Roles of DNA interstrand crosslinking and its repair in the induction of sister-chromatid exchange and a higher induction in Fanconi's anemia cells.
The roles of DNA crosslink and its repair in the induction of sister-chromatid exchanges (SCEs) were studied in normal, xeroderma pigmentosum (XP) complementation group A, and Fanconi's anemia (FA) fibroblasts after treatment with mitomycin C (MC) or decarbamoyl mitomycin C (DMC) for 1 h. FA strains were 5-30-fold more sensitive to MC killing than normal cells, but normally responded to DMC killing. XP group-A cells were twice and only slightly more sensitive to DMC and MC killings, respectively, than normal cells. The induction rate of immediate SCEs by MC was 1.7 times higher, despite a normal SCE rate by DMC, in FA strains than that in normal cells. Alternatively, SCE rates by DMC and MC were 6 times and only 1.3 times higher, respectively, in XP cells than in normal cells. In normal cells, the reduction of MC-induced SCEs as a function of repair time followed a biphasic curve of the first rapid (half-life, 2 h) and the second slow (half-life, 14 h) components. Such components corresponded exactly to the first half-excision and the second slow repair processes of molecular crosslink repair. In MC-induced SCEs, FA17JTO cells exhibited only the slow reduction component without the first rapid component and a higher saturation level in the time-dependent reduction in SCEs. This indicates that SCEs are produced by crosslinks remaining unrepaired for long times (24-48 h) after treatment of FA cells. Conversely, XP group-A cells capable of the first half-excision manifested the first rapid reduction in SCEs, although the second component declined at the slowest rate (half-life, 48 h) owing to a defect in the second mono-adduct repair. The reduction in DMC-induced SCEs followed only the slow component. Thus, these results demonstrate that crosslink can be the lesion leading to SCE, and the MC-induced SCE frequency is higher in FA cells than in normal cells. In the FA20JTO strain, such a repair defect seemed to be less than in FA17JTO cells, judged from the survival and SCE characteristics.
D000741:Anemia, Aplastic / Q000235:genetics*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003434:Crossing Over, Genetic; D004247:DNA / Q000235:genetics*; D004260:DNA Repair; D004305:Dose-Response Relationship, Drug; D005199:Fanconi Anemia / Q000235:genetics*; D005347:Fibroblasts; D006801:Humans; D008937:Mitomycins / Q000494:pharmacology; D012854:Sister Chromatid Exchange; D014983:Xeroderma Pigmentosum / Q000235:genetics
D008937:Mitomycins; D004247:DNA