| Literature DB >> 28834754 |
Waaqo Daddacha1, Allyson E Koyen1, Amanda J Bastien1, PamelaSara E Head1, Vishal R Dhere1, Geraldine N Nabeta1, Erin C Connolly1, Erica Werner2, Matthew Z Madden1, Michele B Daly3, Elizabeth V Minten1, Donna R Whelan4, Ashley J Schlafstein1, Hui Zhang1, Roopesh Anand5, Christine Doronio1, Allison E Withers1, Caitlin Shepard3, Ranjini K Sundaram6, Xingming Deng1, William S Dynan2, Ya Wang1, Ranjit S Bindra6, Petr Cejka5, Eli Rothenberg4, Paul W Doetsch2, Baek Kim3, David S Yu7.
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.Entities:
Keywords: AGS; CLL; CtIP; DNA damage response; DNA end resection; DNA repair; HIV; autoimmune; dNTP; homologous recombination
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Year: 2017 PMID： 28834754 PMCID： PMC5576576 DOI： 10.1016/j.celrep.2017.08.008
Source DB: PubMed Journal: Cell Rep Impact factor: 9.423