Jayakrishnan Nandakumar, "Roles of the telomere protein complex POT1-TPP1 in chromosome end protection and end replication"
Dec 04, 2012 (Tue) | 4:15 PM -6:15 PM
393 Serra Mall, Herrin T-175 : Stanford, CA
Abstract: The maintenance of linear chromosomes such as those found in eukaryotes requires countering two biological problems: the chromosome end-protection problem and the chromosome end-replication problem. The ends of linear chromosomes must be distinguished from damaged DNA ends that require repair. In the absence of such discrimination, linear chromosomes are prone to illicit ‘repair’ that may result in catastrophic end-to-end chromosomal fusions. Such reactions represent the chromosome end-protection problem. On the other hand, the chromosome end-replication problem results from the loss of DNA sequence at the extreme end of chromosomes due to incomplete replication by replicative polymerases. Telomerase, a unique enzyme that contains both a protein and an RNA subunit, facilitates the solution of both chromosome end-related problems. By synthesizing multiple tandem repeats of DNA (called telomeric DNA), telomerase compensates for the loss of DNA ends during replication and provides the binding sites for telomeric proteins that bind specifically to the ends of chromosomes to distinguish them from broken DNA ends. However, if a chromosome end is normally coated with telomeric proteins, how does telomerase get recruited to these ends to extend them? The key to the telomerase recruitment puzzle lies in the telomere protein complex POT1-TPP1, which not only protects the ends of chromosomes, but also facilitates telomerase action at these loci. In the first part of my talk I will discuss how POT1-TPP1 utilizes a single deoxythymidine nucleotide in the telomeric DNA substrate to distinguish it from an RNA substrate of the same sequence. Such discrimination against RNA ensures that POT1-TPP1 faithfully protects chromosome ends even in the presence of potential RNA decoys in the nucleus. In the second part of my talk I will show you how we identified the surface on the TPP1 protein that not only binds and recruits telomerase to chromosome ends, but also increases the processivity of the telomerase enzyme. Because telomerase is lowly (or not) expressed in normal non-dividing somatic cells but overexpressed in ~90% cancers, the telomerase-binding surface of TPP1 we identified has important implications for anti-cancer drug discovery.
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