An atr‐dependent function for the ddx19 rna helicase in nuclear r‐loop metabolism
Hodroj, Dana Recolin, Bénédicte Serhal, Kamar Martinez, Susan Tsanov, Nikolay Abou Merhi, Raghida Maiorano, Domenico
Hodroj, Dana
Recolin, Bénédicte
Serhal, Kamar
Martinez, Susan
Tsanov, Nikolay
Abou Merhi, Raghida
Maiorano, Domenico
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Publication Date
2017-03-17
Type
Article
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Citation
Hodroj, Dana; Recolin, Bénédicte; Serhal, Kamar; Martinez, Susan; Tsanov, Nikolay; Abou Merhi, Raghida; Maiorano, Domenico (2017). An atr‐dependent function for the ddx19 rna helicase in nuclear r‐loop metabolism. The EMBO Journal 36 (9), 1182-1198
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.
Funder
Publisher
EMBO
Publisher DOI
10.15252/embj.201695131
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Attribution-NonCommercial-NoDerivs 3.0 Ireland