DNA damage responses protect xeroderma pigmentosum variant from UVC-induced clastogenesis.
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.
Cordeiro-Stone
Marila
M
Department of Pathology and Laboratory Medicine, University of NC at Chapel Hill, Chapel Hill, NC 27599-7525, USA. uncmcs@med.unc.edu
Frank
Alexandra
A
Bryant
Miriam
M
Oguejiofor
Ikechukwu
I
Hatch
Stephanie B
SB
McDaniel
Lisa D
LD
Kaufmann
William K
WK
D015197:Carcinogenicity Tests; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000528:radiation effects*; D002869:Chromosome Aberrations; D004247:DNA / Q000235:genetics* / Q000528:radiation effects; D004249:DNA Damage / Q000528:radiation effects*; D005333:Fetus; D014644:Genetic Variation; D006801:Humans; D007621:Karyotyping; D008168:Lung; D016133:Polymerase Chain Reaction; D012016:Reference Values; D016196:S Phase / Q000528:radiation effects; D019098:Telomerase / Q000235:genetics; D014466:Ultraviolet Rays; D014983:Xeroderma Pigmentosum / Q000235:genetics*
D004247:DNA; D019098:Telomerase