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Cell Rep. 2017 Aug 22;20(8):1921-1935. doi: 10.1016/j.celrep.2017.08.008.

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

Author information

1
Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA; Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA.
2
Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA; Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA; Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA.
3
Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA.
4
Department of Biochemistry and Molecular Pharmacology, NYU School of Medicine, New York, NY 10016, USA.
5
Institute for Research in Biomedicine, Università della Svizzera italiana, Via Vela 6, 6500 Bellinzona, Switzerland.
6
Department of Radiation Oncology, Yale University School of Medicine, New Haven, CT 06520, USA.
7
Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA; Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA. Electronic address: dsyu@emory.edu.

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.

KEYWORDS:

AGS; CLL; CtIP; DNA damage response; DNA end resection; DNA repair; HIV; autoimmune; dNTP; homologous recombination

PMID:
28834754
PMCID:
PMC5576576
DOI:
10.1016/j.celrep.2017.08.008
[Indexed for MEDLINE]
Free PMC Article

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