Department of Molecular Microbiology Washington University School of Medicine, St. Louis, Missouri, United States of America.
PLoS One. 2011;6(7):e21807. doi: 10.1371/journal.pone.0021807. Epub 2011 Jul 18.
Recent evidence indicates that the mycobacterial response to DNA double strand breaks (DSBs) differs substantially from previously characterized bacteria. These differences include the use of three DSB repair pathways (HR, NHEJ, SSA), and the CarD pathway, which integrates DNA damage with transcription. Here we identify a role for the mono-ADP-ribosyltransferase Arr in the mycobacterial DNA damage response. Arr is transcriptionally induced following DNA damage and cellular stress. Although Arr is not required for induction of a core set of DNA repair genes, Arr is necessary for suppression of a set of ribosomal protein genes and rRNA during DNA damage, placing Arr in a similar pathway as CarD. Surprisingly, the catalytic activity of Arr is not required for this function, as catalytically inactive Arr was still able to suppress ribosomal protein and rRNA expression during DNA damage. In contrast, Arr substrate binding and catalytic activities were required for regulation of a small subset of other DNA damage responsive genes, indicating that Arr has both catalytic and noncatalytic roles in the DNA damage response. Our findings establish an endogenous cellular function for a mono-ADP-ribosyltransferase apart from its role in mediating Rifampin resistance.
最近的证据表明，分枝杆菌对 DNA 双链断裂 (DSBs) 的反应与先前表征的细菌有很大的不同。这些差异包括三种 DSB 修复途径 (HR、NHEJ、SSA) 和 CarD 途径，该途径将 DNA 损伤与转录整合在一起。在这里，我们确定了单 ADP-核糖基转移酶 Arr 在分枝杆菌 DNA 损伤反应中的作用。Arr 在 DNA 损伤和细胞应激后转录诱导。尽管 Arr 不是诱导一组核心 DNA 修复基因所必需的，但 Arr 在 DNA 损伤期间对于抑制一组核糖体蛋白基因和 rRNA 是必需的，这使 Arr 处于与 CarD 相似的途径中。令人惊讶的是，Arr 的催化活性对于该功能不是必需的，因为催化失活的 Arr 仍然能够在 DNA 损伤期间抑制核糖体蛋白和 rRNA 的表达。相比之下，Arr 底物结合和催化活性对于一小部分其他 DNA 损伤反应基因的调节是必需的，这表明 Arr 在 DNA 损伤反应中具有催化和非催化作用。我们的发现确立了单 ADP-核糖基转移酶除了在介导利福平耐药性方面的作用之外的内源性细胞功能。
