SAMHD1 Promotes DNA End Resection to Facilitate DNA Repair by Homologous Recombination Academic Article uri icon

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.

authors

  • Daddacha, Waaqo
  • Koyen, Allyson E
  • Bastien, Amanda J
  • Head, PamelaSara E
  • Dhere, Vishal R
  • Nabeta, Geraldine N
  • Connolly, Erin C
  • Werner, Erica
  • Madden, Matthew Z
  • Daly, Michele B
  • Minten, Elizabeth V
  • Whelan, Donna R
  • Schlafstein, Ashley J
  • Zhang, Hui
  • Anand, Roopesh
  • Doronio, Christine
  • Withers, Allison E
  • Shepard, Caitlin
  • Sundaram, Ranjini K
  • Deng, Xingming
  • Dynan, William S
  • Wang, Ya
  • Bindra, Ranjit S
  • Cejka, Petr
  • Rothenberg, Eli
  • Doetsch, Paul W
  • Kim, Baek
  • Yu, David S

publication date

  • 2017