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

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.

BETting on a Transcriptional Deficit as the Main Cause for Cornelia de Lange Syndrome

“…A theoretical possibility raised by the BRD4-NIPBL interplay that might be interesting to address is whether increasing levels of BRD4 could compensate to some extent a partial NIPBL deficiency by enhancing its stabilization on the chromatin. Interestingly, in this mouse model for the BRD4 mutation, despite the transcriptional perturbance observed in MEFs (Olley et al, 2018), the authors did not detect major alterations in the transcriptome in derived mESC (Olley et al, 2021). Instead, they report deficiencies in the regulation of DNA repair in these cells, which highlights the interest of further research on this alteration in additional models of CdLS.…”

“…However, this moderate reduction in the level of NIPBL is sufficient to provoke a global transcriptional dysregulation both in human samples Boudaoud et al, 2017;Mills et al, 2018) and mouse models (Kawauchi et al, 2009;Remeseiro et al, 2013;Muto et al, 2014). Interestingly, an effect on DNA repair through homologous recombination has also been appreciated (Vrouwe et al, 2007) and, very recently, alterations in the response to DNA damage were also reported in two lymphoblastoid cell lines derived from CdLS patients with heterozygous NIPBL mutations (Olley et al, 2021). However, no remarkable DNA repair defects were detected in Nipbl +/primary mouse embryonic fibroblasts (MEFs) (Remeseiro et al, 2013), so further research would be necessary to precise if this phenotype could be cell-type or NIPBL-level specific and to what extent it represents a global feature and underlying causative factor in the CdLS phenotypic spectrum.…”

Disruption of NIPBL/Scc2 in Cornelia de Lange Syndrome provokes cohesin genome-wide redistribution with an impact in the transcriptome

“…The molecular mechanisms of CdLS are not well understood, although the patient phenotypes suggest that the function of cohesin and NIPBL in chromatin structure becomes deregulated, thereby affecting gene transcription. Mutations in genes encoding chromatin regulators such as ANKRD11 15 , 16 , KMT2A 17 , AFF4 18 , and BRD4 19 , 20 are also associated with a CdLS-like disorder.…”

Cornelia de Lange Syndrome: From a Disease to a Broader Spectrum

“…Furthermore, Olley and colleagues showed that CdLS-associated variant in BRD4 delays the cell cycle by perturbing regulation of DNA repair and increasing DNA damage signaling. Similarly, NIPBL deficient cells derived from CdLS patients exhibited an increase in DNA damage response, suggesting the importance of this signaling in the etiology of CdLS [ 30 ]. In addition, the RNA-sequencing of patient specific NIPBL+/− iPSC lines identified an altered expression of many mRNAs, pseudogenes, and non-coding RNAs leading to upregulation of gene sets with functions in epigenetic control and downregulation of WNT pathway [ 31 ].…”