Chromatin-associated MRN complex protects highly transcribing genes from genomic instability
Résumé
MRN-MDC1 plays a central role in the DNA damage response (DDR) and repair. Using proteomics of isolated chro-
matin fragments, we identified DDR factors, such as MDC1, among those highly associating with a genomic locus
upon transcriptional activation. Purification of MDC1 in the absence of exogenous DNA damage revealed interac-
tions with factors involved in gene expression and RNA processing, in addition to DDR factors. ChIP-seq showed
that MRN subunits, MRE11 and NBS1, colocalized throughout the genome, notably at TSSs and bodies of actively
transcribing genes, which was dependent on the RNAPII transcriptional complex rather than transcription per se.
Depletion of MRN increased RNAPII abundance at MRE11/NBS1-bound genes. Prolonged MRE11 or NBS1 deple-
tion induced single-nucleotide polymorphisms across actively transcribing MRN target genes. These data suggest
that association of MRN with the transcriptional machinery constitutively scans active genes for transcription-
induced DNA damage to preserve the integrity of the coding genome.
Domaines
Biologie moléculaire
Origine : Fichiers éditeurs autorisés sur une archive ouverte
Licence : CC BY NC - Paternité - Pas d'utilisation commerciale
Licence : CC BY NC - Paternité - Pas d'utilisation commerciale