2. Academic Validation
  3. SAMHD1 Promotes DNA End Resection to Facilitate DNA Repair by Homologous Recombination

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

  • Cell Rep. 2017 Aug 22;20(8):1921-1935. doi: 10.1016/j.celrep.2017.08.008.
Waaqo Daddacha 1,  Allyson E Koyen 1,  Amanda J Bastien 1,  PamelaSara E Head 1,  Vishal R Dhere 1,  Geraldine N Nabeta 1,  Erin C Connolly 1,  Erica Werner 2,  Matthew Z Madden 1,  Michele B Daly 3,  Elizabeth V Minten 1,  Donna R Whelan 4,  Ashley J Schlafstein 1,  Hui Zhang 1,  Roopesh Anand 5,  Christine Doronio 1,  Allison E Withers 1,  Caitlin Shepard 3,  Ranjini K Sundaram 6,  Xingming Deng 1,  William S Dynan 2,  Ya Wang 1,  Ranjit S Bindra 6,  Petr Cejka 5,  Eli Rothenberg 4,  Paul W Doetsch 2,  Baek Kim 3,  David S Yu 7
Affiliations

Affiliations

  • 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: [email protected].
PMID: 28834754 DOI: 10.1016/j.celrep.2017.08.008
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.

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