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

Daddacha, Waaqo; Koyen, Allyson E.; Bastien, Amanda J.; Head,Pamela Sara 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.

doi:10.1016/j.celrep.2017.08.008

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Journal article

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

22.08.2017

Published in:

Cell reports. - 2017, vol. 20, no. 8, p. 1921-1935

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.

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