Novel XPG ( ERCC5 ) Mutations Affect DNA Repair and Cell Survival after Ultraviolet but not Oxidative Stress
Open accessAbstract
Nucleotide excision repair (NER) is the most flexible of all known DNA-repair mechanisms, and XPG is a 3'-endonuclease that participates in NER. Mutations in this gene (ERCC5) may result in the human syndrome xeroderma pigmentosum (XP) and, in some cases, in the complex phenotype of Cockayne syndrome (CS). Two Brazilian XP siblings, who were mildly affected, were investigated and classified into the XP-G group. The cells from these patients were highly ultraviolet (UV) sensitive but not sensitive to photosensitized methylene blue, an agent that causes oxidative stress. This phenotype is in contrast to XP-G/CS cells, which are highly sensitive to this oxidative agent. Sequencing revealed a compound heterozygous genotype with two novel missense mutations: c.83C>A (p.Ala28Asp) and c.2904G>C (p.Trp968Cys). The first mutation maps to the catalytic site of the XPG protein, whereas the second may compromise binding to DNA. Functional assays indicated that the mutated alleles were unable to perform the complete repair of UV-irradiated plasmids; however, full correction was observed for oxidatively damaged plasmids. Therefore, the XP phenotype of these patients is caused by novel missense mutations that specifically affect DNA repair for UV- but not oxidative-stress-induced DNA damage, and implications for XP versus XP/CS phenotype are discussed.
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The XP phenotype may arise from missense mutations in the XPG gene that generally result in a stable XPG protein, whereas XP/CS originates from mutations that result in a truncated and/or unstable XPG protein.
“These observations suggest that the XP phenotype may arise from missense mutations in the XPG gene that generally result in a stable XPG protein, whereas XP/CS originates from mutations that result in a truncated and/or unstable XPG protein [238][239][240].”
From Sunlight damage to cellular DNA: focus on oxidatively generated lesions (2017) · cites this paper as [238]
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- Authors
- Soltys, D. T., Rocha, C. R. R., Lerner, L. K., de Souza, T. A., Munford, V., Cabral, F., Nardo, T., Stefanini, M., Sarasin, A., Cabral‐Neto, J. B., & Menck, C. F. M.
- Affiliations
- Universidade de São Paulo (BR)
- Department of Microbiology, Institute of Biomedical Sciences University of São Paulo São Paulo SP Brazil
- Universidade Federal do Rio de Janeiro (BR)
- Istituto di Genetica Molecolare Consiglio Nazionale delle Ricerche Pavia Italy
- Istituto di Genetica Molecolare (IT)
- Centre National de la Recherche Scientifique (FR)
- Instituto de Biofísica Carlos Chagas Filho Federal University of Rio de Janeiro Rio de Janeiro RJ Brazil
- Corresponding author
- Menck, Carlos F. M.
- ORCID
- Venue
- Human Mutation
- Publisher
- Hindawi Limited
- Published
- 2013-03
- Volume
- 34
- Issue
- 3
- Pages
- 481-489
- ISSN
- 1059-7794 (ISSN-L)
- 1098-1004
- OpenAlex
- W2112970145
- Cited by
- 48
- References
- 46
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 1 · 2022: 2 · 2021: 4 · 2020: 7 · 2019: 7 · 2018: 4 · 2017: 1 · 2016: 3 · 2015: 7 · 2014: 5 · 2013: 4
- FWCI
- 2.05
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Human Mutation (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Agence Nationale de la Recherche
- Fundação de Amparo à Pesquisa do Estado de São Paulo
- Conselho Nacional de Desenvolvimento Científico e Tecnológico
- Associazione Italiana per la Ricerca sul Cancro
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and rare skin diseases.
- Keywords
- XPG, ERCC5, nucleotide excision repair, xeroderma pigmentosum, Cockayne syndrome, missense mutations, UV-induced DNA damage, oxidative DNA damage, compound heterozygosity, catalytic site, DNA repair deficiency, cell survival
- MeSH terms
- DNA Excision Repair Protein ERCC-5, Adolescent, Alleles, Amino Acid Sequence, Brazil, Cell Line, Cell Survival, Cloning, Molecular, Cockayne Syndrome, DNA Damage, DNA Repair, DNA-Binding Proteins, Endonucleases, Female, Fibroblasts, Heterozygote, Humans, Male, Molecular Sequence Data, Nuclear Proteins, Phenotype, Protein Conformation, Transcription Factors, Ultraviolet Rays, Xeroderma Pigmentosum, Sequence Alignment, Sequence Analysis, DNA, Oxidative Stress, Mutation, Missense, Young Adult
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