Cdc13p is a multi-functional, telomere-binding protein that plays a role in telomere replication, length maintenance, end protection and telomerase regulation (4). CDC13/EST4 is one of five genes required for telomerase activity in vivo. EST1, EST2, TLC1 and EST3 are the other four genes. Mutations in any of these five genes leads to progressive telomere shortening, the so-called ever shorter telomeres (EST) phenotype and eventually to cell death; however, a complete deletion of CDC13 is inviable. CDC13 is the only essential gene among the EST genes (8, 9, 10, 11, 12 and references therein).

The N-terminal region of Cdc13p is crucial for the protein's activity due to its various interactions with different binding proteins (13). The telomere capping function is mediated through its interaction with Stn1p and Ten1p, essential proteins required for telomere length regulation (14, 15, 16). Cdc13p plays a role in telomere replication through its interactions with the Pol1p catalytic subunit of DNA polymerase alpha, and an essential subunit of telomerase, Est1p (17). Cdc13p and Est1p also recruit and activate the telomere-bound Est2p catalytic subunit of telomerase for its replication (18). The telomerase recruitment step is regulated by the yeast ku heterodimer (Yku70p-Yku80p), and Stn1p which impart positive and negative control on the Cdc13p-Est1p interaction (12, 19). Cdc13p is regulated by the phosphorylation of the SQ/TQ motif in the telomerase recruitment domain by the checkpoint kinases, Mec1p and Tel1p (20). Mutation in Cdc13p results in abnormal uncapped telomeres with long exposed G-strands leading to activation of the RAD9 DNA damage pathway, cell cycle arrest at the G2/M phase and cell death (1, 21, 22, 23, 13).

In humans, telomere length is linked to aging and cancer: in human germline cells telomeres are long, whereas in cells of somatic tissues, telomerase activity is absent and the telomeres are short. Upon sufficient shortening, the somatic cells stop dividing and become senescent. Inappropriate telomerase activity is detected in most malignant tumors, and the genes required for telomerase activity are potential targets for cancer therapy (24, 9).

Human orthologs for four of the telomerase subunits are known. Est2p, the telomerase reverse transcriptase catalytic enzyme, is similar to TERT (OMIM), TLC1, the template RNA is similar to TERC/hTR (OMIM), while Cdc13p shares sequence similarity with human POT1 (OMIM) (25, 10). There are three Est1p like proteins in humans, although only hEST1A and hEST1B have been shown to be associated with the telomerase (26). A human ortholog for EST3 hasn't been identified. Mutations in TERT (OMIM) and TERC/hTR (OMIM) cause short telomeres and congenital aplastic anemia (OMIM, 25).

Last updated: 2007-06-27