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Journal of Bacteriology, August 2008, p. 5394-5403, Vol. 190, No. 15
0021-9193/08/$08.00+0     doi:10.1128/JB.00488-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Interaction of DevR with Multiple Binding Sites Synergistically Activates Divergent Transcription of narK2-Rv1738 Genes in Mycobacterium tuberculosis ^,

Santosh Chauhan and Jaya Sivaswami Tyagi^*

Department of Biotechnology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India

Received 9 April 2008/ Accepted 11 May 2008

Under hypoxic conditions or upon exposure to low concentrations of nitric oxide, DevR transcriptional regulator mediates the activation of 50 genes that are believed to assist in dormancy development in Mycobacterium tuberculosis. Most of the strongly induced genes are characterized by the presence of one to four copies of a Dev box-like sequence at an upstream location. Among these are several gene pairs that are transcribed in opposite directions. This arrangement could provide for coordinated control of the adjacent genes under inducing conditions. In this work, we report the first detailed analysis of DevR-mediated hypoxic regulation of narK2-Rv1738 genes that are oppositely oriented in M. tuberculosis. Phosphorylated DevR interacts with intergenic sequences and protects 80 bp of DNA that contains three binding sites, designated Dev boxes D1, D2, and D3. The hypoxia-specific transcription start points of narK2 and Rv1738 were mapped, and it was noted that the –35 elements of both promoters overlapped with the proximally placed Dev box. DevR bound cooperatively to adjacently placed D2 and D3 boxes while binding to D1 was independent of DevR interaction with the D2 and D3 boxes. Mutational analysis and green fluorescent protein reporter assays established that the three Dev boxes function synergistically to mediate maximal transcriptional induction of both narK2 and Rv1738 in hypoxic cultures of M. tuberculosis. Analysis of narK2 promoter activity indicates that it is under negative regulation in addition to DevR-mediated positive regulation and also reveals differences between M. tuberculosis and Mycobacterium bovis BCG.

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* Corresponding author. Mailing address: Department of Biotechnology, All India Institute of Medical Sciences, New Delhi 110029, India. Phone: 91 11 26588491. Fax: 91 11 26588663. E-mail: jstyagi{at}aiims.ac.in

Published ahead of print on 23 May 2008.

Supplemental material for this article may be found at http://jb.asm.org/.

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Journal of Bacteriology, August 2008, p. 5394-5403, Vol. 190, No. 15
0021-9193/08/$08.00+0     doi:10.1128/JB.00488-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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