RT Journal Article
SR Electronic
T1 Cornelia-de Lange syndrome-associated mutations cause a DNA damage signalling and repair defect
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 632992
DO 10.1101/632992
A1 Gabrielle Olley
A1 Madapura M. Pradeepa
A1 David R. FitzPatrick
A1 Wendy A. Bickmore
A1 Charlene Boumendil
YR 2019
UL http://biorxiv.org/content/early/2019/05/09/632992.abstract
AB 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.