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

Gabrielle Olley, Madapura M. Pradeepa, David R. FitzPatrick, Wendy A. Bickmore, Charlene Boumendil

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Received Date: 10th June 19

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 residue substitution 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 in mouse embryonic stem cells, it does not affect transcription. Rather it delays the cell cycle, increases DNA damage signalling, and perturbs regulation of DNA repair in mutant cells. This uncovers a new 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.

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This is an abstract of a preprint hosted on an independent third party site. It has not been peer reviewed but is currently under consideration at Nature Communications.

Nature Communications

Nature Research, Springer Nature