ABSTRACT:
Judith Campisi, Sahn-Ho Kim, and Seung-Wuk Lee of Lawrence Berkeley National Laboratory have invented a series of TIN2-interface-interacting polypeptides and sequences derived from proteins involved in TIN2 telomeric complexes that target a subset of p53-negative cancer cells, which frequently are metastatic. In human cell-based cultures, these peptides have been shown to selectively disrupt telomeric complexes and kill cancer cells, while sparing normal cells.
Cancer cells generally have short telomeres, making them uniquely sensitive to telomeric complexes. The telomere-associated protein TIN2 binds the telomere DNA-binding proteins TRF1 and TRF2 and the TPP1/POT1 (complex). TIN2 is critical for forming telomere complexes that are essential for telomere structure, telomere length regulation, chromosome end protection and cell fates. It is not yet clear how telomere dysfunction causes cell death in p53-deficient cells, how dysfunctional telomeres are sensed as DNA damage, and the nature of the p53-dependent and p53-independent sensing mechanisms. Nevertheless, telomerase inactivation has been proposed as an anti-cancer strategy because most cancer cells maintain telomere length by expressing this enzyme. Disruption of TIN2-complexes provides a strategy for preferential killing of cancer cells, most of which have short telomeres and lack p53 function.
The Berkeley Lab series of polypeptides may provide a method of selectively eliminating susceptible tumor cells to prevent tumor growth, invasion, or metastasis. They could also be used as a discovery tool in high-throughput screening for therapeutics that could synergize with the disruption of telomeric complexes. In addition, they could be combined with conventional chemo- or radiotherapy to increase tumor sensitivity, making it possible to reduce doses and extend treatment times. |