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

Published on Aug 22, 2017in Cell Reports8.109
· DOI :10.1016/J.CELREP.2017.08.008
Waaqo Daddacha12
Estimated H-index: 12
(Emory University),
Allyson E. Koyen5
Estimated H-index: 5
(Emory University)
+ 25 AuthorsDavid S. Yu22
Estimated H-index: 22
(Emory University)
Sources
Abstract
Summary 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-Goutieres 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.
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