UCSF

Telomeres are nucleoprotein structures at the ends of linear chromosomes. One of their critical functions is to protect the natural ends of chromosomes from being treated by the cell as broken DNA, and subjected to inappropriate repair events. In spite of the importance of distinguishing between telomeres and sites of DNA damage, many proteins involved in responding to DNA damage localize to telomeres and are required for their maintenance. We sought to gain greater understanding of the connection between telomere biology and the DNA damage response by investigating one such protein, Tel2, in the yeast Saccharomyces cerevisiae. Tel2 is an essential protein conserved throughout eukaryotes. It has been implicated in telomere length regulation, the DNA damage response, and aging, but its exact role in all of these processes is unknown. We investigated Tel2 function from three different angles. First, our studies of the function of Tel2 in the DNA damage response revealed that Tel2 physically interacts with the Tel1 kinase, and is required for the localization of Tel1 to double-strand breaks and its activation of downstream targets. We also found that Tel2 is predicted to be structurally similar to Ddc2, a partner of the Mec1 kinase that is required for the Mec1-dependent response to DNA damage. Second, we investigated the reasons Tel2 is essential for viability. We found that cells lacking functional Tel2 show defects in progression into and through S phase, suggesting that Tel2 regulates some aspect of DNA replication. A high-copy suppressor screen identified the genes SLX5 and CDC7, which both play roles in the survival of replication stress. Third, we examined the function of Tel2 in telomere length regulation by analysis of the tel2-1 point mutation, which abrogates the function of Tel2 in the Tel1-dependent DNA damage response. In combination with other mutations relevant to telomere maintenance, the tel2-1 mutation caused telomere shortening by a mechanism that appears to act primarily through the Tel1 pathway, with a slight contribution outside that pathway.