Epigenetic control of telomerase and modes of telomere maintenance in aging and abnormal systems.

Department of Biology, University of Alabama at Birmingham, AL 35294-1170, USA.
Frontiers in Bioscience (Impact Factor: 3.52). 02/2005; 10(2):1779-96.
Source: PubMed


Epigenetic control provides a mechanism for the reversible silencing of telomerase expression that occurs as a natural consequence of differentiation. Significant overlap between indirect telomerase regulation pathways and cell cycle checkpoint pathways exist, suggesting that these discrete genetic elements (namely, p21, p53, and hTERT) synergistically cooperate to inhibit tumorigenesis. Mutations in these pathways have been known to contribute to cancer formation. However, the incorporation of epigenetic regulatory mechanisms provides another line of defense against these negative occurrences. These proteins are also implicated in the process of senescence, caused in eukaryotic cell lines by telomere shortening. Although the debate continues, there is significant evidence to classify the process of cellular senescence as an in vitro model for human aging. In addition, the study of stem cells gives information about the down-regulation of hTERT in the aging process. Diseases such as Werner S syndrome, ATM (ataxia telangiectasia mutated kinase), DKC (dyskeratosis congenita), and atherosclerosis have been linked to aberrant telomerase expression and other aging-related tissue malfunctions could be related to the presence of senescent cells changing the cellular microenvironment. Therefore, restoring telomerase activity as a putative therapeutic strategy necessitates further study to elucidate the intricacies linking genetic and epigenetic modulations of hTERT.

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    • "The acetylation of the histone proteins neutralizes the charge status of the histone tails, which decreases the attraction force between DNA and the histone tails, thus conferring an opened chromatin structure, allowing transcription factors, including c-MYC, MAD1 and CTCF, to bind to the DNA. Conversely, the deacetylation of histones results in the transcription factors having less access to the DNA (33,34). It has been demonstrated that Trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, is able to induce hTERT transcription and telomerase activity in normal cells and telomerase-negative immortal cell lines through the inhibition of histone deacetylation (Fig. 1) (35,36). "
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    ABSTRACT: Telomerase activation is a critical step in human carcinogenesis through the maintenance of telomeres. Telomerase activity is primarily regulated by the human telomerase reverse transcriptase gene (hTERT), thus, an improved understanding of the transcriptional control of hTERT may provide potential therapeutic targets for the treatment of leukemia and other forms of cancer. Epigenetic modulation, a significant regulatory process in cell biology, has recently been shown to be involved in the regulation of the hTERT gene. Moreover, several epigenetic modifiers, including DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors, are now in pre- and early clinical trials of leukemia as monotherapies or in combination with other drugs, and have achieved significant clinical success. In the present review, the epigenetic mechanisms associated with telomerase activity in leukemia, and the therapeutic potential of an antitelomerase strategy that combines epigenetic modifiers with telomerase hTR subunit small molecule inhibitors are discussed.
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