Mechanisms of formation of chromosomal aberrations: insights from studies with DNA repair-deficient cells.
In order to understand the mechanisms of formation of chromosomal aberrations, studies performed on human syndromes with genomic instability can be fruitful. In this report, the results from studies in our laboratory on the importance of the transcription-coupled repair (TCR) pathway on the induction of chromosomal damage and apoptosis by ultraviolet light (UV) are discussed. UV61 cells (hamster homologue of human Cockayne's syndrome group B) deficient in TCR showed a dramatic increase in the induction of chromosomal aberrations and apoptosis following UV treatment. At relatively low UV doses, the induction of chromosomal aberrations preceded the apoptotic process. Chromosomal aberrations probably lead to apoptosis and most of the cells had gone through an S phase after the UV treatment before entering apoptosis. At higher doses of UV, the cells could go into apoptosis already in the G1 phase of the cell cycle. Abolition of TCR by treatment with alpha-amanitin (an inhibitor of RNA polymerase II) in the parental cell line AA8 also resulted in the induction of elevated chromosomal damage and apoptotic response similar to the one observed in UV61 cells treated with UV alone. This suggests that the lack of TCR is responsible for the increased frequencies of chromosomal aberrations and apoptosis in UV61 cells. Hypersensitivity to the induction of chromosomal damage by inhibitors of antitopoisomerases I and II in Werner's syndrome cells is also discussed in relation to the compromised G2 phase processes involving the Werner protein.
Palitti
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Department of Agrobiology and Agrochemistry, University of Tuscia, Viterbo, Italy. palitti@unitus.it
D000546:Amanitins / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D002460:Cell Line / Q000187:drug effects / Q000528:radiation effects / Q000648:ultrastructure; D002869:Chromosome Aberrations; D002877:Chromosomes, Human / Q000187:drug effects / Q000528:radiation effects / Q000648:ultrastructure; D003057:Cockayne Syndrome / Q000235:genetics; D006224:Cricetinae; D004247:DNA / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D004249:DNA Damage; D004265:DNA Helicases / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D004260:DNA Repair / Q000235:genetics / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005090:Exodeoxyribonucleases; D042822:Genomic Instability / Q000235:genetics; D006801:Humans; D009386:Neoplastic Syndromes, Hereditary / Q000201:enzymology / Q000235:genetics*; D011740:Pyrimidine Dimers / Q000235:genetics; D012319:RNA Polymerase II / Q000037:antagonists & inhibitors; D053484:RecQ Helicases; D014158:Transcription, Genetic / Q000235:genetics*; D014466:Ultraviolet Rays; D014898:Werner Syndrome / Q000235:genetics / Q000473:pathology; D000071657:Werner Syndrome Helicase
D000546:Amanitins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D011740:Pyrimidine Dimers; D004247:DNA; D012319:RNA Polymerase II; D005090:Exodeoxyribonucleases; D004265:DNA Helicases; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase