ATR Protects the Genome against R Loops through a MUS81-Triggered Feedback Loop

Dominick A. Matos; Jia Min Zhang; Jian Ouyang; Hai Dang Nguyen; Marie Michelle Genois; Lee Zou

doi:10.1016/j.molcel.2019.10.010

ATR Protects the Genome against R Loops through a MUS81-Triggered Feedback Loop

Dominick A. Matos, Jia Min Zhang, Jian Ouyang, Hai Dang Nguyen, Marie Michelle Genois, Lee Zou

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Abstract

R loops cause genomic instability, but how cells respond to R loop-associated genomic stress is poorly understood. Matos et al. show that the ATR-Chk1 pathway senses R loop-impeded replication forks through a MUS81-mediated mechanism and protects replication forks from excessive MUS81 cleavage, revealing a MUS81-triggered and ATR-mediated feedback loop safeguarding the genome against R loops.

Original language	English (US)
Pages (from-to)	514-527.e4
Journal	Molecular Cell
Volume	77
Issue number	3
DOIs	https://doi.org/10.1016/j.molcel.2019.10.010
State	Published - Feb 6 2020
Externally published	Yes

Bibliographical note

Funding Information:
We thank Dr. J.W. Harper for the MUS81 plasmid and Drs. N. Dyson, J. Walter, J.K. Joung, A. Elia, L. Lan, and members of the Zou and Dyson labs for discussions. D.A.M. was partially supported by an NIH F31 fellowship (1F31CA210311). J.-M.Z. is partially supported by the Massachusetts General Hospital Cancer Center Excellence Award. H.D.N. was supported by an NIH T32 postdoctoral training grant (T32 DK007540) and a grant from the Edward P. Evans Foundation. M.-M.G. was partially supported by a postdoctoral fellowship from Fonds de Recherche Sant? Qu?bec (FRQS). L.Z. is the James & Patricia Poitras Endowed Chair in Cancer Research, and was supported by a Jim & Ann Orr Massachusetts General Hospital Research Scholar Award. This work is supported by grants from the NIH (GM076388, CA197779, and CA218856) to L.Z. D.A.M. and L.Z. designed the project. D.A.M. J.-M.Z. J.O. H.D.N. and M.-M.G. performed the experiments and data analysis. L.Z. supervised the experiments and data analysis. D.A.M. and L.Z. wrote the manuscript with help from all of the other authors. L.Z. has consulted for EMD Serono and received research funding from Calico. All of the other authors declare no competing interests.

Funding Information:
We thank Dr. J.W. Harper for the MUS81 plasmid and Drs. N. Dyson, J. Walter, J.K. Joung, A. Elia, L. Lan, and members of the Zou and Dyson labs for discussions. D.A.M. was partially supported by an NIH F31 fellowship ( 1F31CA210311 ). J.-M.Z. is partially supported by the Massachusetts General Hospital Cancer Center Excellence Award . H.D.N. was supported by an NIH T32 postdoctoral training grant ( T32 DK007540 ) and a grant from the Edward P. Evans Foundation . M.-M.G. was partially supported by a postdoctoral fellowship from Fonds de Recherche Santé Québec (FRQS). L.Z. is the James & Patricia Poitras Endowed Chair in Cancer Research, and was supported by a Jim & Ann Orr Massachusetts General Hospital Research Scholar Award . This work is supported by grants from the NIH ( GM076388 , CA197779 , and CA218856 ) to L.Z.

Keywords

ATR
Chk1
Fork reversal
Genomic Instability
MUS81
R loop
checkpoint

PubMed: MeSH publication types

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

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title = "ATR Protects the Genome against R Loops through a MUS81-Triggered Feedback Loop",

abstract = "R loops cause genomic instability, but how cells respond to R loop-associated genomic stress is poorly understood. Matos et al. show that the ATR-Chk1 pathway senses R loop-impeded replication forks through a MUS81-mediated mechanism and protects replication forks from excessive MUS81 cleavage, revealing a MUS81-triggered and ATR-mediated feedback loop safeguarding the genome against R loops.",

keywords = "ATR, Chk1, Fork reversal, Genomic Instability, MUS81, R loop, checkpoint",

author = "Matos, {Dominick A.} and Zhang, {Jia Min} and Jian Ouyang and Nguyen, {Hai Dang} and Genois, {Marie Michelle} and Lee Zou",

note = "Funding Information: We thank Dr. J.W. Harper for the MUS81 plasmid and Drs. N. Dyson, J. Walter, J.K. Joung, A. Elia, L. Lan, and members of the Zou and Dyson labs for discussions. D.A.M. was partially supported by an NIH F31 fellowship (1F31CA210311). J.-M.Z. is partially supported by the Massachusetts General Hospital Cancer Center Excellence Award. H.D.N. was supported by an NIH T32 postdoctoral training grant (T32 DK007540) and a grant from the Edward P. Evans Foundation. M.-M.G. was partially supported by a postdoctoral fellowship from Fonds de Recherche Sant? Qu?bec (FRQS). L.Z. is the James & Patricia Poitras Endowed Chair in Cancer Research, and was supported by a Jim & Ann Orr Massachusetts General Hospital Research Scholar Award. This work is supported by grants from the NIH (GM076388, CA197779, and CA218856) to L.Z. D.A.M. and L.Z. designed the project. D.A.M. J.-M.Z. J.O. H.D.N. and M.-M.G. performed the experiments and data analysis. L.Z. supervised the experiments and data analysis. D.A.M. and L.Z. wrote the manuscript with help from all of the other authors. L.Z. has consulted for EMD Serono and received research funding from Calico. All of the other authors declare no competing interests. Funding Information: We thank Dr. J.W. Harper for the MUS81 plasmid and Drs. N. Dyson, J. Walter, J.K. Joung, A. Elia, L. Lan, and members of the Zou and Dyson labs for discussions. D.A.M. was partially supported by an NIH F31 fellowship ( 1F31CA210311 ). J.-M.Z. is partially supported by the Massachusetts General Hospital Cancer Center Excellence Award . H.D.N. was supported by an NIH T32 postdoctoral training grant ( T32 DK007540 ) and a grant from the Edward P. Evans Foundation . M.-M.G. was partially supported by a postdoctoral fellowship from Fonds de Recherche Sant{\'e} Qu{\'e}bec (FRQS). L.Z. is the James & Patricia Poitras Endowed Chair in Cancer Research, and was supported by a Jim & Ann Orr Massachusetts General Hospital Research Scholar Award . This work is supported by grants from the NIH ( GM076388 , CA197779 , and CA218856 ) to L.Z. ",

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doi = "10.1016/j.molcel.2019.10.010",

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AU - Matos, Dominick A.

AU - Zhang, Jia Min

AU - Ouyang, Jian

AU - Nguyen, Hai Dang

AU - Genois, Marie Michelle

AU - Zou, Lee

N1 - Funding Information: We thank Dr. J.W. Harper for the MUS81 plasmid and Drs. N. Dyson, J. Walter, J.K. Joung, A. Elia, L. Lan, and members of the Zou and Dyson labs for discussions. D.A.M. was partially supported by an NIH F31 fellowship (1F31CA210311). J.-M.Z. is partially supported by the Massachusetts General Hospital Cancer Center Excellence Award. H.D.N. was supported by an NIH T32 postdoctoral training grant (T32 DK007540) and a grant from the Edward P. Evans Foundation. M.-M.G. was partially supported by a postdoctoral fellowship from Fonds de Recherche Sant? Qu?bec (FRQS). L.Z. is the James & Patricia Poitras Endowed Chair in Cancer Research, and was supported by a Jim & Ann Orr Massachusetts General Hospital Research Scholar Award. This work is supported by grants from the NIH (GM076388, CA197779, and CA218856) to L.Z. D.A.M. and L.Z. designed the project. D.A.M. J.-M.Z. J.O. H.D.N. and M.-M.G. performed the experiments and data analysis. L.Z. supervised the experiments and data analysis. D.A.M. and L.Z. wrote the manuscript with help from all of the other authors. L.Z. has consulted for EMD Serono and received research funding from Calico. All of the other authors declare no competing interests. Funding Information: We thank Dr. J.W. Harper for the MUS81 plasmid and Drs. N. Dyson, J. Walter, J.K. Joung, A. Elia, L. Lan, and members of the Zou and Dyson labs for discussions. D.A.M. was partially supported by an NIH F31 fellowship ( 1F31CA210311 ). J.-M.Z. is partially supported by the Massachusetts General Hospital Cancer Center Excellence Award . H.D.N. was supported by an NIH T32 postdoctoral training grant ( T32 DK007540 ) and a grant from the Edward P. Evans Foundation . M.-M.G. was partially supported by a postdoctoral fellowship from Fonds de Recherche Santé Québec (FRQS). L.Z. is the James & Patricia Poitras Endowed Chair in Cancer Research, and was supported by a Jim & Ann Orr Massachusetts General Hospital Research Scholar Award . This work is supported by grants from the NIH ( GM076388 , CA197779 , and CA218856 ) to L.Z.

PY - 2020/2/6

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N2 - R loops cause genomic instability, but how cells respond to R loop-associated genomic stress is poorly understood. Matos et al. show that the ATR-Chk1 pathway senses R loop-impeded replication forks through a MUS81-mediated mechanism and protects replication forks from excessive MUS81 cleavage, revealing a MUS81-triggered and ATR-mediated feedback loop safeguarding the genome against R loops.

AB - R loops cause genomic instability, but how cells respond to R loop-associated genomic stress is poorly understood. Matos et al. show that the ATR-Chk1 pathway senses R loop-impeded replication forks through a MUS81-mediated mechanism and protects replication forks from excessive MUS81 cleavage, revealing a MUS81-triggered and ATR-mediated feedback loop safeguarding the genome against R loops.

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KW - checkpoint

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ATR Protects the Genome against R Loops through a MUS81-Triggered Feedback Loop

Abstract

Bibliographical note

Keywords

PubMed: MeSH publication types

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