Biochemistry and Molecular Biology
Dr. Songyang received the award for his research on the chemistry and protein complexes involved in telomere end protection and regulation. He identified a novel telomere binding protein, PTOP/TPP1, that interacts with telomeric proteins TIN2 and POT1 and participates in telomere regulation. He found that the TPP1-POT1 heterodimer is capable of binding to telomere DNA with higher affinity (than POT1 alone) and interacts directly with telomerase. The TPP1-POT1 interaction affects the chemistry of the telomerase, leading to an increase in the total activity as well as the processivity of the enzyme.
In addition, Dr. Songyang's group has also demonstrated that the enzymatic activity and function of telomerase alone is insufficient for normal telomere maintenance. For example, the group discovered that the six core telomere proteins (TRF1, TRF2, POT1, RAP1, TIN2, and TPP1) form a high-order complex, the telosome/shelterin, and disruption of the interactions between these subunits resulted in telomere dysfunction and cell cycle arrest, even in the presence of telomerase expression. These findings have highlighted the importance of telosome/shelterin in telomere maintenance and cell proliferation.
The Songyang laboratory has purified more than 20 protein complexes related to telomere maintenance in human cancer cell lines. Analyses of these complexes has led Dr. Songyang to propose a "Telomere Interactome", an interaction network of telomere regulators in mammalian cells. The work implies that many different types of enzymes and activities are present at the human telomeres such as those that participate in DNA damage repair, Non-Homologous End Joining (NHEJ) and recombination, origin firing, and non-sense mediated RNA decay. This work represents a conceptual leap that is radically different from the traditional thinking of the "end-replication problem".
Dr. Songyang's nomination was based on the following publications:
Liu D, Safari A, O'Connor MS, Chan DW, Laegeler A, Qin J, Songyang Z. PTOP interacts with POT1 and regulates its localization to telomeres. Nat Cell Biol. 2004 Jul;6(7):673-80.
Xin H, Liu D, Wan M, Safari A, Kim H, Sun W, O'Connor MS, Songyang Z. TPP1 is a homologue of ciliate TEBP-beta and interacts with POT1 to recruit telomerase. Nature. 2007 Feb 1;445(7127):559-62.
Chen LY, Liu D, Songyang Z. Telomere maintenance through spatial control of telomeric proteins. Mol Cell Biol. 2007 Aug;27(16):5898-909.