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Journal of Bacteriology, September 2008, p. 5841-5854, Vol. 190, No. 17
0021-9193/08/$08.00+0     doi:10.1128/JB.00711-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Synthetic Lethality with the dut Defect in Escherichia coli Reveals Layers of DNA Damage of Increasing Complexity Due to Uracil Incorporation{triangledown}

Helen Ting, Elena A. Kouzminova, and Andrei Kuzminov*

Department of Microbiology, University of Illinois at Urbana-Champaign, Urbana, Illinois

Received 20 May 2008/ Accepted 18 June 2008

Synthetic lethality is inviability of a double-mutant combination of two fully viable single mutants, commonly interpreted as redundancy at an essential metabolic step. The dut-1 defect in Escherichia coli inactivates dUTPase, causing increased uracil incorporation in DNA and known synthetic lethalities [SL(dut) mutations]. According to the redundancy logic, most of these SL(dut) mutations should affect nucleotide metabolism. After a systematic search for SL(dut) mutants, we did identify a single defect in the DNA precursor metabolism, inactivating thymidine kinase (tdk), that confirmed the redundancy explanation of synthetic lethality. However, we found that the bulk of mutations interacting genetically with dut are in DNA repair, revealing layers of damage of increasing complexity that uracil-DNA incorporation sends through the chromosomal metabolism. Thus, we isolated mutants in functions involved in (i) uracil-DNA excision (ung, polA, and xthA); (ii) double-strand DNA break repair (recA, recBC, and ruvABC); and (iii) chromosomal-dimer resolution (xerC, xerD, and ftsK). These mutants in various DNA repair transactions cannot be redundant with dUTPase and instead reveal "defect-damage-repair" cycles linking unrelated metabolic pathways. In addition, two SL(dut) inserts (phoU and degP) identify functions that could act to support the weakened activity of the Dut-1 mutant enzyme, suggesting the "compensation" explanation for this synthetic lethality. We conclude that genetic interactions with dut can be explained by redundancy, by defect-damage-repair cycles, or as compensation.

* Corresponding author. Mailing address: B103 C&LSL, 601 South Goodwin Ave., Urbana, IL 61801-3709. Phone: (217) 265-0329. Fax: (217) 244-6697. E-mail: kuzminov{at}life.uiuc.edu

{triangledown} Published ahead of print on 27 June 2008.

Journal of Bacteriology, September 2008, p. 5841-5854, Vol. 190, No. 17
0021-9193/08/$08.00+0     doi:10.1128/JB.00711-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Reimann, S. A., Wolfe, A. J. (2009). A Critical Process Controlled by MalT and OmpR Is Revealed through Synthetic Lethality. J. Bacteriol. 191: 5320-5324 [Abstract] [Full Text]  


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