DNA damage responses protect xeroderma pigmentosum variant from UVC-induced clastogenesis
Autor: | Marila Cordeiro-Stone, Lisa D. McDaniel, Miriam F. Bryant, William K. Kaufmann, Stephanie B. Hatch, Ikechukwu Oguejiofor, Alexandra R. Frank |
---|---|
Rok vydání: | 2002 |
Předmět: |
Cancer Research
Xeroderma pigmentosum Carcinogenicity Tests Ultraviolet Rays DNA polymerase DNA damage Pyrimidine dimer Polymerase Chain Reaction Cell Line S Phase Fetus Reference Values Ultraviolet light Postreplication repair medicine Humans Lung Telomerase Mitosis Chromosome Aberrations Genetics Xeroderma Pigmentosum biology Mutagenesis Genetic Variation DNA General Medicine medicine.disease Molecular biology Cell Transformation Neoplastic Karyotyping biology.protein DNA Damage |
Zdroj: | Carcinogenesis. 23:959-966 |
ISSN: | 1460-2180 0143-3334 |
Popis: | Lack of DNA polymerase eta and the attendant defect in bypass replication of pyrimidine dimers induced in DNA by ultraviolet light (UV) underlie the enhanced mutagenesis and carcinogenesis observed in xeroderma pigmentosum variant (XP-V). We investigated whether diploid XP-V fibroblasts growing in culture are also more susceptible to UV-induced clastogenesis than normal human fibroblasts (NHF). This study utilized diploid fibroblasts immortalized by the ectopic expression of human telomerase. The cell lines displayed checkpoint responses to DNA damage comparable with those measured in the parental strains. Shortly after exposure to low doses of UVC (or =4 J/m2), XP-V cells accumulated daughter strand gaps in excess of normal controls (25-fold). Daughter strand gaps generated in UV-irradiated S phase cells are potential precursors of chromatid-type chromosomal aberrations. Nonetheless, chromatid-type chromosomal aberrations were only 1.5 to 2 times more abundant in XP-V than in NHF exposed to the same UVC dose. XP-V cells, however, displayed S phase delays at lower doses of UVC and for longer periods of time than NHF. These results support the hypothesis that aberrant DNA structures activate S phase checkpoint responses that increase the time available for postreplication repair. Alternatively, cells that cannot be properly repaired remain permanently arrested and never reach mitosis. These responses protect human cells from chromosomal aberrations, especially when other pathways, such as accurate lesion bypass, are lost. |
Databáze: | OpenAIRE |
Externí odkaz: |