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

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

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 languageEnglish (US)
Pages (from-to)514-527.e4
JournalMolecular Cell
Volume77
Issue number3
DOIs
StatePublished - Feb 6 2020
Externally publishedYes

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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