New Scholar Award in Aging
Dominique Broccoli, Ph.D.
Fox Chase Cancer Center

Molecular Mechanisms of Telomere Dependent Senescence

Telomeres are specialized structures at the ends of chromosomes that are essential for stability. They are composed of several thousand base pairs of a repeating DNA sequence, (TTAGGG), and proteins that bind specifically to this sequence. In human cells, telomeric DNA is lost each time the cell divides due to the repression of a specialized enzyme, telomerase, which is responsible for the replication of telomeric DNA. Thus, telomeres become shorter as we age. In immortalized cells, for example tumor cells, telomerase is active and telomere length is stabilized. Recently, it has been demonstrated that expression of telomerase is sufficient to render human cells immortal while inhibition of telomerase in tumor derived cell lines leads to cell death. The current hypothesis developed from these data is that telomere length acts as a clock to limit the total number of divisions any cell is capable of achieving. This limitation on cell growth and renewal is believed to contribute to human aging. Activation of telomerase and concomitant stabilization of telomeric DNA circumvents this restraint on cell growth and permits unlimited numbers of cell division, a process required for tumor formation. Thus, telomeres are critically important in both aging and tumorigenesis in humans.

Although it is now clear that telomere length is a critical feature determining the number of divisions cells may attain, relatively little is known about how this process is regulated. Several components of the mammalian telomeric complex have been isolated in recent years including the DNA element, components of the telomerase enzyme, and two telomeric binding proteins called TRF1 and TRF2. Having these components in hand allows manipulation of the telomeric complex in tissue culture systems. For example, alterations in the levels of the telomeric binding proteins TRF1 and TRF2 can have profound effects on telomere length and cellular viability, respectively.

The work in my laboratory is focussed on determining how telomeres limit cellular proliferation. We will introduce a number of mutant forms of telomere proteins into human cells and establish the effect these mutations have on cellular lifespan. In addition, we are undertaking searches to uncover additional proteins that are associated with human telomeres to gain a deeper understanding of telomere structure and how the telomere functions to protect chromosome ends. The knowledge gained from these experiments will deepen our understanding of the processes underlying human aging and tumorigenesis.

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