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

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.

DOI: 10.15252/embj.201695131

Cite this paper

@article{Hodroj2017AnAF, title={An ATR-dependent function for the Ddx19 RNA helicase in nuclear R-loop metabolism.}, author={Dana Hodroj and B{\'e}n{\'e}dicte Recolin and Kamar Serhal and Susan F Martinez and Nikolay Tsanov and Raghida Abou Merhi and Domenico Maiorano}, journal={The EMBO journal}, year={2017}, volume={36 9}, pages={1182-1198} }