Preferential DNA repair in expressed genes.
Potentially deleterious alterations to DNA occur nonrandomly within the mammalian genome. These alterations include the adducts produced by many chemical carcinogens, but not the UV-induced cyclobutane pyrimidine dimer, which may be an exception. Recent studies in our laboratory have shown that the excision repair of pyrimidine dimers and certain other lesions is nonrandom in the mammalian genome, exhibiting a distinct preference for actively transcribed DNA sequences. An important consequence of this fact is that mutagenesis and carcinogenesis may be determined in part by the activities of the relevant genes. Repair may also be processive, and a model is proposed in which excision repair is coupled to transcription at the nuclear matrix. Similar but freely diffusing repair complexes may account for the lower overall repair efficiencies in the silent domains of the genome. Risk assessment in relation to chemical carcinogenesis requires assays that determine effective levels of DNA damage for producing malignancy. The existence of nonrandom repair in the genome casts into doubt the reliability of overall indicators of DNA binding and lesion repair for such determinations. Furthermore, some apparent differences between the intragenomic repair heterogeneity in rodent cells and that in human cells mandate a reevaluation of rodent test systems for human risk assessment. 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.
Hanawalt
P C
PC
Department of Biological Sciences, Stanford University, CA 94305.
D000818:Animals; D002273:Carcinogens; D002471:Cell Transformation, Neoplastic; D004249:DNA Damage; D004260:DNA Repair; D004261:DNA Replication; D005796:Genes; D006801:Humans; D011519:Proto-Oncogenes; D011740:Pyrimidine Dimers / Q000235:genetics; D012306:Risk; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics
D002273:Carcinogens; D011740:Pyrimidine Dimers; D013762:Tetrahydrofolate Dehydrogenase