Cornelia-de Lange syndrome-associated mutations cause a DNA damage signalling and repair defect

Gabrielle Olley, Madapura M. Pradeepa, Graeme R. Grimes, Sandra Piquet, Sophie E Polo, David R FitzPatrick, Wendy A Bickmore*, Charlene Boumendil*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Cornelia de Lange syndrome is a multisystem developmental disorder typically caused by mutations in the gene encoding the cohesin loader NIPBL. The associated phenotype is generally assumed to be the consequence of aberrant transcriptional regulation. Recently, we identified a missense mutation in BRD4 associated with a Cornelia de Lange-like syndrome that reduces BRD4 binding to acetylated histones. Here we show that, although this mutation reduces BRD4-occupancy at enhancers it does not affect transcription of the pluripotency network in mouse embryonic stem cells. Rather, it delays the cell cycle, increases DNA damage signalling, and perturbs regulation of DNA repair in mutant cells. This uncovers a role for BRD4 in DNA repair pathway choice. Furthermore, we find evidence of a similar increase in DNA damage signalling in cells derived from NIPBL-deficient individuals, suggesting that defective DNA damage signalling and repair is also a feature of typical Cornelia de Lange syndrome.
Original languageEnglish
Pages (from-to)3127
JournalNature Communications
DOIs
Publication statusPublished - 25 May 2021

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