Structure—function relationships in telomerase genes

Abstract

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...

Alternatively Spliced Telomerase Reverse Transcriptase Variants Lacking Telomerase Activity Stimulate Cell Proliferation

“…In many species of Metazoa, TERT transcripts are alternatively spliced. Several AS TERT variants have been reported in a number of species, including human, rat, dog, chicken, zebrafish, and plants (63). In the case of humans and chickens, which have been studied extensively, 21 and 37 singleevent AS TERT variants have been identified (see references 2, 11, 27, 31, 52, and 73 and the data described here).…”

“…Several AS TERT variants have been cloned from plants and different vertebrate species (63). However, only the human and chicken TERT AS variants have been studied extensively, and this allows a comparison of these TERT isoforms in these two vertebrates (2, 11, 31, 52) ( Fig.…”

The Regulation of Telomerase by Alternative Splicing of TERT

“…Twenty-one AS variants of human TERT have been identified and most of the TERT transcripts in adult human tissue are alternatively spliced (Ulaner & Giudice, 1997). In contrast, mice express only a few AS forms (Sýkorová & Fajkus, 2009) suggesting that alternative splicing of TERT also correlates with levels of telomerase in these two species. In conclusion, alternative splicing of the TERT genes appears to be an important factor in the establishment of the interspecies differences in telomerase activity.…”

“…Several AS TERT variants have been reported in a number of species including human, rat, dog, chicken, zebrafish, and plants (Sýkorová & Fajkus, 2009). In the human and chicken, which have been extensively studied, 21 and 37 single-event AS TERT variants have been identified (Amor et al, 2010;Chang & Delany, 2006;Hisatomi et al, 2003;Hrdličková et al, 2012a;Hrdličková et al, 2006;Saebøe-Larssen et al, 2006;Wick et al, 1999).…”

“…Alternatively spliced variants of TERT are abundant and have been cloned from many vertebrate and plant species (Sýkorová & Fajkus, 2009). However, in depth analysis of their expression, evolution and function is limited.…”