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Carcinogenesis, Vol. 23, No. 6, 959-966, June 2002
© 2002 Oxford University Press

CANCER BIOLOGY

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

Marila Cordeiro-Stone1,2,3,5, Alexandra Frank1, Miriam Bryant1, Ikechukwu Oguejiofor1, Stephanie B. Hatch1, Lisa D. McDaniel4 and William K. Kaufmann1,2,3

1 Department of Pathology and Laboratory Medicine,
2 Lineberger Comprehensive Cancer Center,
3 Center for Environmental Health and Susceptibility, University of NC at Chapel Hill, Chapel Hill, NC 27599–7525 and
4 McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390–8591, USA

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 (<=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.


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