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Hypomorphic PCNA mutation underlies a novel human DNA repair disorder
journal contribution
posted on 2023-06-09, 14:35 authored by Emma L Baple, Helen Chambers, Harold E Cross, Heather Fawcett, Yuka Nakazawa, Barry A Chioza, Gaurav V Harlalka, Sahar Mansour, Ajith Sreekantan-Nair, Michael A Patton, Martina Muggenthaler, Phillip Rich, Karin Wagner, Roselyn Coblentz, Constance K Stein, James I Last, A Malcolm R Taylor, Andrew P Jackson, Tomoo Ogi, Alan LehmannAlan Lehmann, Catherine M Green, Andrew H CrosbyA number of human disorders, including Cockayne syndrome, UV-sensitive syndrome, xeroderma pigmentosum and trichothiodystrophy, result from the mutation of genes encoding molecules important for nucleotide excision repair. Here, we describe a novel syndrome in which the cardinal clinical features include postnatal growth retardation, hearing loss, premature aging, telangiectasia, neurological signs and photosensitivity, resulting from a homozygous missense (p.Ser228Ile) sequence alteration of the proliferating cell nuclear antigen (PCNA). PCNA is a highly conserved sliding clamp protein essential for DNA replication and repair. Due to this fundamental role, mutations in PCNA that profoundly impair protein function would be incompatible with life. Interestingly, while the p.Ser228Ile alteration appears to have no effect on protein levels or DNA replication, patient cells exhibit significant abnormalities in response to UV irradiation displaying substantial reductions in both UV survival and RNA synthesis recovery. The p.Ser228Ile change also profoundly alters PCNA’s interaction with Flap endonuclease 1 and DNA Ligase 1, DNA metabolism enzymes. Taken together our findings detail the first mutation of PCNA in humans, associated with a unique neurodegenerative disease displaying clinical and molecular features common to other DNA repair disorders, which we show to be attributable to a hypomorphic amino acid alteration.
History
Publication status
- Published
File Version
- Accepted version
Journal
Journal of Clinical InvestigationISSN
0021-9738Publisher
American Society for Clinical InvestigationExternal DOI
Issue
7Volume
124Page range
3137-3146Department affiliated with
- Sussex Centre for Genome Damage Stability Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2018-08-16First Open Access (FOA) Date
2018-08-16First Compliant Deposit (FCD) Date
2018-08-15Usage metrics
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