Hypomorphic PCNA mutation underlies a human DNA repair disorder

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 R. Lehmann & 2 others Catherine M. Green, Andrew H. Crosby

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Numerous 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 syndrome in which the cardinal clinical features include short stature, hearing loss, premature aging, telangiectasia, neurodegeneration, 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 appeared to have no effect on protein levels or DNA replication, patient cells exhibited marked abnormalities in response to UV irradiation, displaying substantial reductions in both UV survival and RNA synthesis recovery. The p.Ser228Ile change also profoundly altered PCNA's interaction with Flap endonuclease 1 and DNA Ligase 1, DNA metabolism enzymes. Together, our findings detail a mutation of PCNA in humans associated with a neurodegenerative phenotype, displaying clinical and molecular features common to other DNA repair disorders, which we showed to be attributable to a hypomorphic amino acid alteration.

Original languageEnglish (US)
Pages (from-to)3137-3146
Number of pages10
JournalJournal of Clinical Investigation
Volume124
Issue number7
DOIs
StatePublished - Jul 1 2014

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Proliferating Cell Nuclear Antigen
DNA Repair
Mutation
DNA Replication
Trichothiodystrophy Syndromes
Flap Endonucleases
Cockayne Syndrome
DNA Ligases
Premature Aging
Xeroderma Pigmentosum
Telangiectasis
Proteins
Hearing Loss
RNA
Phenotype
Amino Acids
Survival
DNA
Enzymes
Genes

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Baple, E. L., Chambers, H., Cross, H. E., Fawcett, H., Nakazawa, Y., Chioza, B. A., ... Crosby, A. H. (2014). Hypomorphic PCNA mutation underlies a human DNA repair disorder. Journal of Clinical Investigation, 124(7), 3137-3146. https://doi.org/10.1172/JCI74593

Hypomorphic PCNA mutation underlies a human DNA repair disorder. / Baple, Emma L.; Chambers, Helen; Cross, Harold E; Fawcett, Heather; Nakazawa, Yuka; Chioza, Barry A.; Harlalka, Gaurav V.; Mansour, Sahar; Sreekantan-Nair, Ajith; Patton, Michael A.; Muggenthaler, Martina; Rich, Phillip; Wagner, Karin; Coblentz, Roselyn; Stein, Constance K.; Last, James I.; Taylor, A. Malcolm R; Jackson, Andrew P.; Ogi, Tomoo; Lehmann, Alan R.; Green, Catherine M.; Crosby, Andrew H.

In: Journal of Clinical Investigation, Vol. 124, No. 7, 01.07.2014, p. 3137-3146.

Research output: Contribution to journalArticle

Baple, EL, Chambers, H, Cross, HE, Fawcett, H, Nakazawa, Y, Chioza, BA, Harlalka, GV, Mansour, S, Sreekantan-Nair, A, Patton, MA, Muggenthaler, M, Rich, P, Wagner, K, Coblentz, R, Stein, CK, Last, JI, Taylor, AMR, Jackson, AP, Ogi, T, Lehmann, AR, Green, CM & Crosby, AH 2014, 'Hypomorphic PCNA mutation underlies a human DNA repair disorder', Journal of Clinical Investigation, vol. 124, no. 7, pp. 3137-3146. https://doi.org/10.1172/JCI74593
Baple EL, Chambers H, Cross HE, Fawcett H, Nakazawa Y, Chioza BA et al. Hypomorphic PCNA mutation underlies a human DNA repair disorder. Journal of Clinical Investigation. 2014 Jul 1;124(7):3137-3146. https://doi.org/10.1172/JCI74593
Baple, Emma L. ; Chambers, Helen ; Cross, Harold E ; Fawcett, Heather ; Nakazawa, Yuka ; Chioza, Barry A. ; Harlalka, Gaurav V. ; Mansour, Sahar ; Sreekantan-Nair, Ajith ; Patton, Michael A. ; Muggenthaler, Martina ; Rich, Phillip ; Wagner, Karin ; Coblentz, Roselyn ; Stein, Constance K. ; Last, James I. ; Taylor, A. Malcolm R ; Jackson, Andrew P. ; Ogi, Tomoo ; Lehmann, Alan R. ; Green, Catherine M. ; Crosby, Andrew H. / Hypomorphic PCNA mutation underlies a human DNA repair disorder. In: Journal of Clinical Investigation. 2014 ; Vol. 124, No. 7. pp. 3137-3146.
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