Differential and similar responses between rodent and human cells to DNA-damaging agents: possible implications for cellular aging.
We have outlined a model in which aging may be associated with changes in chromatin structure that produce alterations in the extent of DNA supercoiling. Our model would suggest that the major difference in a short-lived rodent and a long-lived human being would be reflected as the rate at which such changes occur. In support of this model we have presented data that rodent cells as a class are more resistant to PUVA than are human cells. Further, we have outlined corroborating data that would suggest that such resistance may reflect a difference in the extent of psoralen intercalation that in turn is dependent on DNA supercoiling. Since it is known that changes in DNA supercoiling can alter both the expression of genes and the repair of DNA, it is feasible that changes in supercoiling could lead to a deterioration both in gene regulation and in DNA fidelity. Our model relates to multistage carcinogenesis in a straightforward manner, predicting that cancer initiators produce a heritable change in chromatin structure, while cancer promoters induce transient changes in chromatin structure. We propose that this model is consistent with the developing molecular model of cancer as caused by the inappropriate expression of dominant transforming oncogene(s). Indeed, our model would predict that aging and carcinogen exposure would share a common capacity to alter chromatin structure within regions of the genome, with carcinogens perhaps more random than aging in their induction of such alterations.(ABSTRACT TRUNCATED AT 250 WORDS)
D000375:Aging; D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D004261:DNA Replication / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D008730:Methoxsalen / Q000494:pharmacology; D008954:Models, Biological; D011701:PUVA Therapy; D013045:Species Specificity; D014466:Ultraviolet Rays
D008730:Methoxsalen