A human homolog of yeast Est1 associates with telomerase and uncaps chromosome ends when overexpressed

Telomeres protect the eukaryotic chromosome ends from degradation and fusion. They are maintained by the ribonucleoprotein telomerase, the core of which is composed of a reverse transcriptase (TERT) and a RNA subunit. In the yeast Saccharomyces cerevisiae, a third critical telomerase subunit, the Ever Shorter Telomeres 1 (EST1) gene product, recruits or activates telomerase at the 3' end of telomeres [1-3]. Est1p has so far only been known in budding yeast, and mechanisms that mediate telomerase access and activation in other eukaryotes have remained elusive. Here, we use iterative profile searches to identify homologs of yeast Est1p in a large variety of eukaryotes, including human. One of three human homologs, designated human EST1A (hEST1A), is shown to be associated with most or all active telomerase in HeLa cell extracts. Overexpression of hEST1A induces anaphase bridges due to chromosome-end fusions, and telomeric DNA persists at the fusion points. Thus, overexpression of hEST1A affects telomere capping. The identification of EST1 homologs in a large variety of eukaryotes may indicate that the mechanisms of telomere extension are more conserved than anticipated previously.