The anaphase promoting complex impacts repair choice by protecting ubiquitin signalling at DNA damage sites.
The anaphase promoting complex impacts repair choice by protecting ubiquitin signalling at DNA damage sites.
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DOI：
10.1038/ncomms15751
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发表时间：
2017-06-12
影响因子：
16.6
通讯作者：
Zhang P
中科院分区：
文献类型：
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作者：
Ha K;Ma C;Lin H;Tang L;Lian Z;Zhao F;Li JM;Zhen B;Pei H;Han S;Malumbres M;Jin J;Chen H;Zhao Y;Zhu Q;Zhang P
双链断裂（DSB）通过两种主要途径修复，同源定向重组（HDR）和非同源末端连接（NHEJ）。HDR仅发生在S/G2期，而NHEJ可发生在所有细胞周期阶段（有丝分裂除外）。那么，S/G2细胞中的修复选择是如何做出的呢？在这里，我们提供的证据表明，APCCdh 1在选择S/G2细胞的修复途径中起着关键作用。我们的研究结果表明，所有DSB的默认情况是招募53 BP 1和RIF 1。BRCA 1被阻断募集到断裂末端，因为它的募集信号，组蛋白上K63连接的多聚泛素链，被去泛素化酶USP 1积极破坏。我们发现，USP 1的去除依赖于APCCdh 1，并需要Chk 1激活已知的ssDNA-RPA-ATR信号在指定为HDR的末端催化，连接状态的最终处理RIF 1或BRCA 1招聘。同源重组和非同源末端连接之间的选择在很大程度上受细胞周期的影响。在这里，作者表明APCCdh 1通过去除USP 1促进同源重组，允许多泛素化组蛋白招募BRCA 1。
Double-strand breaks (DSBs) are repaired through two major pathways, homology-directed recombination (HDR) and non-homologous end joining (NHEJ). While HDR can only occur in S/G2, NHEJ can happen in all cell cycle phases (except mitosis). How then is the repair choice made in S/G2 cells? Here we provide evidence demonstrating that APCCdh1 plays a critical role in choosing the repair pathways in S/G2 cells. Our results suggest that the default for all DSBs is to recruit 53BP1 and RIF1. BRCA1 is blocked from being recruited to broken ends because its recruitment signal, K63-linked poly-ubiquitin chains on histones, is actively destroyed by the deubiquitinating enzyme USP1. We show that the removal of USP1 depends on APCCdh1 and requires Chk1 activation known to be catalysed by ssDNA-RPA-ATR signalling at the ends designated for HDR, linking the status of end processing to RIF1 or BRCA1 recruitment. The choice between homologous recombination and non-homologous end-joining is largely influenced by cell cycle. Here the authors show that APCCdh1 promotes homologous recombination by removing USP1, allowing polyubiquitinated histones to recruit BRCA1.