Intragenomic repair heterogeneity of DNA damage.
The mutagenic and carcinogenic consequences of unrepaired DNA damage depend upon its precise location with respect to the relevant genomic sites. Therefore, it is important to learn the fine structure of DNA damage, in particular, proto-oncogenes, tumor-suppressor genes, and other DNA sequences implicated in tumorigenesis. Both the introduction and the repair of many types of DNA lesions are heterogeneous with respect to chromatin structure and/or gene activity. For example, cyclobutane pyrimidine dimers are removed more efficiently from the transcribed than the nontranscribed strand of the dhfr gene in Chinese hamster ovary cells. In contrast, preferential strand repair of alkali-labile sites is not found at this locus. In mouse 3T3 cells, dimers are more efficiently removed from an expressed proto-oncogene than from a silent one. Persistent damage in nontranscribed domains may account for genomic instability in those regions, particularly during cell proliferation as lesions are encountered by replication forks. The preferential repair of certain lesions in the transcribed strands of active genes results in a bias toward mutagenesis owing to persistent lesions in the nontranscribed strands. Risk assessment in environmental genetic toxicology requires assays that determine effective levels of DNA damage of producing malignancy. The existence of nonrandom repair in the mammalian genome casts doubt on the reliability of overall indicators of carcinogen-DNA binding and lesion repair for such determinations. Tissue-specific and cell-specific differences in the coordinate regulation of gene expression and DNA repair may account for corresponding differences in the carcinogenic response to particular environmental agents.
Scicchitano
D A
DA
Department of Biology, New York University, NY 10003.
Hanawalt
P C
PC
D000478:Alkylation; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D004247:DNA / Q000187:drug effects / Q000528:radiation effects; D004249:DNA Damage / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D004926:Escherichia coli / Q000235:genetics; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D016296:Mutagenesis; D000090063:Proto-Oncogene Mas; D014714:Vertebrates / Q000235:genetics
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D004247:DNA