Regulation of Telomere Length in Mammalian Cells

The ends of linear mammalian chromosomes consist of a simple repeated sequence (T2AG3)n [reviewed in 1,2]. These terminal repeats play a role in prevention of end to end fusion and prot7ection from exonucleolytic degradation [3]. A ribonucleoprotein complex called telomerase, which was first isolated in Tetrahymena and shown to be a specialised reverse transcriptase, facilitates de novo synthesis of terminal repeats to compensate for sequence loss caused by incomplete replication at chromosome ends [4]. Telomerase uses an RNA molecule as a template for the addition of terminal repeat monomers. This enables the cell to overcome the problems associated with replication of terminal sequences encountered by other DNA polymerases. These can only synthesise DNA in a 5′ to 3′ direction using a primer. At chromosome ends, this would result in a 3′ overhang which could not be replicated and over many cell divisions would lead to a progressive loss of DNA. Mammalian telomerase activity was first identified in HeLa cell extracts which can add over sixty T2AG3 repeats onto a T2AG3 oligonucleotide in vitro [5]. Mouse cell extracts were shown to add at most one or two T2AG3 repeats onto a T2AG3 oligonucleotide in vitro suggesting a non processive behaviour which is in contrast to human telomerase [6]. Mammalian telomerase activity is thought to be restricted to germline cells in vivo and immortalised cells in vitro [7–11].