CATALYTIC SUBUNIT OF THE TELOMERASE GENE HEST2

Whitehead Institute For Biomedical Res, Cambridge MA

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Abstract

DESCRIPTION (provided by applicant): Many types of mammalian cells, when placed into culture, halt proliferation and enter into a non-growing state termed senescence. The prevailing theory says that the onset of senescence is dictated by the length of double strand (ds) DNA regions of the telomeres at the ends of chromosomes. We have demonstrated that, on the contrary, senescence is not controlled by the overall length of the ds telomeric DNA, but instead by the length of a short stretch of single-strand DNA that protrudes from (overhangs) from the ends of the dsDNA portion of a telomere (ssOH). ssOH is largely lost when cells enter into senescence. We shall develop assays to gauge the lengths in situ of the ssOH and dsDNA portions. Using these assays as well as more direct molecular measurements, we will test a molecular model whereby physiologic stress suffered by cells provokes loss of the ssOH, and that this loss, in turn, induces a p53-dependent DNA damage response that results in the senescent cell phenotype. We will examine the notion that loss of the ssOH is a common mechanism for triggering senescence in response to a variety of physiologic stresses, and that this loss, is often provoked by cumulative oxidative damage suffered by cells. Use of in situ measurements of the ssOH and dsDNA portions of the telomeres within cells will allow us to determine whether the loss of ssOH occurs in a concerted fashion in individual cells and is thus actively provoked or in an asynchronous, stochastic fashion. In addition, these measurements will allow us to determine whether loss of ssOH and associated p53 activation occur in cells within living tissues, thereby providing evidence that the state of cell senescence occurs in vivo and may contribute to the loss of proliferative potential of cells in aging tissues and in various pathological states.