Abstract 3785: Cdk1 coordinates telomere replication by regulating the temporal recruitment of telomerase and the CST complex

Abstract

Abstract Telomeres are nucleoprotein structures that cap the ends of linear chromosomes. They ensure genomic stability and complete replication of the genome. The enzyme telomerase mediates telomere elongation. Considering that telomerase is up-regulated in about 90% of human cancers and telomerase-mediated telomere elongation is significantly deregulated in cancers, insights from our study can be used to target the telomere replication machinery for therapeutic intervention in cancer. In our study, we use budding yeast to understand the mechanism of telomere maintenance. In budding yeast, Cdk1 coordinates the cell cycle-dependent elongation of telomere by telomerase. Cdk1 phosphorylates the telomere-specific ssDNA binding protein, Cdc13, which promotes the recruitment of telomerase to the telomere and thereby, telomere elongation. Cdc13 is also an integral part of the CST (Cdc13-Stn1-Ten1) complex, which provides the protective cap at the telomere and inhibits telomere elongation by telomerase. Therefore, the telomere length homeostasis is balanced between these two telomerase-extendable and CST-unextendable states. However, the cellular signaling that regulates the switch between these two states is largely unknown. Here we show that Cdk1 phosphorylates Stn1 sequentially to that of Cdc13. Cdk1-dependant phosphorylation of Stn1 is essential for telomere maintenance in vivo, CST stability and the inhibition of telomerase at the telomeres. By controlling the timing of Cdc13 and Stn1 phosphorylation during cell cycle progression, Cdk1 coordinates the recruitment of telomerase holoenzyme and CST complex to the telomeres respectively and hence the switch between the telomerase-extendable and CST-unextendable states of the telomeres in budding yeast. With increasing evidence of human CST complex being involved in telomere length maintenance, the results from my study will provide insights into telomere homeostasis in humans and its disruption in cancers. Citation Format: Veena Gopalakrishnan, Chang-Ching Liu, Lai Fong Poon, Tingdong Yan, Shang Li. Cdk1 coordinates telomere replication by regulating the temporal recruitment of telomerase and the CST complex. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3785. doi:10.1158/1538-7445.AM2015-3785