DNA repair inMycobacterium tuberculosisrevisited

Abstract

Our understanding of Mycobacterium tuberculosis DNA repair mechanisms is still poor compared with that of other bacterial organisms. However, the publication of the first complete M. tuberculosis genome sequence 10 years ago boosted the study of DNA repair systems in this organism. A first step in the elucidation of M. tuberculosis DNA repair mechanisms was taken by Mizrahi and Andersen, who identified homologs of genes involved in the reversal or repair of DNA damage in Escherichia coli and related organisms. Genes required for nucleotide excision repair, base excision repair, recombination, and SOS repair and mutagenesis were identified. Notably, no homologs of genes involved in mismatch repair were identified. Novel characteristics of the M. tuberculosis DNA repair machinery have been found over the last decade, such as nonhomologous end joining, the presence of Mpg, ERCC3 and Hlr - proteins previously presumed to be produced exclusively in mammalian cells - and the recently discovered bifunctional dCTP deaminase:dUTPase. The study of these systems is important to develop therapeutic agents that can counteract M. tuberculosis evolutionary changes and to prevent adaptive events resulting in antibiotic resistance. This review summarizes our current understanding of the M. tuberculosis DNA repair system.

Methodological and Clinical Aspects of the Molecular Epidemiology of Mycobacterium tuberculosis and Other Mycobacteria

“…In the genomes of mycobacteria are homologs of genes involved in several DNA repair mechanisms, including base excision repair, nucleotide excision repair, homologous recombination (HR), and nonhomologous end joining (NHEJ) (23). Notably, even though M. tuberculosis does not possess homologs of genes of mismatch repair (MMR), the number of single nucleotide polymorphisms (SNPs) occurring in this species is not elevated (24)(25)(26). The reason for the limited occurrence of mutations in M. tuberculosis is a matter of dispute, but it is generally attributed to the activities of other DNA repair mechanisms, namely, base excision repair and nucleotide excision repair (27), and purifying/negative selection pressure (24).…”

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

“…During its life, Mycobacterium tuberculosis is exposed to numerous genotoxic insults originating from both antimicrobial host defence mechanisms and the environment (1). 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).…”

Biochemical and Structural Studies of the Mycobacterium tuberculosis O 6 -Methylguanine Methyltransferase and Mutated Variants

“…In order to maintain high genome stability, signaled by a remarkably low level of genetic diversity among isolates (2), it is therefore mandatory for M. tuberculosis to possess efficient systems to counteract the effects of such environmental and host-generated DNAendangering assaults (3)(4)(5)(6). In particular, during its long-term persistence inside infected macrophages, M. tuberculosis must deal with endogenous DNA-alkylating chemical species originated by the action of highly reactive oxidative and nitrosative radicals (7).…”