The TERT (telomerase reverse transcriptase) subunit of telomerase is an intensively studied macromolecule due to its key importance in maintaining genome integrity and role in cellular aging and cancer. In an effort to provide an up-to-date overview of the topic, we discuss the structure of TERT genes, their alternative splicing products and their functions. Nucleotide databases contain more than 90 full-length cDNA sequences of telomerase protein subunits. Numerous in silico, in vitro and in vivo experimental techniques have revealed a great deal of structural and functional data describing particular features of the telomerase subunit in various model organisms. We explore whether particular findings are generally applicable to telomerases or species-specific. We also discuss in an evolutionary context the role of identified functional TERT subdomains.
IntroductionTelomeres are nucleoprotein structures at the ends of eukaryotic chromosomes which protect linear chromosomes against damage and recognition by endogenous nucleases. The vital role of these structures has been demonstrated in observations of a breakage-fusion-bridge cycle by Barbara McClintock (1938) in plants and response to X-ray mediated damage by Hermann Muller (1938) in Drosophila. With understanding of the mechanism of DNA replication, the "end-replication problem" of linear chromosomes became apparent (Olovnikov, 1971; Watson, 1972;Olovnikov, 1973). However, fundamental features of telomere structure and protective function were not solved until later when the ends of Tetrahymena macronuclear minichromosomes were sequenced (Klobutcher et al., 1981) and the activity of telomerase, the enzyme responsible for their synthesis described (Greider and Blackburn, 1985; 1 To whom correspondence should be addressed (email fajkus@sci.muni.cz). Key words: alternative splicing, gene structure, telomerase. Abbreviations used: CTE, C-terminal extension; EST, expressed sequence tag; DAT, dissociate activities of telomerase; Est, ever-shorter telomere; FHC cell, fetal human colon cell; POT1, protection of telomeres protein 1; RT, reverse transcriptase; SWI/SNF, switch/sucrose non-fermentable; TERT, telomerase reverse transcriptase; AtTERT, Arabidopsis thaliana TERT; hTERT, human TERT; OsTERT, rice (Oryza sativa) TERT; TR, telomerase RNA; TRF2, telomere repeat factor 2. Greider and Blackburn, 1987). It is known now that telomere structure is formed by telomeric DNA, histone octamers and specific proteins that bind telomeric DNA either directly or indirectly by proteinprotein interactions (Fajkus and Trifonov, 2001; de Lange, 2005; Bianchi and Shore, 2008;Palm and de Lange, 2008) (Figure 1). The number of components of the telomere supramolecular structure, and knowledge of their roles in protecting and maintaining telomeres, have increased enormously within the last 15 years. Clearly telomerase is among the most important molecules in the field of telomere biology and is the subject of this review.
General telomerase biologyTelomerase adds telomeric DNA re...