期刊
MOLECULAR CELL
卷 64, 期 5, 页码 940-950出版社
CELL PRESS
DOI: 10.1016/j.molcel.2016.10.017
关键词
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资金
- Swiss National Science Foundation [PP00P3 159323]
- Swiss National Science Foundation (SNF) [PP00P3_159323] Funding Source: Swiss National Science Foundation (SNF)
To repair a DNA double-strand break (DSB) by homologous recombination (HR), the 5'-terminated strand of the DSB must be resected. The human MRE11-RAD50-NBS1 (MRN) and CtIP proteins were implicated in the initiation of DNA end resection, but the underlying mechanism remained undefined. Here, we show that CtIP is a co-factor of the MRE11 endonuclease activity within the MRN complex. This function is absolutely dependent on CtIP phosphorylation that includes the key cyclin-dependent kinase target motif at Thr-847. Unlike in yeast, where the Xrs2/NBS1 subunit is dispensable in vitro, NBS1 is absolutely required in the human system. The MRE11 endonuclease in conjunction with RAD50, NBS1, and phosphorylated CtIP preferentially cleaves 50-terminated DNA strands near DSBs. Our results define the initial step of HR that is particularly relevant for the processing of DSBs bearing protein blocks.
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