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Hypomorphic PCNA mutation underlies a novel human DNA repair disorder

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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 Crosby
A 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 Investigation

ISSN

0021-9738

Publisher

American Society for Clinical Investigation

Issue

7

Volume

124

Page range

3137-3146

Department affiliated with

  • Sussex Centre for Genome Damage Stability Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2018-08-16

First Open Access (FOA) Date

2018-08-16

First Compliant Deposit (FCD) Date

2018-08-15

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