The focus of our research is to understand the molecular basis of telomere function. Telomeres, the physical ends of chromosomes, consist of long tandem arrays of TTAGGG repeats bound to specific proteins in a nucleoprotein complex that is required for the stability and replication of chromosome ends. Telomeres are maintained by telomerase, a specialized reverse transcriptase that adds TTAGGG repeats to the ends of chromosomes. During human development, due to the lack of expression of telomerase, telomeres shorten in most somatic tissues. This shortening acts as a signal for replicative senescence and probably functions as a tumor suppressor mechanism in vivo. Activation of telomerase can bypass senescence and lead to immortalization, thereby alleviating a block to tumorigenesis. In fact, most human tumors show an up-regulation of telomerase. In cells where telomerase is expressed, such as in human tumors or in germ cells, cellular mechanisms exist to regulate and maintain telomere length.

We have identified a novel human telomeric protein, termed tankyrase, which is involved in the regulation of telomere length. Tankyrase has homology to ankyrins and to the catalytic domain of poly(ADP-ribose) polymerase (PARP). Tankyrase localizes to telomeres through its interaction with the TTAGGG repeat binding protein, TRF1, a negative regulator of telomere length. ADP-ribosylation of TRF1 by tankyrase inhibits TRF1 binding to telomeric DNA, both in vitro and in vivo. To assess the role of tankyrase in telomere length regulation, we expressed tankyrase in a human fibrosarcoma cell line that expresses telomerase and maintains its telomeres at a constant length. Overexpression of tankyrase induced a gradual and progressive lengthening of telomeres, indicating that tankyrase functions as a positive regulator of telomere length in vivo. Our working model is that ADP-ribosylation of TRF1 by tankyrase releases TRF1 from telomeres, opening up the complex and allowing access to telomerase.

Future work will focus on the mechanism of activation of tankyrase's PARP activity and identification of other proteins and signals that mediate this activation. In addition we would like to understand how tankyrase regulates the activity of telomerase and/or its accessibility to telomeres.