5 years ago

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
Yongxiang Zhao, Kyungsoo Ha, Suxia Han, Zhusheng Lian, Chengxian Ma, Huan Chen, Lichun Tang, Fang Zhao, Jianping Jin, Marcos Malumbres, Bei Zhen, Han Lin, Huadong Pei, Ju-Mei Li, Qing Zhu, Pumin Zhang
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.

Publisher URL: http://www.nature.com/articles/ncomms15751

DOI: 10.1038/ncomms15751

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