Marion Aguirrebengoa

Université de Toulouse

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Didier Trouche

Centre National de la Recherche Scientifique

Philipp Kapranov

Xiamen University

Jean‐Yves Thuret

Université Paris-Saclay

Claire Rougeulle

Epigénétique et Destin Cellulaire

Carl Mann

Medical University of Vienna

Nadine Puget

Université de Toulouse

Sébastien Briois

Université Toulouse III - Paul Sabatier

Estelle Nicolas

Santa Lucía University General Hospital

Gaëlle Legube

Université de Toulouse

Thomas Clouaire

Université de Toulouse

Cooperative Institutions

Centre National de la Recherche Scientifique

Université de Toulouse

Université Toulouse III - Paul Sabatier

Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération

Centre de Biologie du Développement

Inserm

Université de Montpellier

National Institutes of Health

Institut Curie

Institut de Génétique Humaine

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

Nature Communications (2018)

S. Cohen Nadine Puget Yea‐Lih Lin Thomas Clouaire Marion Aguirrebengoa

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.

RNA Helicase A

10.1038/s41467-018-02894-w

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Citations (296)

Erratum: A vlincRNA participates in senescence maintenance by relieving H2AZ-mediated repression at the INK4 locus

Nature Communications (2015)

Sandra Lazorthes Céline Vallot Sébastien Briois Marion Aguirrebengoa Jean‐Yves Thuret

Nature Communications 6: Article number: 5971 (2015); Published 20 January 2015; Updated 8 April 2015. Didier Trouche and Estelle Nicolas were inadvertently listed as equally contributing authors in this Article. Both authors jointly supervised the work.

Senescence

10.1038/ncomms7918

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A POLD3/BLM dependent pathway handles DSBs in transcribed chromatin upon excessive RNA:DNA hybrid accumulation

Nature Communications (2022)

S. Cohen Aude Guénolé Ikrame Lazar Aline Marnef Thomas Clouaire

Abstract Transcriptionally active loci are particularly prone to breakage and mounting evidence suggests that DNA Double-Strand Breaks arising in active genes are handled by a dedicated repair pathway, Transcription-Coupled DSB Repair (TC-DSBR), that entails R-loop accumulation and dissolution. Here, we uncover a function for the Bloom RecQ DNA helicase (BLM) in TC-DSBR in human cells. BLM is recruited in a transcription dependent-manner at DSBs where it fosters resection, RAD51 binding and accurate Homologous Recombination repair. However, in an R-loop dissolution-deficient background, we find that BLM promotes cell death. We report that upon excessive RNA:DNA hybrid accumulation, DNA synthesis is enhanced at DSBs, in a manner that depends on BLM and POLD3. Altogether our work unveils a role for BLM at DSBs in active chromatin, and highlights the toxic potential of RNA:DNA hybrids that accumulate at transcription-associated DSBs.

Transcription

10.1038/s41467-022-29629-2

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A vlincRNA participates in senescence maintenance by relieving H2AZ-mediated repression at the INK4 locus

Nature Communications (2015)

Sandra Lazorthes Céline Vallot Sébastien Briois Marion Aguirrebengoa Jean‐Yves Thuret

Abstract Non-coding RNAs (ncRNAs) play major roles in proper chromatin organization and function. Senescence, a strong anti-proliferative process and a major anticancer barrier, is associated with dramatic chromatin reorganization in heterochromatin foci. Here we analyze strand-specific transcriptome changes during oncogene-induced human senescence. Strikingly, while differentially expressed RNAs are mostly repressed during senescence, ncRNAs belonging to the recently described vlincRNA (very long intergenic ncRNA) class are mainly activated. We show that VAD , a novel antisense vlincRNA strongly induced during senescence, is required for the maintenance of senescence features. VAD modulates chromatin structure in cis and activates gene expression in trans at the INK4 locus, which encodes cell cycle inhibitors important for senescence-associated cell proliferation arrest. Importantly, VAD inhibits the incorporation of the repressive histone variant H2A.Z at INK4 gene promoters in senescent cells. Our data underline the importance of vlincRNAs as sensors of cellular environment changes and as mediators of the correct transcriptional response.

Senescence

10.1038/ncomms6971

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Citations (59)

The histone demethylase JMJD2A/KDM4A links ribosomal RNA transcription to nutrients and growth factors availability

Nature Communications (2016)

Kader Salifou Swagat Ray Laure Verrier Marion Aguirrebengoa Didier Trouche

Abstract The interplay between methylation and demethylation of histone lysine residues is an essential component of gene expression regulation and there is considerable interest in elucidating the roles of proteins involved. Here we report that histone demethylase KDM4A/JMJD2A, which is involved in the regulation of cell proliferation and is overexpressed in some cancers, interacts with RNA Polymerase I, associates with active ribosomal RNA genes and is required for serum-induced activation of rDNA transcription. We propose that KDM4A controls the initial stages of transition from ‘poised’, non-transcribed rDNA chromatin into its active form. We show that PI3K, a major signalling transducer central for cell proliferation and survival, controls cellular localization of KDM4A and consequently its association with ribosomal DNA through the SGK1 downstream kinase. We propose that the interplay between PI3K/SGK1 signalling cascade and KDM4A constitutes a mechanism by which cells adapt ribosome biogenesis level to the availability of growth factors and nutrients.

Demethylase

ribosome biogenesis

Histone Methylation

RNA polymerase II

RNA polymerase I

Transcription

10.1038/ncomms10174

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Citations (38)