DNA interstrand cross-linking, repair, and SCE mechanism in human cells in special reference to Fanconi anemia.
The relation of DNA cross-linking and repair to sister chromatid exchange (SCE) formation was studied in normal human, Fanconi anemia (FA), and xeroderma pigmentosum (XP) cells. Despite a hypersensitive lethality response in FA cells, the SCE induction rates by mitomycin C (MMC), trimethylpsoralen (TMP)-light, cisplatin, and diepoxybutane were twice as high as in normal cells. For MMC, the induced SCE frequency in normal cells was reduced in a biphasic fashion with a repair incubation time (the first decline t1/2 = 2 hr; the second t1/2 = 14-18 hr) which corresponds exactly to the molecular kinetics of cross-link and monoadduct removal. However, FA cells lack the first half-excision process and exhibit a lack of the first rapid decline SCE component. The slow decline component is present, and a higher SCE frequency is observed 24 to 48 hr after treatment. By contrast, XP cells capable of the half-excision process reveal the first rapid decline component, followed by an extremely slow second-reduction component (t1/2 = 48 hr) due to defective monoadduct repair. The endoreduplication-SCE method revealed that rates of both twin (first cycle) and single (second cycle) SCE formations by MMC and TMP-light were higher in FA cells than in normal cells. These results indicate that cross-links remaining unrepaired induce SCEs as do monoadducts. The probabilistic SCE induction occurs at a rate of 1 SCE per 35 MMC cross-links in FA cells. Further, a non-SCE-forming tolerance mechanism also operates in hypersensitive FA cells. These molecular and cytogenetic results allow us to construct a new probabilistic model for cross-link-induced SCE into which the replication-fork model, random cross-link transfer to both chromatids, and chromatid breakage-reunion are incorporated.
D000741:Anemia, Aplastic / Q000235:genetics*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003432:Cross-Linking Reagents / Q000494:pharmacology*; D004260:DNA Repair; D004261:DNA Replication; D005199:Fanconi Anemia / Q000235:genetics*; D006801:Humans; D016685:Mitomycin; D008937:Mitomycins / Q000494:pharmacology; D008938:Mitosis; D008957:Models, Genetic; D012854:Sister Chromatid Exchange / Q000187:drug effects*; D014983:Xeroderma Pigmentosum / Q000235:genetics
D003432:Cross-Linking Reagents; D008937:Mitomycins; D016685:Mitomycin