SAMHD1 Promotes DNA End Resection to Facilitate DNA Repair by Homologous Recombination

作者：Waaqo Daddacha, Allyson E. Koyen, Amanda J. Bastien, PamelaSara E. Head, Vishal R. Dhere, Geraldine Nabeta, Erin C. Connolly, Erica Werner, Matthew Z. Madden, Michele B. Daly, Elizabeth V. Minten, Donna R. Whelan, Ashley Schlafstein, Hui Zhang, Roopesh Anand, Christine A. Doronio, Allison E. Withers, Caitlin Shepard, Ranjini K. Sundaram, Xingming Deng, William S. Dynan, Ya Wang, Ranjit S. Bindra, Petr Ćejka, Eli Rothenberg, Paul W. Doetsch, Baek Kim, David S. Yu · 发表于：Cell Reports · 年份：2017 · DOI：10.1016/j.celrep.2017.08.008 · 被引用次数：214 · 研究领域：DNA Repair Mechanisms、CRISPR and Genetic Engineering、Cancer-related Molecular Pathways

DNA double-strand break (DSB) repair by homologous recombination (HR) is initiated by CtIP/MRN-mediated DNA end resection to maintain genome integrity. SAMHD1 is a dNTP triphosphohydrolase, which restricts HIV-1 infection, and mutations are associated with Aicardi-Goutières syndrome and cancer. We show that SAMHD1 has a dNTPase-independent function in promoting DNA end resection to facilitate DSB repair by HR. SAMHD1 deficiency or Vpx-mediated degradation causes hypersensitivity to DSB-inducing agents, and SAMHD1 is recruited to DSBs. SAMHD1 complexes with CtIP via a conserved C-terminal domain and recruits CtIP to DSBs to facilitate end resection and HR. Significantly, a cancer-associated mutant with impaired CtIP interaction, but not dNTPase-inactive SAMHD1, fails to rescue the end resection impairment of SAMHD1 depletion. Our findings define a dNTPase-independent function for SAMHD1 in HR-mediated DSB repair by facilitating CtIP accrual to promote DNA end resection, providing insight into how SAMHD1 promotes genome integrity.