A cell cycle-dependent BRCA1-UHRF1 cascade regulates DNA double-strand break repair pathway choice.
A cell cycle-dependent BRCA1-UHRF1 cascade regulates DNA double-strand break repair pathway choice.
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细胞周期依赖性 BRCA1-UHRF1 级联调节 DNA 双链断裂修复途径的选择。
DOI：
10.1038/ncomms10201
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发表时间：
2016-01-05
影响因子：
16.6
通讯作者：
Pei H
中科院分区：
文献类型：
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作者：
Zhang H;Liu H;Chen Y;Yang X;Wang P;Liu T;Deng M;Qin B;Correia C;Lee S;Kim J;Sparks M;Nair AA;Evans DL;Kalari KR;Zhang P;Wang L;You Z;Kaufmann SH;Lou Z;Pei H
BRCA1是DNA损伤反应的重要介质，可促进同源重组（homologous recombination， HR），并在S/G2期拮抗53bp1依赖性非同源末端连接。但如何实现这一目标仍不清楚。在这里，我们报道了E3泛素连接酶UHRF1（泛素样，具有PHD和RING finger结构域1）直接参与BRCA1和53BP1之间的相互作用。机制上，UHRF1在S期被BRCA1招募到DNA双链断裂（DSBs）中，这需要BRCA1的BRCT结构域和UHRF1的磷酸化Ser674。随后，UHRF1介导k63连接的RIF1多泛素化，并导致其与53BP1和dsb分离，从而促进HR的启动。因此，UHRF1是DSB修复选择的关键调节因子，这与其在异染色质形成和表观遗传调节中的作用是分开的。BRCA1是DNA双链断裂修复的关键调控因子，具有促进同源重组和抑制非同源末端连接的功能。在这里，作者表明，泛素连接酶UHRF1被BRCA1招募到断裂，在那里它靶向RIF1，从而促进重组。
BRCA1 is an important mediator of the DNA damage response, which promotes homologous recombination (HR) and antagonizes 53BP1-dependent non-homologous end joining in S/G2 phase. But how this is achieved remains unclear. Here, we report that the E3 ubiquitin ligase UHRF1 (Ubiquitin-like, with PHD and RING finger domains 1) directly participates in the interplay between BRCA1 and 53BP1. Mechanistically, UHRF1 is recruited to DNA double-strand breaks (DSBs) by BRCA1 in S phase, which requires the BRCT domain of BRCA1 and phosphorylated Ser674 of UHRF1. Subsequently, UHRF1 mediates K63-linked polyubiquitination of RIF1, and results in its dissociation from 53BP1 and DSBs thereby facilitating HR initiation. Thus, UHRF1 is a key regulator of DSB repair choice, which is separate from its role in heterochromatin formation and epigenetic regulator. BRCA1 is a key regulator of DNA double-strand break repair, functioning to promote homologous recombination and repress non-homologous end-joining. Here the authors show that the ubiquitin ligase UHRF1 is recruited to breaks by BRCA1, where it targets RIF1 and thereby facilitates recombination.