New function of CDC13 in positive telomere length regulation

Two roles for the Saccharomyces cerevisiae Cdc13 protein at the telomere ha ve previously been characterized: it recruits telomerase to the telomere an d protects chromosome ends from degradation. In a synthetic lethality scree n with YKU70, the 70-kDa subunit of the telomere-associated Yku heterodimer , we identified a new mutation in CDC13, cdc13-4, that points toward an add itional regulatory function of CDC13. Although CDC13 is an essential telome rase component in vivo, no replicative senescence can be observed in cdc13- 4 cells. Telomeres of cdc13-4 mutants shorten for about 150 generations unt il they reach a stable level. Thus, in cdc13-4 mutants, telomerase seems to be inhibited at normal telomere length but fully active at short telomeres . Furthermore, chromosome end structure remains protected in cdc13-4 mutant s. Progressive telomere shortening to a steady-state level has also been de scribed for mutants of the positive telomere length regulator TEL1. Strikin gly, cdc13-4/tell Delta double mutants display shorter telomeres than eithe r single mutant after 125 generations and a significant amplification of Y' elements after 225 generations. Therefore CDC13, TEL1, and the Yku heterod imer seem to represent distinct pathways in telomere length maintenance. Wh ereas several CDC13 mutants have been reported to display elongated telomer es indicating that Cdc13 functions in negative telomere length control, we report a new mutation leading to shortened and eventually stable telomeres. Therefore we discuss a key role of CDC13 not only in telomerase recruitmen t but also in regulating telomerase access, which might be modulated by pro tein-protein interactions acting as inhibitors or activators of telomerase activity.