Expression of the
            <i>Mycobacterium tuberculosis acr</i>
            -Coregulated Genes from the DevR (DosR) Regulon Is Controlled by Multiple Levels of Regulation

Vasudeva-Rao, Hema M.; McDonough, Kathleen A.

doi:10.1128/iai.01443-07

Cited by 36 publications

(42 citation statements)

References 56 publications

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“…The C terminus of DosR can bind DNA, and the 54th conserved aspartate is essential for the binding. There is a 20-mer degenerate palindromic motif associating with DosR regulon [Park et al, 2003;Rustad et al, 2009;Vasudeva-Rao and McDonough, 2008]. One variant of this consensus sequence locates upstream of nearly all …”

Section: The Components and Distribution Of The Dosr Regulonmentioning

confidence: 99%

The Mycobacterium DosR regulon structure and diversity revealed by comparative genomic analysis

Chen

Deng

et al. 2012

J of Cellular Biochemistry

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Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), which claims approximately two million people annually, remains a global health concern. The non-replicating or dormancy like state of this pathogen which is impervious to anti-tuberculosis drugs is widely recognized as the culprit for this scenario. The dormancy survival regulator (DosR) regulon, composed of 48 co-regulated genes, is held as essential for Mtb persistence. The DosR regulon is regulated by a two-component regulatory system consisting of two sensor kinases-DosS (Rv3132c) and DosT (Rv2027c), and a response regulator DosR (Rv3133c). The underlying regulatory mechanism of DosR regulon expression is very complex. Many factors are involved, particularly the oxygen tension. The DosR regulon enables the pathogen to persist during lengthy hypoxia. Comparative genomic analysis demonstrated that the DosR regulon is widely distributed among the mycobacterial genomes, ranging from the pathogenic strains to the environmental strains. In-depth studies on the DosR response should provide insights into its role in TB latency in vivo and shape new measures to combat this exceeding recalcitrant pathogen.

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Section: The Components and Distribution Of The Dosr Regulonmentioning

confidence: 99%

The Mycobacterium DosR regulon structure and diversity revealed by comparative genomic analysis

Chen

Deng

et al. 2012

J of Cellular Biochemistry

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“…To delineate promoters within the Rv0081 upstream region, transcriptional start points (TSPs) were identified by 5Ј-RACE. RNA was derived from cultures of wild-type, ⌬dosR mutant (⌬devR mutant), or ⌬mprAB mutant strains of M. tuberculosis that were either grown with shaking or were grown statically to induce expression of dosR (devR) (64). For each reaction, two gene-specific reverse primers generated to the 5Ј end of Rv0081 were used in combination with a forward primer generated to the 5Ј-RACE adaptor.…”

Section: Vol 193 2011 Regulation Of M Tuberculosis Rv0081-rv0088 Lmentioning

confidence: 99%

Components of the Rv0081-Rv0088 Locus, Which Encodes a Predicted Formate Hydrogenlyase Complex, Are Coregulated by Rv0081, MprA, and DosR in Mycobacterium tuberculosis

Bretl

Penoske

et al. 2011

J Bacteriol

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Mycobacterium tuberculosis, the etiological agent of tuberculosis, remains a significant cause of morbidity and mortality throughout the world despite a vaccine and cost-effective antibiotics. The success of this organism can be attributed, in part, to its ability to adapt to potentially harmful stress within the host and establish, maintain, and reactivate from long-term persistent infection within granulomatous structures. The DosRSDosT/DevRS-Rv2027c, and MprAB two-component signal transduction systems have previously been implicated in aspects of persistent infection by M. tuberculosis and are known to be responsive to conditions likely to be found within the granuloma. Here, we describe initial characterization of a locus (Rv0081-Rv0088) encoding components of a predicted formate hydrogenylase enzyme complex that is directly regulated by DosR/DevR and MprA, and the product of the first gene in this operon, Rv0081. In particular, we demonstrate that Rv0081 negatively regulates its own expression and that of downstream genes by binding an inverted repeat element in its upstream region. In contrast, DosR/DevR and MprA positively regulate Rv0081 expression by binding to recognition sequences that either partially or completely overlap that recognized by Rv0081, respectively. Expression of Rv0081 initiates from two promoter elements; one promoter located downstream of the DosR/DevR binding site but overlapping the sequence recognized by both Rv0081 and MprA and another promoter downstream of the DosR/DevR, Rv0081, and MprA binding sites. Interestingly, Rv0081 represses Rv0081 and downstream determinants following activation of DosRS-DosT/DevRS-Rv2027c by nitric oxide, suggesting that expression of this locus is complex and subject to multiple levels of regulation. Based on this and other published information, a model is proposed detailing Rv0081-Rv0088 expression by these transcription factors within particular growth environments.

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“…As with many other twocomponent systems, the dosRS operon is autoregulated (2). The DosR-binding motif, an 18-bp palindrome, has been found by experiment (45) and by computational analysis of eight DosR-regulated promoters from M. tuberculosis (13).…”

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confidence: 99%

Comparative Genomics of the Dormancy Regulons in Mycobacteria

et al. 2011

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In response to stresses, Mycobacterium cells become dormant. This process is regulated by the DosR transcription factor. In Mycobacterium tuberculosis, the dormancy regulon is well characterized and contains the dosR gene itself and dosS and dosT genes encoding DosR kinases, nitroreductases (acg; Rv3131), diacylglycerol acyltransferase (DGAT) (Rv3130c), and many universal stress proteins (USPs). In this study, we apply comparative genomic analysis to characterize the DosR regulons in nine Mycobacterium genomes, Rhodococcus sp. RHA1, Nocardia farcinica, and Saccharopolyspora erythraea. The regulons are highly labile, containing eight core gene groups (regulators, kinases, USPs, DGATs, nitroreductases, ferredoxins, heat shock proteins, and the orthologs of the predicted kinase [Rv2004c] from M. tuberculosis) and 10 additional genes with more restricted taxonomic distribution that are mostly involved in anaerobic respiration. The largest regulon is observed in M. marinum and the smallest in M. abscessus. Analysis of large gene families encoding USPs, nitroreductases, and DGATs demonstrates a mosaic distribution of regulated and nonregulated members, suggesting frequent acquisition and loss of DosR-binding sites.Mycobacterium tuberculosis is a dangerous human pathogen infecting nearly one-third of the human population (1). An important feature of tuberculosis is the prevalence of latent infection without disease manifestation (14). During latency, M. tuberculosis is believed to exist in a state of nonreplicating persistence with low metabolic activity (40,46,49). Understanding the mechanisms used by M. tuberculosis to exist in this state and to switch to a metabolically active, infectious form is an important problem in tuberculosis research.M. tuberculosis is an obligate aerobe; under hypoxia, it ceases growth, decreases protein and RNA synthesis, and enters a dormant state (48,49). Low oxygen tension, nitric oxide, and carbon monoxide activate a three-component regulatory system comprised of two sensor kinases, DosS (Rv3132c) and DosT (Rv2027c), and a response regulator, DosR (Rv3133c) (21,34,38,(46)(47)(48). DosR-DosS is the dormancy regulon, which has been studied in M. tuberculosis, M. bovis (19), and M. smegmatis (5, 25). For M. tuberculosis and M. bovis, not only DosS, but also DosT, was shown to be a sensor kinase for DosR (17,18,42). DosR activates transcription of genes that allow bacteria to survive long periods of anaerobiosis and hence may be important for long-term survival within the host during latent infection (3,7,13,18,34,35).Both kinases, DosT and DosS, respond to nitric oxide, but DosT is more important at the early stage of hypoxia. When oxygen becomes limited, DosT becomes less prominent in the regulatory cascade and DosS alone maintains induction of the dormancy regulon (18,22,23,50). As with many other twocomponent systems, the dosRS operon is autoregulated (2). The DosR-binding motif, an 18-bp palindrome, has been found by experiment (45) and by computational analysis of eight DosR-regulate...

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Expression of the Mycobacterium tuberculosis acr -Coregulated Genes from the DevR (DosR) Regulon Is Controlled by Multiple Levels of Regulation

Cited by 36 publications

References 56 publications

The Mycobacterium DosR regulon structure and diversity revealed by comparative genomic analysis

The Mycobacterium DosR regulon structure and diversity revealed by comparative genomic analysis

Components of the Rv0081-Rv0088 Locus, Which Encodes a Predicted Formate Hydrogenlyase Complex, Are Coregulated by Rv0081, MprA, and DosR in Mycobacterium tuberculosis

Comparative Genomics of the Dormancy Regulons in Mycobacteria

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