The anaphase promoting complex impacts repair choice by protecting ubiquitin signalling at DNA damage sites

Kyungsoo Ha, Chengxian Ma, Han Lin, Lichun Tang, Zhusheng Lian, Fang Zhao, Ju-Mei Li, Bei Zhen, Huadong Pei, Suxia Han, Marcos Malumbres, Jianping Jin, Huan Chen, Yongxiang Zhao (), Qing Zhu () and Pumin Zhang ()
Additional contact information
Kyungsoo Ha: National Center for Protein Sciences Beijing, Life Sciences Park
Chengxian Ma: The Second Affiliated Hospital of Xi'an Jiaotong University Medical College
Han Lin: Baylor College of Medicine
Lichun Tang: National Center for Protein Sciences Beijing, Life Sciences Park
Zhusheng Lian: The First Affiliated Hospital of Xi'an Jiaotong University Medical College
Fang Zhao: National Center for International Research of Biological Targeting Diagnosis and Therapy, and Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University
Ju-Mei Li: University of Texas Health Sciences Center
Bei Zhen: National Center for Protein Sciences Beijing, Life Sciences Park
Huadong Pei: National Center for Protein Sciences Beijing, Life Sciences Park
Suxia Han: The First Affiliated Hospital of Xi'an Jiaotong University Medical College
Marcos Malumbres: Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro 3
Jianping Jin: University of Texas Health Sciences Center
Huan Chen: National Center for Protein Sciences Beijing, Life Sciences Park
Yongxiang Zhao: National Center for International Research of Biological Targeting Diagnosis and Therapy, and Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Guangxi Medical University
Qing Zhu: The Second Affiliated Hospital of Xi'an Jiaotong University Medical College
Pumin Zhang: National Center for Protein Sciences Beijing, Life Sciences Park

Nature Communications, 2017, vol. 8, issue 1, 1-17

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/ncomms15751

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