Chromatin-associated MRN complex protects highly transcribing genes from genomic instability.

Science advances 2021 May

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MRN-MDC1 plays a central role in the DNA damage response (DDR) and repair. Using proteomics of isolated chromatin 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 interactions 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 depletion 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. Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

Citation

Kader Salifou, Callum Burnard, Poornima Basavarajaiah, Giuseppa Grasso, Marion Helsmoortel, Victor Mac, David Depierre, Céline Franckhauser, Emmanuelle Beyne, Xavier Contreras, Jérôme Dejardin, Sylvie Rouquier, Olivier Cuvier, Rosemary Kiernan. Chromatin-associated MRN complex protects highly transcribing genes from genomic instability. Science advances. 2021 May;7(21)