Normal diploid human somatic cells have a limited capacity to proliferate, a process termed replicative senescence. Increasing evidence over the last decade has implicated telomeres, the structures that cap the ends of the chromosomes, as the molecular clock that counts the number of times the cell has divided The mechanism of lagging strand DNA synthesis prevents DNA polymerase from replicating the DNA all the way to the 3' end of a linear chromosome, causing the chromosomes to shorten every time a cell divides. Human telomeres prevent the cell from recognizing the end of the chromosome as a DNA break needing repair. In yeast, telomere length can influence the expression of adjacent genes (telomere positional effects). Cellular senescence may occur when some of the telomeres have shortened sufficiently to induce a DNA damaged signal, or when the expression of regulatory loci in the subtelomeric DNA changes and induces a growth arrest program. Cellular immortalization is usually accompanied by the reactivation of the enzyme telomerase, which is able to add telomeric repeats to the ends of the chromosomes and thus prevent their shortening. This proposal consists of two braid aims.
Aim 1 is directed towards understanding the molecular basis for the regulation of telomerase. We will determine the mechanism by which it is reactivated by identifying members of the repressive pathway those inactivation permits the re- expression of the mRNA for the telomerase catalytic subunit. We will also study the telomerase gene and how factors that positively regulate expression such as c-Myc alter its chromatin structure.
Aim 2 pursues the signal transduction mechanism by which telomere shortening affects cell behavior, and will developing evidence for or against the presence of telomere position effects in human cells. The information resulting from these studies should help define the molecular mechanisms underlying replicative senescence and its relationship to cancer.
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