Initiating the uninitiated: replication of damaged DNA and carcinogenesis.
Cancer is a genetic disease and carcinogenesis is the process whereby the relevant genetic alterations are acquired. Environmental carcinogens may damage DNA to induce mutations and chromosomal aberrations as permanent heritable changes in the genome that initiate carcinogenesis. For many carcinogens initiation of carcinogenesis requires the initiation of DNA replication suggesting that genetic alterations are fixed in the genome during replication of damaged DNA. It is of great interest to understand the mechanisms whereby carcinogen-induced damage to DNA causes mutations and chromosomal aberrations and how cells may resist such events. It is clear now that cells express a complex repertoire of responses to DNA damage including several pathways of DNA repair and cell cycle checkpoints that protect against carcinogenesis. This commentary is concerned with the protective influence of DNA damage checkpoints that delay or arrest progression through the cell division cycle and especially with the responses of S phase cells to the environmental carcinogens UV and benzo[a]pyrene diolepoxide I (BPDE). Recent studies indicate that checkpoint responses may act at the very point of replication of damaged DNA to slow DNA chain elongation, inhibit replicon initiation and suppress initiation of carcinogenesis.
Kaufmann
William K
WK
Department of Pathology and Laboratory Medicine, Center for Environmental Health and Susceptibility, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, 27599-7295, USA. wkarlk@med.unc.edu
D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000633:toxicity; D000818:Animals; D002274:Carcinogens, Environmental / Q000633:toxicity; D002352:Carrier Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D004249:DNA Damage; D004261:DNA Replication; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D009154:Mutation / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics*; D009687:Nuclear Proteins / Q000378:metabolism*; D016196:S Phase / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D014466:Ultraviolet Rays
D002274:Carcinogens, Environmental; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; C509770:Timeless protein, mouse; C518120:Tipin protein, mouse; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide