Hypomorphic PCNA mutation underlies a human DNA repair disorder
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 sh...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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American Society for Clinical Investigation
2014
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| _version_ | 1826274476949504000 |
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| author | Baple, E Chambers, H Cross, H Fawcett, H Nakazawa, Y Chioza, B Harlalka, G Mansour, S Sreekantan-Nair, A Patton, M Muggenthaler, M Rich, P Wagner, K Coblentz, R Stein, C Last, J Taylor, A Jackson, A Ogi, T Lehmann, A Green, C Crosby, A |
| author_facet | Baple, E Chambers, H Cross, H Fawcett, H Nakazawa, Y Chioza, B Harlalka, G Mansour, S Sreekantan-Nair, A Patton, M Muggenthaler, M Rich, P Wagner, K Coblentz, R Stein, C Last, J Taylor, A Jackson, A Ogi, T Lehmann, A Green, C Crosby, A |
| author_sort | Baple, E |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-06T22:44:01Z |
| format | Journal article |
| id | oxford-uuid:5c8b0844-487a-4f79-a88b-2e0ee1f7696b |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T22:44:01Z |
| publishDate | 2014 |
| publisher | American Society for Clinical Investigation |
| record_format | dspace |
| spelling | oxford-uuid:5c8b0844-487a-4f79-a88b-2e0ee1f7696b2022-03-26T17:28:52ZHypomorphic PCNA mutation underlies a human DNA repair disorderJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:5c8b0844-487a-4f79-a88b-2e0ee1f7696bEnglishSymplectic Elements at OxfordAmerican Society for Clinical Investigation2014Baple, EChambers, HCross, HFawcett, HNakazawa, YChioza, BHarlalka, GMansour, SSreekantan-Nair, APatton, MMuggenthaler, MRich, PWagner, KCoblentz, RStein, CLast, JTaylor, AJackson, AOgi, TLehmann, AGreen, CCrosby, ANumerous 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. |
| spellingShingle | Baple, E Chambers, H Cross, H Fawcett, H Nakazawa, Y Chioza, B Harlalka, G Mansour, S Sreekantan-Nair, A Patton, M Muggenthaler, M Rich, P Wagner, K Coblentz, R Stein, C Last, J Taylor, A Jackson, A Ogi, T Lehmann, A Green, C Crosby, A Hypomorphic PCNA mutation underlies a human DNA repair disorder |
| title | Hypomorphic PCNA mutation underlies a human DNA repair disorder |
| title_full | Hypomorphic PCNA mutation underlies a human DNA repair disorder |
| title_fullStr | Hypomorphic PCNA mutation underlies a human DNA repair disorder |
| title_full_unstemmed | Hypomorphic PCNA mutation underlies a human DNA repair disorder |
| title_short | Hypomorphic PCNA mutation underlies a human DNA repair disorder |
| title_sort | hypomorphic pcna mutation underlies a human dna repair disorder |
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