Journal Article

DNA damage responses protect xeroderma pigmentosum variant from UVC-induced clastogenesis

Marila Cordeiro-Stone, Alexandra Frank, Miriam Bryant, Ikechukwu Oguejiofor, Stephanie B. Hatch, Lisa D. McDaniel and William K. Kaufmann

in Carcinogenesis

Volume 23, issue 6, pages 959-966
Published in print June 2002 | ISSN: 0143-3334
Published online June 2002 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/23.6.959
DNA damage responses protect xeroderma pigmentosum variant from UVC-induced clastogenesis

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Lack of DNA polymerase η 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 (≤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.

Keywords: hTERT, human telomerase; NHF, normal human fibroblasts; UV, ultraviolet light; XP-V, xeroderma pigmentosum variant.

Journal Article.  6304 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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