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 Deng; William S. Dynan; Ya Wang; Ranjit S. Bindra; Petr Cejka; Eli Rothenberg; Paul W. Doetsch; Baek Kim; David S. Yu

doi:10.1016/j.celrep.2017.08.008

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 journal › Article › peer-review

121 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 language	English (US)
Pages (from-to)	1921-1935
Number of pages	15
Journal	Cell Reports
Volume	20
Issue number	8
DOIs	https://doi.org/10.1016/j.celrep.2017.08.008
State	Published - Aug 22 2017
Externally published	Yes

Keywords

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

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2017.08.008

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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

Daddacha, W, Koyen, AE, Bastien, AJ, Head, PSE, Dhere, VR, Nabeta, GN, Connolly, EC, Werner, E, Madden, MZ, Daly, MB, Minten, EV, Whelan, DR, Schlafstein, AJ, Zhang, H, Anand, R, Doronio, C, Withers, AE, Shepard, C, Sundaram, RK, Deng, X, Dynan, WS, Wang, Y, Bindra, RS, Cejka, P, Rothenberg, E, Doetsch, PW, Kim, B & Yu, DS 2017, 'SAMHD1 Promotes DNA End Resection to Facilitate DNA Repair by Homologous Recombination', Cell Reports, vol. 20, no. 8, pp. 1921-1935. https://doi.org/10.1016/j.celrep.2017.08.008

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title = "SAMHD1 Promotes DNA End Resection to Facilitate DNA Repair by Homologous Recombination",

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-Gouti{\`e}res 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.",

keywords = "AGS, CLL, CtIP, DNA damage response, DNA end resection, DNA repair, HIV, autoimmune, dNTP, homologous recombination",

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

note = "Publisher Copyright: {\textcopyright} 2017 The Author(s)",

year = "2017",

month = aug,

day = "22",

doi = "10.1016/j.celrep.2017.08.008",

language = "English (US)",

volume = "20",

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T1 - SAMHD1 Promotes DNA End Resection to Facilitate DNA Repair by Homologous Recombination

AU - Daddacha, Waaqo

AU - Koyen, Allyson E.

AU - Bastien, Amanda J.

AU - Head, Pamela Sara E.

AU - Dhere, Vishal R.

AU - Nabeta, Geraldine N.

AU - Connolly, Erin C.

AU - Werner, Erica

AU - Madden, Matthew Z.

AU - Daly, Michele B.

AU - Minten, Elizabeth V.

AU - Whelan, Donna R.

AU - Schlafstein, Ashley J.

AU - Zhang, Hui

AU - Anand, Roopesh

AU - Doronio, Christine

AU - Withers, Allison E.

AU - Shepard, Caitlin

AU - Sundaram, Ranjini K.

AU - Deng, Xingming

AU - Dynan, William S.

AU - Wang, Ya

AU - Bindra, Ranjit S.

AU - Cejka, Petr

AU - Rothenberg, Eli

AU - Doetsch, Paul W.

AU - Kim, Baek

AU - Yu, David S.

PY - 2017/8/22

Y1 - 2017/8/22

N2 - 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.

AB - 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.

KW - AGS

KW - CLL

KW - CtIP

KW - DNA damage response

KW - DNA end resection

KW - DNA repair

KW - HIV

KW - autoimmune

KW - dNTP

KW - homologous recombination

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UR - http://www.scopus.com/inward/citedby.url?scp=85028324495&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2017.08.008

DO - 10.1016/j.celrep.2017.08.008

M3 - Article

C2 - 28834754

AN - SCOPUS:85028324495

SN - 2211-1247

VL - 20

SP - 1921

EP - 1935

JO - Cell Reports

JF - Cell Reports

IS - 8

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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