Genome maintenance is an important mechanism for assuring organismal longevity. In complex organisms, DNA repair systems postpone aging by preventing mutations, which ensures cell and tissue function and suppresses cancer, and by promoting rapid repair, which prevents apoptosis and senescence, cellular responses to DNA damage that suppress cancer but are thought to contribute to aging. Werner syndrome (WS) is hereditary progeroid syndrome in humans caused by loss of WRN, a DNA helicase related to a bacterial DNA repair protein. WS manifests after puberty with multiple age-related phenotypes and pathologies, including an aged appearance, atherosclerosis, type II diabetes, cataracts, osteoporosis and cancer. About half the cancers are mesenchymal, compared to <10% in the general population. WS individuals typically die of cardiovascular disease or cancer in the fifth decade of life. WRN deficient mice do not show WS phenotypes. WRN has been shown to modulate the repair of DNA double strand breaks (DSBs), and may play a role in telomere maintenance. Thus, WRN is a human longevity assurance gene that participates in multiple genome maintenance processes with cell-type and species specificity. To understand how WRN functions to postpone aging, we propose to determine the role of WRN and its catalytic activities in the responses to DNA damage, including senescence, apoptosis, replicative life span, telomere dynamics, and DSB repair. We also propose to explore the cell type specificity of WRN action and test the hypothesis that diverse cell types respond differently to WRN deficiency. Finally we propose to explore the species specificity of WRN action by determining whether there are differences between mouse and human cells in WRN regulation, localization or function. Understanding WRN function will provide a unique opportunity to understand an important human longevity assurance mechanism with a level of sophistication that includes cell type and species specificity, which are at present poorly understood.
| Bird, Joseph L E; Jennert-Burston, Katrin C B; Bachler, Marcus A et al. (2012) Recapitulation of Werner syndrome sensitivity to camptothecin by limited knockdown of the WRN helicase/exonuclease. Biogerontology 13:49-62 |
| Kim, Sahn-Ho; Davalos, Albert R; Heo, Seok-Jin et al. (2008) Telomere dysfunction and cell survival: roles for distinct TIN2-containing complexes. J Cell Biol 181:447-60 |
