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PMID:12694625

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Citation

Park, HD, Guinn, KM, Harrell, MI, Liao, R, Voskuil, MI, Tompa, M, Schoolnik, GK and Sherman, DR (2003) Rv3133c/dosR is a transcription factor that mediates the hypoxic response of Mycobacterium tuberculosis. Mol. Microbiol. 48:833-43

Abstract

Unlike many pathogens that are overtly harmful to their hosts, Mycobacterium tuberculosis can persist for years within humans in a clinically latent state. Latency is often linked to hypoxic conditions within the host. Among M. tuberculosis genes induced by hypoxia is a putative transcription factor, Rv3133c/DosR. We performed targeted disruption of this locus followed by transcriptome analysis of wild-type and mutant bacilli. Nearly all the genes powerfully regulated by hypoxia require Rv3133c/DosR for their induction. Computer analysis identified a consensus motif, a variant of which is located upstream of nearly all M. tuberculosis genes rapidly induced by hypoxia. Further, Rv3133c/DosR binds to the two copies of this motif upstream of the hypoxic response gene alpha-crystallin. Mutations within the binding sites abolish both Rv3133c/DosR binding as well as hypoxic induction of a downstream reporter gene. Also, mutation experiments with Rv3133c/DosR confirmed sequence-based predictions that the C-terminus is responsible for DNA binding and that the aspartate at position 54 is essential for function. Together, these results demonstrate that Rv3133c/DosR is a transcription factor of the two-component response regulator class, and that it is the primary mediator of a hypoxic signal within M. tuberculosis.

Links

PubMed PMC1992516

Keywords

Anoxia/metabolism; Aspartic Acid/metabolism; Bacterial Proteins/genetics; Bacterial Proteins/metabolism; Gene Expression Regulation, Bacterial; Gene Targeting; Genes, Reporter; Humans; Mycobacterium tuberculosis/genetics; Mycobacterium tuberculosis/metabolism; Oligonucleotide Array Sequence Analysis; Oxygen/metabolism; Protein Binding; Regulatory Sequences, Nucleic Acid; Transcription Factors/genetics; Transcription Factors/metabolism; Tuberculosis/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MYCTU:DEVR

GO:0071456: cellular response to hypoxia

ECO:0000315:

P

Figure 5B demonstrates that DosR (Asp-54Glu) mutants have significantly reduced hypoxic gene induction compared to the wild-type DosR.

complete
CACAO 4107

MYCTU:DEVR

involved_in

GO:0001666: response to hypoxia

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MYCTU:DEVR

enables

GO:0003700: DNA-binding transcription factor activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete


See also

References

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