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EMBO J. 2017 May 2;36(9):1182-1198. doi: 10.15252/embj.201695131. Epub 2017 Mar 17.

An ATR-dependent function for the Ddx19 RNA helicase in nuclear R-loop metabolism.

Author information

1
Genome Surveillance and Stability Laboratory, Institute of Human Genetics, UMR9002, CNRS-UM, University of Montpellier, Montpellier Cedex 5, France.
2
Genomics and Health Laboratory, Biology Department, Faculty of Sciences, R. Hariri Campus, Lebanese University, Hadath, Lebanon.
3
Genome Surveillance and Stability Laboratory, Institute of Human Genetics, UMR9002, CNRS-UM, University of Montpellier, Montpellier Cedex 5, France domenico.maiorano@igh.cnrs.fr.

Abstract

Coordination between transcription and replication is crucial in the maintenance of genome integrity. Disturbance of these processes leads to accumulation of aberrant DNA:RNA hybrids (R-loops) that, if unresolved, generate DNA damage and genomic instability. Here we report a novel, unexpected role for the nucleopore-associated mRNA export factor Ddx19 in removing nuclear R-loops formed upon replication stress or DNA damage. We show, in live cells, that Ddx19 transiently relocalizes from the nucleopore to the nucleus upon DNA damage, in an ATR/Chk1-dependent manner, and that Ddx19 nuclear relocalization is required to clear R-loops. Ddx19 depletion induces R-loop accumulation, proliferation-dependent DNA damage and defects in replication fork progression. Further, we show that Ddx19 resolves R-loops in vitro via its helicase activity. Furthermore, mutation of a residue phosphorylated by Chk1 in Ddx19 disrupts its interaction with Nup214 and allows its nuclear relocalization. Finally, we show that Ddx19 operates in resolving R-loops independently of the RNA helicase senataxin. Altogether these observations put forward a novel, ATR-dependent function for Ddx19 in R-loop metabolism to preserve genome integrity in mammalian cells.

KEYWORDS:

Xenopus ; Chk1; DNA damage; camptothecin; replication stress

PMID:
28314779
PMCID:
PMC5412905
DOI:
10.15252/embj.201695131
[Indexed for MEDLINE]
Free PMC Article

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