(from the application): Although there is good evidence for the involvement of p21 as a major effector of cellular aging, the connection between the counting mechanism and induction of p21 has not been convincingly demonstrated. Telomere shortening has emerged as a major candidate for the counting mechanism. The telomere hypothesis of cellular aging has been greatly strengthened by experiments demonstrating that cells expressing the catalytic subunit of telomerase (hTERT) maintained their telomere length and were able to divide indefinitely. It has been shown that as cells age in culture, they lose methyl cytosine from genomic DNA. It is known that DNA methylation can have profound effects on the pattern of gene expression. Interestingly, it has recently been reported that simply decreasing DNA methyltransferase (DNA MeTase) activity causes induction of p21, without changes in DNA methylation. Therefore, the observed changes in MeTase activity and/or DNA methylation could account for the changes in gene expression seen with cellular aging. A recent observation in our laboratory, that cells expressing hTERT maintain DNA MeTase, provides a possible explanation for the prevention, by hTERT, of changes in gene expression that normally occur with cellular aging. The studies proposed here are designed to: 1) elucidate the mechanism by which telomerase or telomere length regulate dnmt1 activity and DNA methylation, 2) determine if there is a causal link between decreasing dnmt1 activity and DNA methylation and cellular aging, and 3) distinguish the changes in gene expression that occur during cellular aging and provide the trigger for cellular senescence from the myriad changes that occur as a result of p21 induction and growth arrest.
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