Characteristics of UV-induced Mutation Spectra in Human XP-D/ERCC2 Gene-mutated Xeroderma Pigmentosum and Trichothiodystrophy Cells
Abstract
To study the relationships between mutagenesis and carcinogenesis, we compared the mutations and their frequency induced by ultraviolet irradiation at 254 nm (UV-C) in XP-D (GM-08207B/XP6BE), TTD/XP-D (TTD1VI-LAS-KMT11) and wild-type (MRC-5V1) human cells. XP-D and TTD/XP-D cells, mutated in the same XP-D/ERCC2 gene, are deficient in nucleotide excision repair. Whereas XP-D patients develop early skin tumors, TTD patients do not exhibit abnormal levels of cancers. After verification of UV hypersensitivity and DNA repair defect of the immortalized cell lines XP-D and TTD compared with a wild-type cell line, UV-induced mutagenesis was studied with a new shuttle vector pR2, carrying the target lacZ' gene. The UV-mutation frequencies in XP-D and TTD cells were similar and significantly increased compared with normal cells. Sequence analysis of 312 independent mutant plasmids revealed that more rearrangements were induced in TTD cells (16%) than in XP-D (5%) and normal cells (1%), while XP-D cells exhibited a twofold higher rate of tandem mutations compared with TTD and normal cells. In the three cell lines, a predominance of G:C to A:T transitions was found, especially in chiefly on the cytosine at 5'-TC-3' sites. The types of UV-induced point mutations in TTD cells were, however, more similar to those in normal cells than those found in XP-D cells. XP-D mutations were preferentially located in 5'-TCPur-3' sites, while mutations in normal and TTD cells were mostly at 5'-TCC-3' sites. Analysis of mutation spectra revealed differences in the location of the mutational hotspots between the three lines. Although the mutation frequency of the UV-irradiated pR2 vector is much higher in TTD and XP-D cells than in normal cells, the mutation spectrum is closer between TTD and normal cells as compared with XP-D cells. These dissimilarities could contribute to an explanation of some of the differences between the two syndromes.
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TCC to T dominated the mutational spectra of single genes isolated from UV-irradiated cell cultures.
“In the mid-1990s, Drobetsky et al. (29) and Marionnet et al. (30) observed that TCC → T dominated the mutational spectra of single genes isolated from UV-irradiated cell cultures.”
From Evidence for recent, population-specific evolution of the human mutation rate (2015) · cites this paper as [30]
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- Authors
- Marionnet, C., Benoit, A., Benhamou, S., Sarasin, A., & Stary, A.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Sarasin, Alain
- Venue
- Journal of Molecular Biology
- Publisher
- Elsevier BV
- Published
- 1995-10
- Volume
- 252
- Issue
- 5
- Pages
- 550-562
- ISSN
- 0022-2836 (ISSN-L)
- OpenAlex
- W1989931721
- Cited by
- 31
- References
- 0
- Citations by year
- 2022: 1 · 2016: 1 · 2015: 1 · 2014: 1
- FWCI
- 0.74
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Ligue Contre le Cancer
- Centre National de la Recherche Scientifique
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Carcinogens and Genotoxicity Assessment
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Keywords
- xeroderma pigmentosum, trichothiodystrophy, UV mutagenesis, mutation spectrum, nucleotide excision repair deficiency, UV hypersensitivity, mutational hotspots, G:C to A:T transitions, carcinogenesis, DNA repair
- MeSH terms
- Amino Acid Sequence, Base Sequence, Cell Line, Cell Line, Transformed, Cell Survival, DNA Repair, Fibroblasts, Genetic Vectors, Hair Diseases, Humans, Lac Operon, Molecular Sequence Data, Mutation, Ultraviolet Rays, Xeroderma Pigmentosum, Mutagenesis, Point Mutation
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