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| Status |
Public on Mar 09, 2021 |
| Title |
Cornelia-de-Lange syndrome associated mutations cause a DNA damage signalling and repair defect |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
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-enhancer interaction in mouse embryonic stem cells, it does not affect transcription. Rather it delays the cell cycle, increased 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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| Overall design |
Examination of Y430C BRD4 mutation in mESCs. Two cell lines were used, a wild type one (WT) and CRISPR-Cas9 generated Y430C mutant one (MUT)
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| Contributor(s) |
Olley G, Madapura PM, FitzPatrick DR, Bickmore WA, Boumendil C |
| Citation(s) |
34035299 |
| Submission date |
May 03, 2019 |
| Last update date |
Jun 09, 2021 |
| Contact name |
Ilya M. Flyamer |
| E-mail(s) |
flyamer@gmail.com
|
| Organization name |
University of Edinburgh
|
| Department |
IGMM, HGU
|
| Lab |
Bickmore
|
| Street address |
Crewe Road, Western General Hospital
|
| City |
Edinburgh |
| ZIP/Postal code |
EH4 2GH |
| Country |
United Kingdom |
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| Platforms (1) |
| GPL21103 |
Illumina HiSeq 4000 (Mus musculus) |
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| Samples (18)
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| Relations |
| BioProject |
PRJNA540927 |
| SRA |
SRP194726 |
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