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

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.

• Authors: Sarah Cohen, Nadine Puget, Yea-Lih Lin, Thomas Clouaire, Marion Aguirrebengoa, Vincent Rocher, Philippe Pasero, Yvan Canitrot, Gaëlle Legube
• Journal: Nature communications (Nat Commun) Vol. 9 Issue 1 Pg. 533 (02 07 2018) ISSN: 2041-1723 [Electronic] England
• PMID: 29416069 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Chromatin
• Multifunctional Enzymes
• RNA
• DNA
• SETX protein, human
• DNA Helicases
• RNA Helicases

Topics

• Cell Line, Tumor
• Cell Survival (genetics)
• Chromatin (genetics, metabolism)
• DNA (genetics, metabolism)
• DNA Breaks, Double-Stranded
• DNA Helicases
• DNA Repair
• Humans
• Multifunctional Enzymes
• RNA (genetics, metabolism)
• RNA Helicases (genetics, metabolism)
• RNA Interference
• Translocation, Genetic