Mycobacterial RadA Functions in Cyclic Di-AMP Mediated Homologous Recombination in Addition to Supporting RecA Activity

IF 3.1 2区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Microbiology Pub Date : 2026-02-12 DOI:10.1111/mmi.70057

Nisha Goyal, Sudhanshu Mudgal, Rahul Saginela, Hanuman Singh Dagur, Rajakumara Eerappa, Krishna Murari Sinha

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Abstract

Mycobacterium possesses unique DNA repair and recombination pathways that are absent in E. coli. The pathways are linked to mycobacterial virulence and survival within the host. Cyclic di-AMP, a secondary messenger present in Mycobacterium regulates DNA recombination, genome stability and SOS response. radA and disA exist in a conserved operon in several bacteria including Mycobacterium suggesting a role of RadA in cyclic di-AMP mediated DNA damage repair pathways. We show here that RadA is indeed involved in cyclic di-AMP mediated DSB repair pathways in Mycobacterium and has non-canonical function in DSB repair as well. Deletion of radA expectedly decreases HR efficiency but interestingly also results in illegitimate recombination outcome GC*. The illegitimate recombination GC* leads to increased stress induced mutagenesis giving rise to drug resistant mutants. We have also found that RadA influences NHEJ repair and in its absence the cells adopt alternative route of DNA repair. Our work shows active participation of RadA in several DNA repair and recombination pathways which could be targeted for potential therapeutics against Mycobacterium.

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分枝杆菌RadA在环二磷酸腺苷介导的同源重组中除了支持RecA活性外还起作用

分枝杆菌具有大肠杆菌所没有的独特的DNA修复和重组途径。这些途径与分枝杆菌的毒力和宿主内的存活有关。环状二磷酸腺苷，一个次级信使存在于分枝杆菌调节DNA重组，基因组的稳定性和SOS响应。radA和disA存在于包括分枝杆菌在内的几种细菌的保守操纵子中，提示radA在环二磷酸腺苷介导的DNA损伤修复途径中发挥作用。我们在这里表明RadA确实参与了分枝杆菌中环二磷酸腺苷介导的DSB修复途径，并且在DSB修复中也具有非规范功能。radA的缺失预期会降低HR效率，但有趣的是也会导致不合理的重组结果GC*。不合理的GC*重组导致应激诱导诱变增加，从而产生耐药突变体。我们还发现RadA影响NHEJ的修复，在没有RadA的情况下，细胞采用替代的DNA修复途径。我们的研究表明RadA积极参与了几种DNA修复和重组途径，这可能是针对分枝杆菌的潜在治疗方法的目标。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Microbiology 生物-生化与分子生物学

CiteScore

7.20

自引率

5.60%

发文量

132

审稿时长

1.7 months

期刊介绍： Molecular Microbiology, the leading primary journal in the microbial sciences, publishes molecular studies of Bacteria, Archaea, eukaryotic microorganisms, and their viruses. Research papers should lead to a deeper understanding of the molecular principles underlying basic physiological processes or mechanisms. Appropriate topics include gene expression and regulation, pathogenicity and virulence, physiology and metabolism, synthesis of macromolecules (proteins, nucleic acids, lipids, polysaccharides, etc), cell biology and subcellular organization, membrane biogenesis and function, traffic and transport, cell-cell communication and signalling pathways, evolution and gene transfer. Articles focused on host responses (cellular or immunological) to pathogens or on microbial ecology should be directed to our sister journals Cellular Microbiology and Environmental Microbiology, respectively.