Senataxin resolves RNA:DNA hybrids forming at DNA double-strand breaks to prevent translocations

Sarah Cohen, Nadine Puget, Yea-Lih Lin, Thomas Clouaire, Marion Aguirrebengoa, Vincent Rocher, Philippe Pasero, Yvan Canitrot and Gaëlle Legube ()
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Sarah Cohen: Université de Toulouse
Nadine Puget: Université de Toulouse
Yea-Lih Lin: Université de Montpellier
Thomas Clouaire: Université de Toulouse
Marion Aguirrebengoa: Université de Toulouse
Vincent Rocher: Université de Toulouse
Philippe Pasero: Université de Montpellier
Yvan Canitrot: Université de Toulouse
Gaëlle Legube: Université de Toulouse

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: Abstract Ataxia with oculomotor apraxia 2 (AOA-2) and amyotrophic lateral sclerosis (ALS4) are neurological disorders caused by mutations in the gene encoding for senataxin (SETX), a putative RNA:DNA helicase involved in transcription and in the maintenance of genome integrity. Here, using ChIP followed by high throughput sequencing (ChIP-seq), we report that senataxin is recruited at DNA double-strand breaks (DSBs) when they occur in transcriptionally active loci. Genome-wide mapping unveiled that RNA:DNA hybrids accumulate on DSB-flanking chromatin but display a narrow, DSB-induced, depletion near DNA ends coinciding with senataxin binding. Although neither required for resection nor for timely repair of DSBs, senataxin was found to promote Rad51 recruitment, to minimize illegitimate rejoining of distant DNA ends and to sustain cell viability following DSB production in active genes. Our data suggest that senataxin functions at DSBs in order to limit translocations and ensure cell viability, providing new insights on AOA2/ALS4 neuropathies.

Date: 2018
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DOI: 10.1038/s41467-018-02894-w

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