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
  • 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.