SAMHD1 promotes DNA end resection to facilitate DNA repair by homologous recombination
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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
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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
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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
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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
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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
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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
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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
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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
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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
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Daly, Michele B.
Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA
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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
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Whelan, Donna R.
Department of Biochemistry and Molecular Pharmacology, NYU School of Medicine, New York, NY 10016, USA
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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
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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
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Anand, Roopesh
Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
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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
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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
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Shepard, Caitlin
Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA
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Sundaram, Ranjini K.
Department of Radiation Oncology, Yale University School of Medicine, New Haven, CT 06520, USA
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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
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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
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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
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Bindra, Ranjit S.
Department of Radiation Oncology, Yale University School of Medicine, New Haven, CT 06520, USA
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Cejka, Petr
Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
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Rothenberg, Eli
Department of Biochemistry and Molecular Pharmacology, NYU School of Medicine, New York, NY 10016, USA
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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
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Kim, Baek
Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA
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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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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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Medicine
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CC BY-NC-ND
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Open access status
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gold
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https://n2t.net/ark:/12658/srd1319133
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