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Oral-Facial-Digital syndrome Type I cells exhibit impaired DNA repair; unanticipated consequences of defective OFD1 outside of the cilia network
journal contribution
posted on 2023-06-09, 04:28 authored by Iga Abramowicz, Gillian Carpenter, Mariaevelina Alfieri, Rita Colnaghi, Emily OutwinEmily Outwin, Philippe Parent, Christel Thauvin-Robinet, Daniela Iaconis, Brunella Franco, Mark O'DriscollMark O'DriscollDefects in OFD1 underlie the clinically complex ciliopathy, Oral-Facial-Digital syndrome Type I (OFD Type I). Our understanding of the molecular, cellular and clinical consequences of impaired OFD1 originate from its characterised roles at the centrosome/basal body/cilia network. Nonetheless, the first described OFD1 interactors were components of the TIP60 histone acetyltransferase complex. We find that OFD1 can also localise to chromatin and its reduced expression is associated with mislocalization of TIP60 in patient-derived cell lines. TIP60 plays important roles in controlling DNA repair. OFD Type I cells exhibit reduced histone acetylation and altered chromatin dynamics in response to DNA double strand breaks (DSBs). Furthermore, reduced OFD1 impaired DSB repair via homologous recombination repair (HRR). OFD1 loss also adversely impacted upon the DSB-induced G2-M checkpoint, inducing a hypersensitive and prolonged arrest. Our findings show that OFD Type I patient cells have pronounced defects in the DSB-induced histone modification, chromatin remodelling and DSB-repair via HRR; effectively phenocopying loss of TIP60. These data extend our knowledge of the molecular and cellular consequences of impaired OFD1, demonstrating that loss of OFD1 can negatively impact upon important nuclear events; chromatin plasticity and DNA repair.
History
Publication status
- Published
File Version
- Accepted version
Journal
Human Molecular GeneticsISSN
0964-6906Publisher
Oxford University PressExternal DOI
Issue
1Volume
26Page range
19-32Department affiliated with
- Sussex Centre for Genome Damage Stability Publications
Research groups affiliated with
- Genome Damage and Stability Centre Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2016-12-19First Open Access (FOA) Date
2017-10-26First Compliant Deposit (FCD) Date
2016-12-19Usage metrics
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