UC San Diego

The ends of linear chromosomes are composed of a long array of highly conserved repeat sequences that are essential for genome stability. These chromosome ends, called telomeres, act as a molecular clock that dictates cell division potential. With every cell division, a small amount of DNA erodes from each chromosome terminus, and while this erosion process is initially insignificant, the cumulative effect after many cell divisions can be catastrophic, ultimately resulting in cell death or cancerous transformations. At a certain point, so much telomeric DNA is lost that a signal is sent to halt further cell division. This block to indefinite cell division can be alleviated by the enzyme telomerase which adds telomeric DNA to chromosome ends, thereby preventing telomere shortening. Telomerase has been the subject of intensive studies since its discovery, as the contribution of telomere length regulation to human health, with regard to both cancer biology and human aging, is substantial. A major goal of the Lundblad lab is to achieve a full understanding of how this enzyme is regulated, in order to uncover novel insights into how chromosome ends can make such wide-spread contributions to human biology. In budding yeast, a telomeric dedicated RPA complex (the t-RPA complex), formed by the three essential proteins Cdc13, Stn1 and Ten1 is central to ensuring telomere homeostasis as it ensures the elongation of the telomeres by recruiting the cellular retro-transcriptase telomerase. Furthermore, it promotes efficient replication of the telomere as a telomeric specific complex that becomes part of the replisome as the replication fork advances through the duplex telomeric DNA. This dissertation describes my efforts to uncover how a third complex, the canonical RPA complex, performs a role in telomere maintenance with t-RPA and telomerase.