DNA repair in <i>Mycobacterium tuberculosis</i>. What have we learnt from the genome sequence?

Mizrahi, Valerie; Andersen, Susan J.

doi:10.1046/j.1365-2958.1998.01038.x

Cited by 163 publications

(135 citation statements)

References 74 publications

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“…Reactive oxygen and nitrogen intermediates represent more physiologically relevant DNA damaging agents (2). Nitrosative and oxidative stress conditions were modelled by exposure to acidified sodium nitrite and t -butyl hydroperoxide, respectively (Figure 1c and d), which have been shown previously to cause these types of damage (40,41).…”

Section: Resultsmentioning

confidence: 99%

“…Since persistence within the infected macrophage and reactivation of the bacillus from the dormant state are key features of infection, the maintenance of genome integrity is considered a vital aspect in the biology of M. tuberculosis (2,3). …”

Section: Introductionmentioning

confidence: 99%

“…Information is beginning to emerge concerning the role of NER in the biology of mycobacteria, an observation that assumes even more emphasis considering that these bacteria lack a functional DNA mismatch repair system (2). Transcription of the uvr A gene has been shown to be up-regulated in human macrophage-grown M. tuberculosis bacilli hours post-infection (10).…”

Section: Introductionmentioning

confidence: 99%

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The biological and structural characterization of Mycobacterium tuberculosis UvrA provides novel insights into its mechanism of action

Rossi

Khanduja

Bortoluzzi

et al. 2011

Nucleic Acids Research

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Mycobacterium tuberculosis is an extremely well adapted intracellular human pathogen that is exposed to multiple DNA damaging chemical assaults originating from the host defence mechanisms. As a consequence, this bacterium is thought to possess highly efficient DNA repair machineries, the nucleotide excision repair (NER) system amongst these. Although NER is of central importance to DNA repair in M. tuberculosis, our understanding of the processes in this species is limited. The conserved UvrABC endonuclease represents the multi-enzymatic core in bacterial NER, where the UvrA ATPase provides the DNA lesion-sensing function. The herein reported genetic analysis demonstrates that M. tuberculosis UvrA is important for the repair of nitrosative and oxidative DNA damage. Moreover, our biochemical and structural characterization of recombinant M. tuberculosis UvrA contributes new insights into its mechanism of action. In particular, the structural investigation reveals an unprecedented conformation of the UvrB-binding domain that we propose to be of functional relevance. Taken together, our data suggest UvrA as a potential target for the development of novel anti-tubercular agents and provide a biochemical framework for the identification of small-molecule inhibitors interfering with the NER activity in M. tuberculosis.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The biological and structural characterization of Mycobacterium tuberculosis UvrA provides novel insights into its mechanism of action

Rossi

Khanduja

Bortoluzzi

et al. 2011

Nucleic Acids Research

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“…A number of base excision repair (BER) pathways, dedicated to preventing such mutations, play a crucial role in restoration of genomic integrity. The genome sequences of Mycobacterium tuberculosis and Mycobacterium smegmatis have revealed that they lack the mismatch repair and the very short patch repair pathway enzymes (Cole et al, 1998;Mizrahi & Andersen, 1998). Furthermore, RecA-mediated repair also does not appear to play a significant role in mutation prevention in mycobacteria (Boshoff et al, 2003;Rand et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Synergistic effects of UdgB and Ung in mutation prevention and protection against commonly encountered DNA damaging agents in Mycobacterium smegmatis

et al. 2010

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The incorporation of dUMP during replication or the deamination of cytosine in DNA results in the occurrence of uracils in genomes. To maintain genomic integrity, uracil DNA glycosylases (UDGs) excise uracil from DNA and initiate the base-excision repair pathway. Here, we cloned, purified and biochemically characterized a family 5 UDG, UdgB, from Mycobacterium smegmatis to allow us to use it as a model organism to investigate the physiological significance of the novel enzyme. Studies with knockout strains showed that compared with the wild-type parent, the mutation rate of the udgB " strain was approximately twofold higher, whereas the mutation rate of a strain deficient in the family 1 UDG (ung " ) was found to be~8.4-fold higher. Interestingly, the mutation rate of the double-knockout (ung " /udgB " ) strain was remarkably high, at~19.6-fold. While CG to TA mutations predominated in the ung " and ung " /udgB " strains, AT to GC mutations were enhanced in the udgB " strain. The ung " /udgB " strain was notably more sensitive to acidified nitrite and hydrogen peroxide stresses compared with the single knockouts (ung " or udgB " ). These observations reveal a synergistic effect of UdgB and Ung in DNA repair, and could have implications for the generation of attenuated strains of Mycobacterium tuberculosis.

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“…It not only tolerates the hostile environment within macrophages but also survives environmental stresses like exposure to UV, dehydration and low temperature during host exchanges (Manganelli et al, 2004). Although the DNA damage response mechanisms in M. tuberculosis are not well understood, it is clear that for its persistence in the host, DNA repair strategies are vital for this pathogen (Mizrahi & Andersen, 1998).…”

Section: Introductionmentioning

confidence: 99%

Important role of the nucleotide excision repair pathway in Mycobacterium smegmatis in conferring protection against commonly encountered DNA-damaging agents

et al. 2008

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Mycobacteria are an important group of human pathogens. Although the DNA repair mechanisms in mycobacteria are not well understood, these are vital for the pathogen's persistence in the host macrophages. In this study, we generated a null mutation in the uvrB gene of Mycobacterium smegmatis to allow us to compare the significance of the nucleotide excision repair (NER) pathway with two important base excision repair pathways, initiated by uracil DNA glycosylase (Ung) and formamidopyrimidine DNA glycosylase (Fpg or MutM), in an isogenic strain background. The strain deficient in NER was the most sensitive to commonly encountered DNAdamaging agents such as UV, low pH, reactive oxygen species, hypoxia, and was also sensitive to acidified nitrite. Taken together with previous observations on NER-deficient M. tuberculosis, these results suggest that NER is an important DNA repair pathway in mycobacteria.

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DNA repair in Mycobacterium tuberculosis. What have we learnt from the genome sequence?

Cited by 163 publications

References 74 publications

The biological and structural characterization of Mycobacterium tuberculosis UvrA provides novel insights into its mechanism of action

The biological and structural characterization of Mycobacterium tuberculosis UvrA provides novel insights into its mechanism of action

Synergistic effects of UdgB and Ung in mutation prevention and protection against commonly encountered DNA damaging agents in Mycobacterium smegmatis

Important role of the nucleotide excision repair pathway in Mycobacterium smegmatis in conferring protection against commonly encountered DNA-damaging agents

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