期刊
NUCLEIC ACIDS RESEARCH
卷 49, 期 22, 页码 12805-12819出版社
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkab1169
关键词
-
资金
- National Institutes of Health [AI 064693, P30 CA008748]
The DNA repair systems in microbes, such as Mycobacterium tuberculosis, play distinct and overlapping roles in survival and mutagenesis, depending on the type of DNA damage. Quinolone antibiotics and replication fork perturbation induce the PafBC pathway, while chromosomal mutagenesis is codependent on PafBC and SOS through regulation of the DnaE2/ImuA/B mutasome. This study provides new insights into the regulatory mechanisms controlling the genesis of antibiotic resistance in M. tuberculosis.
DNA repair systems allow microbes to survive in diverse environments that compromise chromosomal integrity. Pathogens such as Mycobacterium tuberculosis must contend with the genotoxic host environment, which generates the mutations that underlie antibiotic resistance. Mycobacteria encode the widely distributed SOS pathway, governed by the LexA repressor, but also encode PafBC, a positive regulator of the transcriptional DNA damage response (DDR). Although the transcriptional outputs of these systems have been characterized, their full functional division of labor in survival and mutagenesis is unknown. Here, we specifically ablate the PafBC or SOS pathways, alone and in combination, and test their relative contributions to repair. We find that SOS and PafBC have both distinct and overlapping roles that depend on the type of DNA damage. Most notably, we find that quinolone antibiotics and replication fork perturbation are inducers of the PafBC pathway, and that chromosomal mutagenesis is codependent on PafBC and SOS, through shared regulation of the DnaE2/ImuA/B mutasome. These studies define the complex transcriptional regulatory network of the DDR in mycobacteria and provide new insight into the regulatory mechanisms controlling the genesis of antibiotic resistance in M. tuberculosis.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据