Telomerase reverse transcriptase
Telomerase reverse transcriptase (abbreviated to TERT, or hTERT in humans) is a catalytic subunit of the enzyme telomerase, which, together with the telomerase RNA component (TERC), comprises the most important unit of the telomerase complex.[5][6]
Telomerases are part of a distinct subgroup of RNA-dependent polymerases. Telomerase lengthens telomeres in
hTERT absence (usually as a result of a
Function
Regulation
The hTERT gene, located on chromosome 5, consists of 16
Telomere deficiency is often linked to aging, cancers and the conditions
Stem cells
hTERT is often
High expression of hTERT is also often used as a landmark for
Immortalization
hTERT immortalizes various normal cells in culture, thereby endowing the self-renewal properties of stem cells to non-stem cell cultures.[14][22] There are multiple ways in which immortalization of non-stem cells can be achieved, one of which being via the introduction of hTERT into the cells. Differentiated cells often express hTERC and TP1, a telomerase-associated protein that helps form the telomerase assembly, but does not express hTERT. Hence, hTERT acts as the limiting factor for telomerase activity in differentiated cells.[14][23] However, with hTERT over-expression, active telomerase can be formed in differentiated cells. This method has been used to immortalize prostate epithelial and stromal-derived cells, which are typically difficult to culture in vitro. hTERT introduction allows in vitro culture of these cells and available for possible future research. The introduction of hTERT has an advantage over the use of viral protein for immortalization in that it does not involve the inactivation of tumor suppressor gene, which might lead to cancer formation.[22]
Enhancement
Over-expression of hTERT in stem cells changes the properties of the cells.
Increasing the telomerase activities in stem cells gives different effects depending on the intrinsic nature of the different types of stem cells.
Clinical significance
Deregulation of telomerase expression in somatic cells may be involved in
Genome-wide association studies suggest TERT is a susceptibility gene for development of many cancers,[25] including lung cancer.[26]
Role in cancer
The hTERT gene has been examined for
Therapeutic potential
If increased
hTERT
Medical implications
iPS cells
Early development of iPS cell lines were not efficient, as they yielded up to 5% of somatic cells successfully reprogrammed into a stem cell-like state.
The reactivation of hTERT, and subsequently
Telomere length in healthy adult cells elongates and acquires epigenetic characteristics similar to those of
DKC (
The functionality and efficiency of a reprogrammed iPS cell is determined by the ability of the cell to re-activate the telomerase complex and elongate its telomeres allowing for self-renewal. hTERT is a major limiting component of the telomerase complex and a deficiency of intact hTERT impedes the activity of telomerase, making iPS cells an unsuitable pathway towards therapy for telomere-deficient disorders.[38]
Androgen therapy
Although the mechanism is not fully understood, exposure of TERT-deficient
Aging
As organisms age and cells proliferate, telomeres shorten with each round of replication. Cells restricted to a specific lineage are capable of division only a set number of times, set by the length of telomeres, before they
Relation to epigenetic clock
Paradoxically, genetic variants in the TERT locus, which are associated with longer leukocyte telomere length, are associated with faster epigenetic aging rates in blood according to a molecular biomarker of aging known as epigenetic clock.[44] Similarly, human TERT expression did not arrest epigenetic aging in human fibroblasts.[44]
Gene therapy
The hTERT
Another method that has been studied is manipulating the hTERT promoter to induce apoptosis in tumor cells. Plasmid DNA sequences can be manufactured using the hTERT promoter followed by genes encoding for specific proteins. The protein can be a toxin, an apoptotic factor, or a viral protein. Toxins such as diphtheria toxin interfere with cellular processes and eventually induce apoptosis.[45] Apoptotic death factors like FADD (Fas-Associated protein with Death Domain) can be used to force cells expressing hTERT to undergo apoptosis.[48] Viral proteins like viral thymidine kinase can be used for specific targeting of a drug.[49] By introducing a prodrug only activated by the viral enzyme, specific targeting of cells expressing hTERT can be achieved.[49] By using the hTERT promoter, only cells expressing hTERT will be affected and this allows for specific targeting of tumor cells.[45][48][49]
Aside from cancer therapies, the hTERT gene has been used to promote the growth of hair follicles.[50] A schematic animation for gene therapy is shown as follows.
Interactions
Telomerase reverse transcriptase has been shown to
See also
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000164362 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000021611 – Ensembl, May 2017
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- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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Further reading
- Mattson MP, Fu W, Zhang P (May 2001). "Emerging roles for telomerase in regulating cell differentiation and survival: a neuroscientist's perspective". Mechanisms of Ageing and Development. 122 (7): 659–71. S2CID 23242866.
- Castillo Ureta H, Barrera Saldaña HA, Martínez Rodríguez HG (2003). "[Telomerase: an enzyme with multiple applications in cancer research]". Revista de Investigacion Clinica. 54 (4): 342–8. PMID 12415959.
- Janknecht R (April 2004). "On the road to immortality: hTERT upregulation in cancer cells". FEBS Letters. 564 (1–2): 9–13. S2CID 37540149.
- Cristofari G, Sikora K, Lingner J (March 2007). "Telomerase unplugged". ACS Chemical Biology. 2 (3): 155–8. PMID 17373762.
- Beliveau A, Yaswen P (June 2007). "Soothing the watchman: telomerase reduces the p53-dependent cellular stress response". Cell Cycle. 6 (11): 1284–7. PMID 17534147.
- Bellon M, Nicot C (2007). "Telomerase: a crucial player in HTLV-I-induced human T-cell leukemia". Cancer Genomics & Proteomics. 4 (1): 21–5. PMID 17726237.
External links
- GeneReviews/NCBI/NIH/UW entry on Dyskeratosis Congenita
- GeneReviews/NCBI/NIH/UW entry on Pulmonary Fibrosis, Familial
- TERT+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)