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

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

Research output: Contribution to journalArticle

37 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1921-1935
Number of pages15
JournalCell Reports
Volume20
Issue number8
DOIs
StatePublished - Aug 22 2017

    Fingerprint

Keywords

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Daddacha, W., Koyen, A. E., Bastien, A. J., Head, P. S. E., Dhere, V. R., Nabeta, G. N., Connolly, E. C., Werner, E., Madden, M. Z., Daly, M. B., Minten, E. V., Whelan, D. R., Schlafstein, A. J., Zhang, H., Anand, R., Doronio, C., Withers, A. E., Shepard, C., Sundaram, R. K., ... Yu, D. S. (2017). SAMHD1 Promotes DNA End Resection to Facilitate DNA Repair by Homologous Recombination. Cell Reports, 20(8), 1921-1935. https://doi.org/10.1016/j.celrep.2017.08.008