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 () and Charlene Boumendil ()
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Gabrielle Olley: MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Crewe Road
Madapura M. Pradeepa: MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Crewe Road
Graeme R. Grimes: MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Crewe Road
Sandra Piquet: Epigenetics and Cell Fate Centre, UMR7216 CNRS, Université de Paris
Sophie E. Polo: Epigenetics and Cell Fate Centre, UMR7216 CNRS, Université de Paris
David R. FitzPatrick: MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Crewe Road
Wendy A. Bickmore: MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Crewe Road
Charlene Boumendil: MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Crewe Road

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-23500-6

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