SUMMARY PARAGRAPH for EST1
Telomerase is a ribonucleoprotein complex that is essential for maintenance of telomeres, special sequences which terminate the ends of linear chromosomes. Telomerase is a reverse transcriptase that elongates the single-stranded G-rich 3' protruding ends of chromosomal DNA using an RNA molecule that is part of the telomerase complex. The extended strand provides a template for synthesis of the lagging strand by DNA polymerase, thus preventing the otherwise inevitable loss of terminal DNA at each round of replication.
In yeast, five gene products are required for telomerase activity in vivo: Est2p (the catalytic reverse transcriptase subunit), TLC1 (the template RNA), Est1p, Est3p and Cdc13p. Mutations in any of these five genes lead to progressive telomere shortening, the so-called ever shorter telomeres (EST) phenotype, followed by cell death. CDC13 is the only essential gene among the EST genes. Est2p and TLC1 form the catalytic core of telomerase, while Est1p, Est3p and Cdc13p which are dispensable for in vitro telomerase catalytic activity, play regulatory roles (6, 7, 8, 3, 9 and references therein). Cdc13p, a single stranded DNA binding protein required for telomere maintenance and elongation, binds to Est1p and this interaction is necessary for recruiting telomerase to the chromosomal ends. Est1p, Est2p and Est3p all bind to the TLC1 RNA template and Est1p also binds to 3' ends of single stranded DNA. Est1p forms a stable complex with TLC1 in the absence of Est2p or Est3p while association of Est3p with the enzyme requires an intact catalytic core. Est1p and Est3p are stable components of the telomerase holoenzyme (3).
Est1p makes multiple contributions to the function of telomerase. It recruits the telomerase catalytic to chromosome ends by serving as a bridge between the catalytic Est2p subunit and the single-stranded DNA-binding protein Cdc13p. Est1p also binds to the TLC1 RNA subunit of telomerase and once bound, Est1p interacts with the chromosome bound Cdc13p molecules to promote an activated state of the telomere-bound Est2p-TLC1 core complex. These interactions occur during S phase of the cell cycle since the abundance of Est1p is cell cycle regulated and Est1p is associated with telomeric chromatin only in late S phase (10, 11, 12, 3). The Cdc13p-Est1p interaction is positively regulated by the yeast ku heterodimer (Yku70p-Yku80p) and negatively by Stn1p, a telomere end-binding protein (9, 12).
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 (13, 7).
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) (14, 8). There are three Est1p like proteins in humans, although only hEST1A and hEST1B have been shown to be associated with the telomerase (15). 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, 14).
Last updated: 2007-06-27