Nonhomologous end-joining promotes resistance to DNA damage in the absence of an ADP-ribosyltransferase that signals DNA single strand breaks
Nonhomologous end-joining promotes resistance to DNA damage in the absence of an ADP-ribosyltransferase that signals DNA single strand breaks
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DOI：
10.1242/jcs.128769
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发表时间：
2013-08-01
影响因子：
4
通讯作者：
Lakin, Nicholas D.
中科院分区：
文献类型：
--
作者：
Couto, C. Anne-Marie;Hsu, Duen-Wei;Lakin, Nicholas D.
adp核糖基转移酶（ARTs）对DNA损伤处蛋白质的adp核糖基化是DNA损伤的早期反应。adp核糖基化在DNA损伤反应中最明确的作用是修复单链断裂（SSBs）。最近，我们启动了一项关于adp -核糖基化如何调节Dictyostelium DNA修复的研究，发现细胞对SSBs的耐受性需要两种ART (Adprt1b和Adprt2)，而第三种ART （Adprt1a）促进非同源末端连接（NHEJ）。在这里，我们报告了adprt2的破坏导致暴露于诱导碱基损伤和DNA SSBs的物质后，在整个细胞周期中DNA损伤的积累。虽然adp核糖基化在暴露于甲基甲磺酸盐（MMS）的adprt2（-）细胞中很明显，但adprt1a和adprt2联合破坏会消除这种反应，并进一步使细胞对该药物敏感，这表明在缺乏adprt2的情况下，adprt1a发出MMS诱导的DNA损伤信号，以促进细胞对DNA损伤的抵抗。由于Adprt2对SSBs的信号传导缺陷，需要Adprt1a在染色质中组装NHEJ因子，并且NHEJ通路的破坏与Adprt2的结合增加了细胞对MMS的敏感性。综上所述，这些数据表明了不同的art在DNA损伤信号传导中的重叠功能，并说明了NHEJ在缺乏有效SSB应答时维持细胞活力的关键要求。
ADP-ribosylation of proteins at DNA lesions by ADP-ribosyltransferases (ARTs) is an early response to DNA damage. The best defined role of ADP-ribosylation in the DNA damage response is in repair of single strand breaks (SSBs). Recently, we initiated a study of how ADP-ribosylation regulates DNA repair in Dictyostelium and found that two ARTs (Adprt1b and Adprt2) are required for tolerance of cells to SSBs, and a third ART (Adprt1a) promotes nonhomologous end-joining (NHEJ). Here we report that disruption of adprt2 results in accumulation of DNA damage throughout the cell cycle following exposure to agents that induce base damage and DNA SSBs. Although ADP-ribosylation is evident in adprt2(-) cells exposed to methylmethanesulfonate (MMS), disruption of adprt1a and adprt2 in combination abolishes this response and further sensitises cells to this agent, indicating that in the absence of Adprt2, Adprt1a signals MMS-induced DNA lesions to promote resistance of cells to DNA damage. As a consequence of defective signalling of SSBs by Adprt2, Adprt1a is required to assemble NHEJ factors in chromatin, and disruption of the NHEJ pathway in combination with adprt2 increases sensitivity of cells to MMS. Taken together, these data indicate overlapping functions of different ARTs in signalling DNA damage, and illustrate a critical requirement for NHEJ in maintaining cell viability in the absence of an effective SSB response.