Effect of Aging on Efficiency and Accuracy of DNA Double-Strand Break Repair
Aging cells and tissues accumulate point mutations and genomic rearrangements, consistent with a failing ability to defend their genomes against DNA damage. Rearrangements result primarily from errors in repair of double-strand breaks (DSBs), which arise commonly by breakage of replication forks, as a result of damage due to ionizing radiation, and as a step in the repair of DNA cross-links. The role of DSB repair and recombination in aging is further supported by the studies showing that mutations in the genes involved in DSB repair and recombination lead to accelerated aging. Our hypothesis is that in the aging cells the machinery for DSB repair becomes error-prone. Errors in DSB repair result in accumulation of genomic rearrangements, which lead to cancer and other age-associated diseases. Careful measurements of the efficiency and accuracy DSB repair during aging will provide important information on the basic mechanisms of aging and the higher incidence of cancer in the elderly. We are developing an easy-to-score fluorescence-based assay to examine the status of DSB repair in senescent human cells and in aging mice. We will compare the efficiency and accuracy of DNA repair in various organs, and test whether DNA repair becomes more error-prone in the old animals. In the future, we will use transgenic mice carrying fluorescent reporter cassettes for analysis of DSB repair as a model to search for possible treatments to prevent age-associated decline in DNA repair.