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SAMHD1 promotes DNA end resection to facilitate DNA repair by homologous recombination

  • Daddacha, Waaqo Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA - Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA
  • Koyen, Allyson E. Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA - Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA
  • Bastien, Amanda J. Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA - Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA
  • Head,Pamela Sara E. Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA - Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA
  • Dhere, Vishal R. Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA - Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA
  • Nabeta, Geraldine N. Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA - Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA
  • Connolly, Erin C. Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA - Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA
  • Werner, Erica 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
  • Madden, Matthew Z. Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA - Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA
  • Daly, Michele B. Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA
  • Minten, Elizabeth V. Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA - Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA
  • Whelan, Donna R. Department of Biochemistry and Molecular Pharmacology, NYU School of Medicine, New York, NY 10016, USA
  • Schlafstein, Ashley J. Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA - Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA
  • Zhang, Hui Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA - Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA
  • Anand, Roopesh Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
  • Doronio, Christine Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA - Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA
  • Withers, Allison E. Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA - Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA
  • Shepard, Caitlin Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA
  • Sundaram, Ranjini K. Department of Radiation Oncology, Yale University School of Medicine, New Haven, CT 06520, USA
  • Deng, Xingming Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA - Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA
  • Dynan, William S. 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
  • Wang, Ya Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA - Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA
  • Bindra, Ranjit S. Department of Radiation Oncology, Yale University School of Medicine, New Haven, CT 06520, USA
  • Cejka, Petr Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
  • Rothenberg, Eli Department of Biochemistry and Molecular Pharmacology, NYU School of Medicine, New York, NY 10016, USA
  • Doetsch, Paul W. 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
  • Kim, Baek Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA
  • Yu, David S. Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA - Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA
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    22.08.2017
Published in:
  • Cell reports. - 2017, vol. 20, no. 8, p. 1921-1935
DNA repair
DNA damage response
DNA end resection
HIV
AGS
CLL
CtIP
dNTP
Homologous recombination
Autoimmune
English 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.
Language
  • English
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Medicine
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https://n2t.net/ark:/12658/srd1319133
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