학술논문
SAMHD1 Promotes DNA End Resection to Facilitate DNA Repair by Homologous Recombination
Document Type
article
Author
Waaqo Daddacha; Allyson E. Koyen; Amanda J. Bastien; PamelaSara E. Head; Vishal R. Dhere; Geraldine N. Nabeta; Erin C. Connolly; Erica Werner; Matthew Z. Madden; Michele B. Daly; Elizabeth V. Minten; Donna R. Whelan; Ashley J. Schlafstein; Hui Zhang; Roopesh Anand; Christine Doronio; Allison E. Withers; Caitlin Shepard; Ranjini K. Sundaram; Xingming Deng; William S. Dynan; Ya Wang; Ranjit S. Bindra; Petr Cejka; Eli Rothenberg; Paul W. Doetsch; Baek Kim; David S. Yu
Source
Cell Reports, Vol 20, Iss 8, Pp 1921-1935 (2017)
Subject
Language
English
ISSN
2211-1247
Abstract
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.