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Mol Cell. 2020 Feb 6;77(3):514-527.e4. doi: 10.1016/j.molcel.2019.10.010. Epub 2019 Nov 7.

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

Author information

1
Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
2
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.

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.

KEYWORDS:

ATR; Chk1; Fork reversal; Genomic Instability; MUS81; R loop; checkpoint

PMID:
31708417
PMCID:
PMC7007873
[Available on 2021-02-06]
DOI:
10.1016/j.molcel.2019.10.010

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