrossRefPubMedWeb of Science
  74. 74.↵
    1. Castilla-Llorente V,
    2. Munoz-Espin D,
    3. Villar L,
    4. Salas M,
    5. Meijer WJ
    . 2006. Spo0A, the key transcriptional regulator for entrance into sporulation, is an inhibitor of DNA replication. EMBO J. 25:3890–3899. doi:10.1038/sj.emboj.7601266.
    OpenUrlAbstract/FREE Full Text
  75. 75.↵
    1. Siam R,
    2. Marczynski GT
    . 2000. Cell cycle regulator phosphorylation stimulates two distinct modes of binding at a chromosome replication origin. EMBO J. 19:1138–1147. doi:10.1093/emboj/19.5.1138.
    OpenUrlAbstract/FREE Full Text
  76. 76.↵
    1. Boonstra M,
    2. de Jong IG,
    3. Scholefield G,
    4. Murray H,
    5. Kuipers OP,
    6. Veening JW
    . 2013. Spo0A regulates chromosome copy number during sporulation by directly binding to the origin of replication in Bacillus subtilis. Mol. Microbiol. 87:925–938. doi:10.1111/mmi.12141.
    OpenUrlCrossRefPubMed
  77. 77.↵
    1. Taylor JA,
    2. Ouimet MC,
    3. Wargachuk R,
    4. Marczynski GT
    . 2011. The Caulobacter crescentus chromosome replication origin evolved two classes of weak DnaA binding sites. Mol. Microbiol. 82:312–326. doi:10.1111/j.1365-2958.2011.07785.x.
    OpenUrlCrossRefPubMed
  78. 78.↵
    1. Jakimowicz D,
    2. Majka J,
    3. Messer W,
    4. Speck C,
    5. Fernandez M,
    6. Martin MC,
    7. Sanchez J,
    8. Schauwecker F,
    9. Keller U,
    10. Schrempf H,
    11. Zakrzewska-Czerwinska J
    . 1998. Structural elements of the Streptomyces oriC region and their interactions with the DnaA protein. Microbiology 144(Pt 5):1281–1290. doi:10.1099/00221287-144-5-1281.
    OpenUrlCrossRefPubMedWeb of Science
  79. 79.↵
    1. Moriya S,
    2. Atlung T,
    3. Hansen FG,
    4. Yoshikawa H,
    5. Ogasawara N
    . 1992. Cloning of an autonomously replicating sequence (ars) from the Bacillus subtilis chromosome. Mol. Microbiol. 6:309–315. doi:10.1111/j.1365-2958.1992.tb01473.x.
    OpenUrlCrossRefPubMedWeb of Science
  80. 80.↵
    1. Zakrzewska-Czerwińska J,
    2. Majka J,
    3. Schrempf H
    . 1995. Minimal requirements of the Streptomyces lividans 66 oriC region and its transcriptional and translational activities. J. Bacteriol. 177:4765–4771.
    OpenUrlAbstract/FREE Full Text
  81. 81.↵
    1. Jakimowicz D,
    2. Majka J,
    3. Konopa G,
    4. Wegrzyn G,
    5. Messer W,
    6. Schrempf H,
    7. Zakrzewska-Czerwinska J
    . 2000. Architecture of the Streptomyces lividans DnaA protein-replication origin complexes. J. Mol. Biol. 298:351–364. doi:10.1006/jmbi.2000.3686.
    OpenUrlCrossRefPubMedWeb of Science
  82. 82.↵
    1. Krause M,
    2. Ruckert B,
    3. Lurz R,
    4. Messer W
    . 1997. Complexes at the replication origin of Bacillus subtilis with homologous and heterologous DnaA protein. J. Mol. Biol. 274:365–380. doi:10.1006/jmbi.1997.1404.
    OpenUrlCrossRefPubMedWeb of Science
  83. 83.↵
    1. Marczynski GT,
    2. Shapiro L
    . 1992. Cell-cycle control of a cloned chromosomal origin of replication from Caulobacter crescentus. J. Mol. Biol. 226:959–977. doi:10.1016/0022-2836(92)91045-Q.
    OpenUrlCrossRefPubMedWeb of Science
  84. 84.↵
    1. Quon KC,
    2. Yang B,
    3. Domian IJ,
    4. Shapiro L,
    5. Marczynski GT
    . 1998. Negative control of bacterial DNA replication by a cell cycle regulatory protein that binds at the chromosome origin. Proc. Natl. Acad. Sci. U. S. A. 95:120–125. doi:10.1073/pnas.95.1.120.
    OpenUrlAbstract/FREE Full Text
  85. 85.↵
    1. Bastedo DP,
    2. Marczynski GT
    . 2009. CtrA response regulator binding to the Caulobacter chromosome replication origin is required during nutrient and antibiotic stress as well as during cell cycle progression. Mol. Microbiol. 72:139–154. doi:10.1111/j.1365-2958.2009.06630.x.
    OpenUrlCrossRefPubMedWeb of Science
  86. 86.↵
    1. Marczynski GT,
    2. Lentine K,
    3. Shapiro L
    . 1995. A developmentally regulated chromosomal origin of replication uses essential transcription elements. Genes Dev. 9:1543–1557. doi:10.1101/gad.9.12.1543.
    OpenUrlAbstract/FREE Full Text
  87. 87.↵
    1. Biondi EG,
    2. Reisinger SJ,
    3. Skerker JM,
    4. Arif M,
    5. Perchuk BS,
    6. Ryan KR,
    7. Laub MT
    . 2006. Regulation of the bacterial cell cycle by an integrated genetic circuit. Nature 444:899–904. doi:10.1038/nature05321.
    OpenUrlCrossRefPubMedWeb of Science
  88. 88.↵
    1. Jenal U,
    2. Fuchs T
    . 1998. An essential protease involved in bacterial cell-cycle control. EMBO J. 17:5658–5669. doi:10.1093/emboj/17.19.5658.
    OpenUrlAbstract
  89. 89.↵
    1. McGrath PT,
    2. Iniesta AA,
    3. Ryan KR,
    4. Shapiro L,
    5. McAdams HH
    . 2006. A dynamically localized protease complex and a polar specificity factor control a cell cycle master regulator. Cell 124:535–547. doi:10.1016/j.cell.2005.12.033.
    OpenUrlCrossRefPubMedWeb of Science
  90. 90.↵
    1. Duerig A,
    2. Abel S,
    3. Folcher M,
    4. Nicollier M,
    5. Schwede T,
    6. Amiot N,
    7. Giese B,
    8. Jenal U
    . 2009. Second messenger-mediated spatiotemporal control of protein degradation regulates bacterial cell cycle progression. Genes Dev. 23:93–104. doi:10.1101/gad.502409.
    OpenUrlAbstract/FREE Full Text
  91. 91.↵
    1. Iniesta AA,
    2. McGrath PT,
    3. Reisenauer A,
    4. McAdams HH,
    5. Shapiro L
    . 2006. A phospho-signaling pathway controls the localization and activity of a protease complex critical for bacterial cell cycle progression. Proc. Natl. Acad. Sci. U. S. A. 103:10935–10940. doi:10.1073/pnas.0604554103.
    OpenUrlAbstract/FREE Full Text
  92. 92.↵
    1. Domian IJ,
    2. Reisenauer A,
    3. Shapiro L
    . 1999. Feedback control of a master bacterial cell-cycle regulator. Proc. Natl. Acad. Sci. U. S. A. 96:6648–6653. doi:10.1073/pnas.96.12.6648.
    OpenUrlAbstract/FREE Full Text
  93. 93.↵
    1. Reisenauer A,
    2. Shapiro L
    . 2002. DNA methylation affects the cell cycle transcription of the CtrA global regulator in Caulobacter. EMBO J. 21:4969–4977. doi:10.1093/emboj/cdf490.
    OpenUrlAbstract/FREE Full Text
  94. 94.↵
    1. Gora KG,
    2. Tsokos CG,
    3. Chen YE,
    4. Srinivasan BS,
    5. Perchuk BS,
    6. Laub MT
    . 2010. A cell-type-specific protein-protein interaction modulates transcriptional activity of a master regulator in Caulobacter crescentus. Mol. Cell 39:455–467. doi:10.1016/j.molcel.2010.06.024.
    OpenUrlCrossRefPubMedWeb of Science
  95. 95.↵
    1. Tan MH,
    2. Kozdon JB,
    3. Shen X,
    4. Shapiro L,
    5. McAdams HH
    . 2010. An essential transcription factor, SciP, enhances robustness of Caulobacter cell cycle regulation. Proc. Natl. Acad. Sci. U. S. A. 107:18985–18990. doi:10.1073/pnas.1014395107.
    OpenUrlAbstract/FREE Full Text
  96. 96.↵
    1. Collier J,
    2. McAdams HH,
    3. Shapiro L
    . 2007. A DNA methylation ratchet governs progression through a bacterial cell cycle. Proc. Natl. Acad. Sci. U. S. A. 104:17111–17116. doi:10.1073/pnas.0708112104.
    OpenUrlAbstract/FREE Full Text
  97. 97.↵
    1. Fernandez-Fernandez C,
    2. Grosse K,
    3. Sourjik V,
    4. Collier J
    . 2013. The beta-sliding clamp directs the localization of HdaA to the replisome in Caulobacter crescentus. Microbiology 159:2237–2248. doi:10.1099/mic.0.068577-0.
    OpenUrlCrossRefPubMed
  98. 98.↵
    1. Collier J,
    2. Murray SR,
    3. Shapiro L
    . 2006. DnaA couples DNA replication and the expression of two cell cycle master regulators. EMBO J. 25:346–356. doi:10.1038/sj.emboj.7600927.
    OpenUrlCrossRefPubMedWeb of Science
  99. 99.↵
    1. Shaheen SM,
    2. Ouimet MC,
    3. Marczynski GT
    . 2009. Comparative analysis of Caulobacter chromosome replication origins. Microbiology 155:1215–1225. doi:10.1099/mic.0.025528-0.
    OpenUrlCrossRefPubMedWeb of Science
  100. 100.↵
    1. Gonzalez D,
    2. Kozdon JB,
    3. McAdams HH,
    4. Shapiro L,
    5. Collier J
    . 2014. The functions of DNA methylation by CcrM in Caulobacter crescentus: a global approach. Nucleic Acids Res. 42:3720–3735. doi:10.1093/nar/gkt1352.
    OpenUrlCrossRefPubMedWeb of Science
  101. 101.↵
    1. Xenopoulos P,
    2. Piggot PJ
    . 2011. Regulation of growth of the mother cell and chromosome replication during sporulation of Bacillus subtilis. J. Bacteriol. 193:3117–3126. doi:10.1128/JB.00204-11.
    OpenUrlAbstract/FREE Full Text
  102. 102.↵
    1. Chibazakura T,
    2. Kawamura F,
    3. Takahashi H
    . 1991. Differential regulation of spo0A transcription in Bacillus subtilis: glucose represses promoter switching at the initiation of sporulation. J. Bacteriol. 173:2625–2632.
    OpenUrlAbstract/FREE Full Text
  103. 103.↵
    1. Chastanet A,
    2. Losick R
    . 2011. Just-in-time control of Spo0A synthesis in Bacillus subtilis by multiple regulatory mechanisms. J. Bacteriol. 193:6366–6374. doi:10.1128/JB.06057-11.
    OpenUrlAbstract/FREE Full Text
  104. 104.↵
    1. Chibazakura T,
    2. Kawamura F,
    3. Asai K,
    4. Takahashi H
    . 1995. Effects of spo0 mutations on spo0A promoter switching at the initiation of sporulation in Bacillus subtilis. J. Bacteriol. 177:4520–4523.
    OpenUrlAbstract/FREE Full Text
  105. 105.↵
    1. Strauch MA,
    2. Trach KA,
    3. Day J,
    4. Hoch JA
    . 1992. Spo0A activates and represses its own synthesis by binding at its dual promoters. Biochimie 74:619–626. doi:10.1016/0300-9084(92)90133-Y.
    OpenUrlCrossRefPubMedWeb of Science
  106. 106.↵
    1. Grossman AD
    . 1995. Genetic networks controlling the initiation of sporulation and the development of genetic competence in Bacillus subtilis. Annu. Rev. Genet. 29:477–508. doi:10.1146/annurev.ge.29.120195.002401.
    OpenUrlCrossRefPubMedWeb of Science
  107. 107.↵
    1. Ogura Y,
    2. Imai Y,
    3. Ogasawara N,
    4. Moriya S
    . 2001. Autoregulation of the dnaA-dnaN operon and effects of DnaA protein levels on replication initiation in Bacillus subtilis. J. Bacteriol. 183:3833–3841. doi:10.1128/JB.183.13.3833-3841.2001.
    OpenUrlAbstract/FREE Full Text
  108. 108.↵
    1. Rahn-Lee L,
    2. Gorbatyuk B,
    3. Skovgaard O,
    4. Losick R
    . 2009. The conserved sporulation protein YneE inhibits DNA replication in Bacillus subtilis. J. Bacteriol. 191:3736–3739. doi:10.1128/JB.00216-09.
    OpenUrlAbstract/FREE Full Text
  109. 109.↵
    1. Scholefield G,
    2. Errington J,
    3. Murray H
    . 2012. Soj/ParA stalls DNA replication by inhibiting helix formation of the initiator protein DnaA. EMBO J. 31:1542–1555. doi:10.1038/emboj.2012.6.
    OpenUrlCrossRefPubMedWeb of Science
  110. 110.↵
    1. Briggs GS,
    2. Smits WK,
    3. Soultanas P
    . 2012. Chromosomal replication initiation machinery of low-G+C-content Firmicutes. J. Bacteriol. 194:5162–5170. doi:10.1128/JB.00865-12.
    OpenUrlAbstract/FREE Full Text
  111. 111.↵
    1. Burkholder WF,
    2. Kurtser I,
    3. Grossman AD
    . 2001. Replication initiation proteins regulate a developmental checkpoint in Bacillus subtilis. Cell 104:269–279. doi:10.1016/S0092-8674(01)00211-2.
    OpenUrlCrossRefPubMedWeb of Science
  112. 112.↵
    1. Li R,
    2. Liu G,
    3. Xie Z,
    4. He X,
    5. Chen W,
    6. Deng Z,
    7. Tan H
    . 2010. PolY, a transcriptional regulator with ATPase activity, directly activates transcription of polR in polyoxin biosynthesis in Streptomyces cacaoi. Mol. Microbiol. 75:349–364. doi:10.1111/j.1365-2958.2009.06968.x.
    OpenUrlCrossRefPubMed
  113. 113.↵
    1. Xu W,
    2. Huang J,
    3. Lin R,
    4. Shi J,
    5. Cohen SN
    . 2010. Regulation of morphological differentiation in S. coelicolor by RNase III (AbsB) cleavage of mRNA encoding the AdpA transcription factor. Mol. Microbiol. 75:781–791. doi:10.1111/j.1365-2958.2009.07023.x.
    OpenUrlCrossRefPubMed
  114. 114.↵
    1. den Hengst CD,
    2. Tran NT,
    3. Bibb MJ,
    4. Chandra G,
    5. Leskiw BK,
    6. Buttner MJ
    . 2010. Genes essential for morphological development and antibiotic production in Streptomyces coelicolor are targets of BldD during vegetative growth. Mol. Microbiol. 78:361–379. doi:10.1111/j.1365-2958.2010.07338.x.
    OpenUrlCrossRefPubMed
  115. 115.↵
    1. Nguyen KT,
    2. Tenor J,
    3. Stettler H,
    4. Nguyen LT,
    5. Nguyen LD,
    6. Thompson CJ
    . 2003. Colonial differentiation in Streptomyces coelicolor depends on translation of a specific codon within the adpA gene. J. Bacteriol. 185:7291–7296. doi:10.1128/JB.185.24.7291-7296.2003.
    OpenUrlAbstract/FREE Full Text
  116. 116.↵
    1. Takano E,
    2. Tao M,
    3. Long F,
    4. Bibb MJ,
    5. Wang L,
    6. Li W,
    7. Buttner MJ,
    8. Deng ZX,
    9. Chater KF
    . 2003. A rare leucine codon in adpA is implicated in the morphological defect of bldA mutants of Streptomyces coelicolor. Mol. Microbiol. 50:475–486. doi:10.1046/j.1365-2958.2003.03728.x.
    OpenUrlCrossRefPubMedWeb of Science
  117. 117.↵
    1. Pettersson BM,
    2. Kirsebom LA
    . 2011. tRNA accumulation and suppression of the bldA phenotype during development in Streptomyces coelicolor. Mol. Microbiol. 79:1602–1614. doi:10.1111/j.1365-2958.2011.07543.x.
    OpenUrlCrossRefPubMed
  118. 118.↵
    1. Higo A,
    2. Horinouchi S,
    3. Ohnishi Y
    . 2011. Strict regulation of morphological differentiation and secondary metabolism by a positive feedback loop between two global regulators AdpA and BldA in Streptomyces griseus. Mol. Microbiol. 81:1607–1622. doi:10.1111/j.1365-2958.2011.07795.x.
    OpenUrlCrossRefPubMed
  119. 119.↵
    1. Majka J,
    2. Jakimowicz D,
    3. Messer W,
    4. Schrempf H,
    5. Lisowski M,
    6. Zakrzewska-Czerwinska J
    . 1999. Interactions of the Streptomyces lividans initiator protein DnaA with its target. Eur. J. Biochem. 260:325–335.
    OpenUrlPubMedWeb of Science
  120. 120.↵
    1. Madiraju MV,
    2. Moomey M,
    3. Neuenschwander PF,
    4. Muniruzzaman S,
    5. Yamamoto K,
    6. Grimwade JE,
    7. Rajagopalan M
    . 2006. The intrinsic ATPase activity of Mycobacterium tuberculosis DnaA promotes rapid oligomerization of DnaA on oriC. Mol. Microbiol. 59:1876–1890. doi:10.1111/j.1365-2958.2006.05068.x.
    OpenUrlCrossRefPubMedWeb of Science
  • Copyright © 2014, American Society for Microbiology. All Rights Reserved.
Figure1

Marcin Wolański obtained his M.Sc. (Biotechnology) from the Faculty of Chemistry at the Technical University of Wrocław, Poland, in 2005 and his Ph.D. (Molecular Biology) from the Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland, in 2011. Shortly after obtaining his Ph.D., he has started working as a postdoctoral fellow at the Department of Molecular Microbiology (Faculty of Biotechnology) of the University of Wrocław. During the course of his Ph.D. studies, he investigated protein factors involved in the regulation of chromosome replication and differentiation in Streptomyces coelicolor. Since 2011, his research has been also focused on the transcription regulation of antibiotic gene clusters in Actinomycetales.

Figure2

Dagmara Jakimowicz obtained her M.Sc. in biotechnology from the Faculty of Natural Sciences, University of Wrocław, Poland, in 1996, and her Ph.D. in biological sciences from the Department of Microbiology at the Institute of Immunology and Experimental Therapy, Polish Academy of Science, Wroclaw, Poland, in 2000. She worked as a postdoctoral research assistant at the John Innes Centre, Norwich, United Kingdom (2001 to 2005), where she carried out research on chromosome segregation in Streptomyces. Since her return to Poland (2005), she has been continuing research on chromosome segregation and its coordination with replication in Streptomyces and also in Mycobacterium. Since 2007, she has been Associate Professor and the group leader in the Molecular Microbiology Department at the Faculty of Biotechnology, University of Wrocław.

Figure3

Jolanta Zakrzewska-Czerwińska is a Professor of molecular microbiology. She obtained her M.Sc. (chemistry/bioengineering) from the Faculty of Chemistry at the Wrocław University of Technology, Poland, in 1984 and her Ph.D. from the Institute of Immunology and Experimental Therapy, Wrocław, Poland, in 1989. She did postdoctoral research as the Alexander von Humboldt fellow at the Osnabruck University, Germany (1991 to 1992), where she carried out research on initiation of chromosome replication in Streptomyces. In 1999 to 2013, she was a head of the Department of Microbiology at the Institute of Immunology and Experimental Therapy and her research focused on the molecular taxonomy of Actinomycetales and initiation of chromosome replication in bacteria. Since 2007, she has worked as a head of the Department of Molecular Microbiology at the Faculty of Biotechnology, University of Wrocław, Poland. Currently, her main area of research is chromosome replication and regulation of this process in various bacteria, particularly in Streptomyces and Mycobacterium.

View Abstract
PreviousNext
Back to top
Download PDF
Citation Tools
Fifty Years after the Replicon Hypothesis: Cell-Specific Master Regulators as New Players in Chromosome Replication Control
Marcin Wolański, Dagmara Jakimowicz, Jolanta Zakrzewska-Czerwińska
Journal of Bacteriology Jul 2014, 196 (16) 2901-2911; DOI: 10.1128/JB.01706-14

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Print

Alerts
Sign In to Email Alerts with your Email Address
Email

Thank you for sharing this Journal of Bacteriology article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Fifty Years after the Replicon Hypothesis: Cell-Specific Master Regulators as New Players in Chromosome Replication Control
(Your Name) has forwarded a page to you from Journal of Bacteriology
(Your Name) thought you would be interested in this article in Journal of Bacteriology.
Share
Fifty Years after the Replicon Hypothesis: Cell-Specific Master Regulators as New Players in Chromosome Replication Control
Marcin Wolański, Dagmara Jakimowicz, Jolanta Zakrzewska-Czerwińska
Journal of Bacteriology Jul 2014, 196 (16) 2901-2911; DOI: 10.1128/JB.01706-14
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Top
  • Article
    • ABSTRACT
    • INTRODUCTION
    • MASTER TRANSCRIPTION FACTORS CONTROL CELL CYCLE PROGRESSION IN BACTERIA THAT UNDERGO COMPLEX DEVELOPMENTAL CYCLES
    • MASTER REGULATORS INHIBIT REPLICATION INITIATION DURING THE TRANSITION TO NONREPLICATING CELLS
    • SUMMARY AND PERSPECTIVES
    • ACKNOWLEDGMENTS
    • FOOTNOTES
    • REFERENCES
  • Figures & Data
  • Info & Metrics
  • PDF

Related Articles

Cited By...

About

  • About JB
  • Editor in Chief
  • Editorial Board
  • Policies
  • For Reviewers
  • For the Media
  • For Librarians
  • For Advertisers
  • Alerts
  • RSS
  • FAQ
  • Permissions
  • Journal Announcements

Authors

  • ASM Author Center
  • Submit a Manuscript
  • Article Types
  • Ethics
  • Contact Us

Follow #Jbacteriology

@ASMicrobiology

       

ASM Journals

ASM journals are the most prominent publications in the field, delivering up-to-date and authoritative coverage of both basic and clinical microbiology.

About ASM | Contact Us | Press Room

 

ASM is a member of

Scientific Society Publisher Alliance

Copyright © 2019 American Society for Microbiology | Privacy Policy | Website feedback

Print ISSN: 0021-9193; Online ISSN: 1098-5530