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ATR Protects the Genome against R Loops through a MUS81-Triggered Feedback Loop.
Mol Cell 2019MC

Abstract

R loops arising during transcription induce genomic instability, but how cells respond to the R loop-associated genomic stress is still poorly understood. Here, we show that cells harboring high levels of R loops rely on the ATR kinase for survival. In response to aberrant R loop accumulation, the ataxia telangiectasia and Rad3-related (ATR)-Chk1 pathway is activated by R loop-induced reversed replication forks. In contrast to the activation of ATR by replication inhibitors, R loop-induced ATR activation requires the MUS81 endonuclease. ATR protects the genome from R loops by suppressing transcription-replication collisions, promoting replication fork recovery, and enforcing a G2/M cell-cycle arrest. Furthermore, ATR prevents excessive cleavage of reversed forks by MUS81, revealing a MUS81-triggered and ATR-mediated feedback loop that fine-tunes MUS81 activity at replication forks. These results suggest that ATR is a key sensor and suppressor of R loop-induced genomic instability, uncovering a signaling circuitry that safeguards the genome against R loops.

Authors+Show Affiliations

Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. Electronic address: zou.lee@mgh.harvard.edu.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31708417

Citation

Matos, Dominick A., et al. "ATR Protects the Genome Against R Loops Through a MUS81-Triggered Feedback Loop." Molecular Cell, 2019.
Matos DA, Zhang JM, Ouyang J, et al. ATR Protects the Genome against R Loops through a MUS81-Triggered Feedback Loop. Mol Cell. 2019.
Matos, D. A., Zhang, J. M., Ouyang, J., Nguyen, H. D., Genois, M. M., & Zou, L. (2019). ATR Protects the Genome against R Loops through a MUS81-Triggered Feedback Loop. Molecular Cell, doi:10.1016/j.molcel.2019.10.010.
Matos DA, et al. ATR Protects the Genome Against R Loops Through a MUS81-Triggered Feedback Loop. Mol Cell. 2019 Oct 28; PubMed PMID: 31708417.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - ATR Protects the Genome against R Loops through a MUS81-Triggered Feedback Loop. AU - Matos,Dominick A, AU - Zhang,Jia-Min, AU - Ouyang,Jian, AU - Nguyen,Hai Dang, AU - Genois,Marie-Michelle, AU - Zou,Lee, Y1 - 2019/10/28/ PY - 2019/03/14/received PY - 2019/08/11/revised PY - 2019/10/08/accepted PY - 2019/11/12/entrez PY - 2019/11/12/pubmed PY - 2019/11/12/medline KW - ATR KW - Chk1 KW - Fork reversal KW - Genomic Instability KW - MUS81 KW - R loop KW - checkpoint JF - Molecular cell JO - Mol. Cell N2 - R loops arising during transcription induce genomic instability, but how cells respond to the R loop-associated genomic stress is still poorly understood. Here, we show that cells harboring high levels of R loops rely on the ATR kinase for survival. In response to aberrant R loop accumulation, the ataxia telangiectasia and Rad3-related (ATR)-Chk1 pathway is activated by R loop-induced reversed replication forks. In contrast to the activation of ATR by replication inhibitors, R loop-induced ATR activation requires the MUS81 endonuclease. ATR protects the genome from R loops by suppressing transcription-replication collisions, promoting replication fork recovery, and enforcing a G2/M cell-cycle arrest. Furthermore, ATR prevents excessive cleavage of reversed forks by MUS81, revealing a MUS81-triggered and ATR-mediated feedback loop that fine-tunes MUS81 activity at replication forks. These results suggest that ATR is a key sensor and suppressor of R loop-induced genomic instability, uncovering a signaling circuitry that safeguards the genome against R loops. SN - 1097-4164 UR - https://www.unboundmedicine.com/medline/citation/31708417/ATR_Protects_the_Genome_against_R_Loops_through_a_MUS81-Triggered_Feedback_Loop L2 - https://linkinghub.elsevier.com/retrieve/pii/S1097-2765(19)30770-1 DB - PRIME DP - Unbound Medicine ER -