Genomic heterogeneity of DNA repair. Role in aging?
The introduction and repair of DNA lesions are generally heterogeneous with respect to different genomic domains. In particular, the repair of helix-distorting damage, such as the cyclobutane pyrimidine dimers (CPD) induced by ultraviolet light occurs selectively in expressed genes. This is due in large part to the preferential repair of transcribed DNA strands, which is then reflected in a bias toward mutagenesis from persisting lesions in nontranscribed strands. Consequently, determination of overall genomic repair efficiencies may not be a good indicator of cellular sensitivity to agents that damage DNA. Although some studies suggest an age-related accumulation of altered nucleotides in DNA, we do not know the intragenomic distribution of those changes and whether they are relevant to the physiological aspects of aging. Subtle changes in the pattern of preferential repair during maturation could have profound effects on cell and tissue function. DNA repair has been analyzed in differentiating cell systems as possible models for aging. We have observed attenuated overall repair of CPD in differentiated rat myoblasts or PC12 neuron-like cells. In both model systems, several expressed genes have been shown to be repaired relatively efficiently but without strand specificity. In another model system of human HT1080 fibroblasts differentiating in the presence of dexamethasone, we demonstrated enhanced repair in the gene for plasminogen activator inhibitor I whose transcription is induced and, correspondingly, a reduced repair rate in the urokinase plasminogen activator gene whose transcription is suppressed. We conclude that any attempted correlation of the phenomena of aging with DNA repair should focus on the relevant genes in the tissue of interest.
Hanawalt
P C
PC
Department of Biological Sciences, Stanford University, California 94305-5020.
Gee
P
P
Ho
L
L
Hsu
R K
RK
Kane
C J
CJ
D000375:Aging; D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D004249:DNA Damage; D004260:DNA Repair; D015870:Gene Expression; D005796:Genes; D006801:Humans; D066298:In Vitro Techniques; D009132:Muscles / Q000502:physiology; D009474:Neurons / Q000502:physiology; D016716:PC12 Cells; D011740:Pyrimidine Dimers; D051381:Rats; D014158:Transcription, Genetic; D014945:Wound Healing
D011740:Pyrimidine Dimers