Abstract：
Maintenance of DNA integrity is essential to all forms of life. DNA damage generated by reaction with genotoxic chemicals results in deleterious mutations, genome instability, and cell death. Pathogenic bacteria encounter several genotoxic agents during infection. In keeping with this, the loss of DNA repair networks results in virulence attenuation in several bacterial species. Interstrand DNA crosslinks (ICLs) are a type of DNA lesion formed by covalent linkage of opposing DNA strands and are particularly toxic as they interfere with replication and transcription. Bacteria have evolved specialized DNA glycosylases that unhook ICLs, thereby initiating their repair. In this study, we describe AlkX, a DNA glycosylase encoded by the multidrug resistant pathogen Acinetobacter baumannii. AlkX exhibits ICL unhooking activity similar to that of its Escherichia coli homolog YcaQ. Interrogation of the in vivo role of AlkX revealed that its loss sensitizes cells to DNA crosslinking and impairs A. baumannii colonization of the lungs and dissemination to distal tissues during pneumonia. These results suggest that AlkX participates in A. baumannii pathogenesis and protects the bacterium from stress conditions encountered in vivo. Consistent with this, we found that acidic pH, an environment encountered during host colonization, results in A. baumannii DNA damage and that alkX is induced by, and contributes to, defense against acidic conditions. Collectively, these studies reveal functions for a recently described class of proteins encoded in a broad range of pathogenic bacterial species.
摘要：
维持DNA的完整性对所有形式的生命都至关重要。与基因毒性化学物质反应产生的DNA损伤会导致有害突变，基因组不稳定，细胞死亡。病原菌在感染过程中会遇到几种遗传毒性剂。为了与此保持一致，DNA修复网络的丢失导致几种细菌的毒力减弱。链间DNA交联(ICL)是通过相对DNA链的共价连接形成的一种DNA损伤,并且特别有毒,因为它们干扰复制和转录。细菌已经进化出专门的DNA糖基化酶，可以解开ICL，从而开始修复。在这项研究中,我们描述AlkX,由多重耐药病原体鲍曼不动杆菌编码的DNA糖基化酶。AlkX表现出与其大肠杆菌同源物YcaQ相似的ICL脱钩活性。对AlkX的体内作用的询问表明，其损失会使细胞对DNA交联敏感，并在肺炎期间损害鲍曼不动杆菌在肺部的定植和向远端组织的传播。这些结果表明，AlkX参与鲍曼不动杆菌的发病机理，并保护细菌免受体内应激条件的影响。与此一致，我们发现酸性pH值,寄主定殖期间遇到的环境，导致鲍曼不动杆菌DNA损伤，并有助于，防御酸性条件。总的来说，这些研究揭示了最近描述的一类蛋白质在广泛的病原细菌物种中编码的功能。
