The structure of ends determines the pathway choice and Mre11 nuclease dependency of DNA double-strand break repair.
The structure of ends determines the pathway choice and Mre11 nuclease dependency of DNA double-strand break repair.
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DOI：
10.1093/nar/gkw274
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发表时间：
2016-07-08
影响因子：
14.9
通讯作者：
Yan H
中科院分区：
文献类型：
--
作者：
Liao S;Tammaro M;Yan H
DNA双链断裂（DSB）修复途径选择的关键事件是末端的初始加工。非同源末端连接（NHEJ）涉及有限的加工，但同源依赖性修复（HDR）需要广泛切除5′链。细胞如何决定是否将末端引导至切除或NHEJ尚不清楚。我们假设，末端的结构是一个主要的决定因素，并测试了这一假设与模型DNA基板爪蟾卵提取物。虽然具有正常核苷酸的末端被有效地引导至NHEJ，但具有受损核苷酸或大体积加合物的末端被引导至切除。切除依赖于Mre11，但其核酸酶活性仅对具有5′大加合物的末端至关重要。CtIP是激活Mre 11的核酸酶依赖性机制而非核酸酶非依赖性机制所必需的。总之，这些发现表明，末端的结构是DSB修复的途径选择和切除的Mre11核酸酶依赖性的主要决定因素。
The key event in the choice of repair pathways for DNA double-strand breaks (DSBs) is the initial processing of ends. Non-homologous end joining (NHEJ) involves limited processing, but homology-dependent repair (HDR) requires extensive resection of the 5′ strand. How cells decide if an end is channeled to resection or NHEJ is not well understood. We hypothesize that the structure of ends is a major determinant and tested this hypothesis with model DNA substrates in Xenopus egg extracts. While ends with normal nucleotides are efficiently channeled to NHEJ, ends with damaged nucleotides or bulky adducts are channeled to resection. Resection is dependent on Mre11, but its nuclease activity is critical only for ends with 5′ bulky adducts. CtIP is absolutely required for activating the nuclease-dependent mechanism of Mre11 but not the nuclease-independent mechanism. Together, these findings suggest that the structure of ends is a major determinant for the pathway choice of DSB repair and the Mre11 nuclease dependency of resection.