Preferential repair of damage in actively transcribed DNA sequences in vivo.
My colleagues and I have discovered intragenomic heterogeneity in DNA repair in mammalian cells. Consequences of unrepaired DNA damage depend upon the precise location of the damage with respect to relevant genes. It is therefore important to understand rules governing accessibility of specific DNA sequences in chromatin to damage and repair. The efficiency of removal of pyrimidine dimers has been determined in the active dihydrofolate reductase (DHFR) gene in Chinese hamster ovary (CHO) cells. Repair within the gene was shown to be much more efficient than that in nontranscribed downstream sequences or in the genome overall. Preferential repair of active and essential genes such as DHFR may account for the fact that rodent cells are as uv-resistant as human cells in spite of their much lower overall repair efficiencies. In repair-proficient human cells the rate of repair in the DHFR gene is greater than that in the overall genome or in nontranscribed alpha-DNA sequences. The efficiency of removal of pyrimidine dimers is much higher in the transcribed than the nontranscribed DNA strands of the DHFR gene in both CHO and human cells. An excision-repair complex may be directly coupled to the transcription machinery to ensure early removal of transcription-blocking lesions in active genes. Sequences in the active c-abl proto-oncogene are repaired much more efficiently than are sequences containing the inactive c-mos proto-oncogene in Swiss mouse 3T3 cells. Tissue-specific and cell-specific differences in the coordinate regulation of proto-oncogene expression and DNA repair may account for corresponding differences in the carcinogenic response.(ABSTRACT TRUNCATED AT 250 WORDS)
Hanawalt
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PC
Herrin Biology Labs, Department of Biological Sciences, Stanford University, CA 94305-5020.
D000818:Animals; D002478:Cells, Cultured; D002843:Chromatin / Q000648:ultrastructure; D006224:Cricetinae; D003412:Cricetulus; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004249:DNA Damage; D004260:DNA Repair; D005260:Female; D005796:Genes / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D051379:Mice; D010053:Ovary; D000090063:Proto-Oncogene Mas; D011519:Proto-Oncogenes / Q000528:radiation effects; D011740:Pyrimidine Dimers / Q000378:metabolism; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics; D014158:Transcription, Genetic
D002843:Chromatin; D003432:Cross-Linking Reagents; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011740:Pyrimidine Dimers; D013762:Tetrahydrofolate Dehydrogenase