Telomerase regulation and stem cell behaviour
Introduction
The ends of chromosomes are formed by a special chromatin structure, known as the telomere, which is essential to protect chromosome-ends from degradation and DNA repair activities [1••, 2]. Telomeric chromatin is formed by tandem TTAGGG repeats and associated proteins [1••, 2]. Telomere repeats span ∼10–15 Kb in humans and 25–40 Kb in mice [3]. The proteins that associate with these repeats include the telomere repeat binding factors TRF1 and TRF2 as well as their interacting factors, which form a large protein complex recently named ‘shelterin’ [1••]. This complex is proposed to regulate both telomere length and telomere protection [1••]. Importantly, telomeres are also bound by nucleosome arrays, which show histone modifications characteristic of constitutive heterochromatin domains [3, 4]. Constitutive heterochromatin is generally found at transcriptionally inactive (‘silenced’) genomic regions of repetitive DNA, such as pericentric satellite repeats. Similar to pericentric chromatin, telomeres are enriched for binding of the heterochromatin protein 1 (HP1) and contain high levels of trimethylated H3-K9 and H4-K20, two histone modifications carried out by the histone methyltransferases (HMTases) suppressor of variegation 3–9 homolog (Suv39h) and suppressor of variegation 4-20 homolog (Suv4-20h), respectively [5, 6••, 7••]. The Retinoblastoma proteins are also required for efficient H4-K20 trimethylation at both telomeres and centromeres through direct interaction with the Suv4-20h HMTases [5, 7••]. The heterochromatic nature of telomeres, therefore, suggests that chromosome ends are in a compacted and ‘silenced’ chromatin conformation, which has to be finely regulated in order to properly control telomere length.
Interestingly, during cell division telomeres lose TTAGGG repeats as a result of the incomplete replication of linear chromosomes by conventional DNA polymerases, the so-called ‘end-replication problem’. This progressive telomere shortening is proposed to be one of the molecular mechanisms underlying organismal aging, since critically short telomeres trigger chromosome instability and loss of cell viability [3, 8]. As an exception, germ cells, certain populations of stem cells, and the vast majority of cancer cells express high levels of telomerase [3]. Telomerase is a reverse transcriptase encoded by the Tert (telomerase reverse transcriptase) and Terc (telomerase RNA component) genes, which adds telomeric repeats onto the chromosome ends [2, 8].
Defective telomerase activity and short telomeres have been implicated in the pathobiology of several age-related diseases and premature aging syndromes [3, 8, 9]. In contrast, telomerase is abnormally up-regulated in >90% of human tumors, where it is though to sustain tumor growth by maintaining telomeres above a threshold length. In this review, we will discuss recent advances on how telomerase is regulated, as well as on novel roles of telomeres and telomerase in stem cell biology. These new findings have profound implications for how telomerase regulates the balance between aging and cancer.
Section snippets
Telomerase regulation
It is of great interest to understand how telomerase activity is regulated in normal and pathological conditions in order to evaluate its potential as a therapeutic target. A number of different mechanisms have been shown to regulate telomerase activity. Regulation of Tert mRNA expression seems to be the most important and rate-limiting step for telomerase activation [10]. Other mechanisms for telomerase regulation include alternative splicing [11], post-translational Tert modification [12, 13,
Telomerase and stem cell behavior
Telomerase is up-regulated in cells that undergo rapid expansion, such as lymphocytes or keratinocytes, and notably in germ cells and in different stem cell compartments, even within tissues with a low cell turnover such as the brain [47]. The fact that telomerase activity is largely restricted to stem cells suggests that telomerase levels in these cells may be determinant for organism fitness. Indeed, mutations in the telomerase core components, Tert and Terc, are present in patients suffering
Terc as an optimal target for telomerase inhibition in cancer
As discussed above, Terc is required for the tumor-promoting effects of transgenic Tert over-expression in vivo [59], as well as to maintain the enhanced proliferative response of Tert-transgenic ESCs in vitro [57••]. Similarly, it has recently been reported that Terc is needed to maintain cell growth in different human cancer cell lines that over-express Tert [66, 67]. In particular, Terc knockdown rapidly inhibits the growth of human cancer cells in the absence of bulk telomere shortening or
Conclusions and perspectives
Despite great progress having been made on how telomere length and telomerase activity are regulated by genetic and epigenetic factors, additional biochemical and genetic studies are required to fully understand these processes during normal development and disease. Further knowledge on how telomerase is regulated should provide new avenues for targeting telomerase in cancer patients as well as in premature aging pathologies associated with short telomeres.
Importantly, the fact that telomerase
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
We thank G. Morel for helping with Figure design. Research in the laboratory of M.A.B. laboratory is funded by the MCYT (SAF2001-1869, GEN2001-4856-C13-08), by the Regional Government of Madrid, CAM (08.1/0054/01), by the European Union (TELOSENS FIGH-CT.2002-00217, INTACT LSHC-CT-2003-506803, ZINCAGE FOOD-CT-2003-506850, RISC-RAD F16R-CT-2003-508842), and the Josef Steiner Cancer Award 2003.
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