Surupa Chakraborty, Amity University, Kolkata
“The longer your telomeres, the better off you are”, remarkedElizabeth H. Blackburn, an eminent biologist and the Nobel Prize (2009) awardee for the remarkable discovery of how chromosomes are protected by telomeres and the enzyme telomerase.
Insight into the fountain of youth:
Telomeres are specialized minuscule molecular structures made from DNA sequences and proteins found at the terminal region of eukaryotic chromosomes. They contain a variable number of G-rich, repetitive, non-coding DNA sequences, unique for different species (mammals have a hexameric TTAGGG nucleotide repeat). They are supposed to serve several functions such as allowing the chromosomes to be replicated properly, maintaining genomic integrity, acting as a barrier to protect the genetic information from progressive degradation arising from incomplete DNA replication, as well as capping and protecting the ends of the chromosome from illicit ligation and resection. With every single cell division, the telomeres progressively shorten, ultimately leading to the cells responding with a cell cycle arrest, better defined as cell senescence which occurs when the cells reach the “Hayflick limit”. Hence, telomere shortening is a natural consequence of cell division which leads to the critically shortened length of telomeres which in turn triggers DNA damage response (DDR), finally leading to apoptosis.
Telomerase is a ribonucleoprotein (RNP) enzyme complex with specialized reverse transcriptase action to perform de novo synthesis of telomeric DNA using telomerase reverse transcriptase (TERT), other proteins, and a single long non-coding telomeric RNA (TERC) as a template. This telomerase-mediated restoration of telomeres, partially or completely (depending on cell type) counterbalances the attrition from incomplete DNA replication and inevitable DNA damage-induced inhibitory signaling pathways, as observed in cells undergoing oxidative stress or senescence. However, if a cell keeps diving uncontrollably and overcomes the limitations of telomeres, a cancerous tumor can form. Human carcinomas (tumors derived from epithelial tissues) and premalignant cells can universally bypass the cellular senescence barrier and enter into an extended lifespan period by upregulating telomerase or the rare ALT pathway (prevalent in cancers arising from mesenchymal tissues, neuroendocrine system, peripheral nervous system, central nervous system) and continue to proliferate.
Interplay of telomerase and TERT in the context of cancer:
Nudging up telomerase decreases the risk of many diseases but also has downsides of certain others including cancer risks. Telomerase activity is widespread and highly detected in most types of human malignancies, and thus can be considered as potential targets for anti-cancer approaches. In addition, the TERT gene is significantly upregulated in 85-95% of human cancers, via multiple genetic and epigenetic mechanisms viz. TERT promoter mutations, alterations in alternative splicing of TERT mRNA, epigenetic modifications through TERT promoter methylation and/or disruption of telomere position effect (TPE) mechanism, unlike in normal somatic cells where they are usually down-regulated and somewhat detectable. Although research studies have identified that telomerase is normally activated in germline, hematopoietic, stem and mitotically active cells with high proliferative potential like basal skin layer, endometrial tissue, intestinal crypts and hair follicles.
Given the cumulative evidence of the extensive role of telomerase or TERT in carcinogenesis, continued efforts have been made to dissect the underlying mechanisms of transcriptional controlling of the TERTgene, telomerase activation and TERT regulation at multiple levels via various positive and negative signaling pathways. Besides honing the unlimited cancer cell proliferation potential, TERT induction and telomerase activation also contribute to other oncogenic effects viz. repression of ROS-dependent activation, DNA damage repair, RNA-dependent RNA polymerase activity, effects on mitochondrial and ubiquitin-proteasomal function, microRNA (miRNA) expression, gene transcription and epithelial-mesenchymal transition, significant in giving rise to invasive phenotypes.
Medical relevance and therapeutic outlook:
Telomeres and Telomerase provide cancer cells with replicative immortality and therefore serve as potential biomarkers for cancer diagnosis, prognosis evaluation and anti-cancer therapeutic interventions. Multiple anti-cancer therapeutics targeting telomerase have garnered interest among the research community viz. developing small inhibitors of the catalytic subunit of telomerase, G-quadruplex stabilizing ligands, antitumor drug development, anti-telomerase immunotherapy and gene therapy, a few of which are enlisted below.
- A panel of non-protein-coding miRNAs, functioning as oncogenes and tumor suppressors have been the subject of recent clinical attention due to their involvement in cancer progression or in silencing the genes involved with cancer metastasis, by directly or indirectly targeting hTERT, causing it to be upregulated or downregulated, respectively.
- In contrast with the traditional cancer treatment modalities, novel therapies employing ribo- and deoxyribo-oligonucleotides (like Imetelstat /GRN163L and T-oligos) have shown improved therapeutic efficacy in various cancer types. They have huge clinical applications due to their nuclease resistance, high solubility, high stability in acidic solutions or in presence of metabolites and have been rigorously employed to uniquely target hTERT under specific domains (hTERT promoter, mRNA, or in its protein form).
- Potential telomeric G-quadruplex or G4 structures (non-canonical structures, non-randomly distributed within genomes, with multiple runs of guanine bases that can spontaneously fold into secondary structures) function in a regulatory capacity by providing a capping structure for telomeres, leading researchers to investigate the use of G4-targeted therapies in cancer treatment. Few G4 binding ligands or molecules including BRACO-19, RHPS4, and telomestatin which have demonstrated an ability to disrupt telomere replication by inhibiting the capping and catalytic functions of telomerase, highlight their therapeutic potential in producing an anti-cancer effect.
- Telomerase-based vaccines using hTERT-derived peptides are being tested in clinical trials based on their safety profile, immune response, and antitumor effects. They possess both MHC I and MHC II epitopes within their amino acid sequences, thereby sensitizing immune cells to cancer cells expressing hTERT peptides as surface antigens via HLA class I and class II pathways. They act on cancerous cells directly and elicit potent expansion of CD4+ and CD8+ and cytotoxic T lymphocytes (CTL) activation specific for oncogenic telomerase, thereby causing T cells to kill telomerase-positive tumor cells.
- Studies have demonstrated that telomeres are sensitive to reactive oxygen species (ROS) induced damage. Antioxidant enzymes such as peroxiredoxin 1 (PRDX1) and the nudix phosphohydrolase superfamily enzyme (MTH1) act in unison to prevent ROS dependent inhibition of telomerase in cancer cells. Thus, combination therapy with ROS-inducing chemotherapeutic agents and inhibitors of PRDX1/MTH1 that protect telomeres from ROS might open new avenues to selectively target telomere maintenance in cancer cells.
Challenges and future directions.
Deciphering the structure of telomeres and the mechanism of action of telomerase has been fundamental in understanding a telomerase-associated molecular landscape in cancers, thereby helped scientists to exploit their knowledge of it to advance therapeutic opportunities for cancer treatment. The high specificity of telomerase and the potential for inhibiting its activity at various stages underlie its value as an efficient biomarker for novel targeted therapeutics in order to eliminate the unlimited replicative potential, characteristic of most cancers. While most of these novel approaches restore hope for advanced treatment/cure, achievements in the field of telomere biology have only been a modest one.
Current studies have found that clinically relevant doses of GRN163L in vitro, do not interfere with the self-renewal and differentiation of stem cells (MSCs), the long-term effects of which have not yet been explored and require further investigation. Novel therapies developed in light of T-oligos and other telomerase inhibitors have not yet progressed to clinical trials due to lack of enough supporting evidence of T-oligo’s interaction with telomerase and shelterin components in several cancers. Despite an explosion in research interest on the use of miRNAs in studying tumorigenesis and cancer progression, application of the same are yet to be clinically manifested, owing to their limited stability, susceptibility to degradation by nucleases and possibility of triggering sequence-specific immune responses in non-cancer cells.
More avenues of investigation and clinical studies should be pursued to fight the foes of ignorance and controversies, and validate the efficacies of ligands, inhibitors, drugs, etc in the context of cancer. This can significantly optimize the application of telomerase-based diagnostics in cancer treatment and management, thereby contributing to precision oncology. Continued research on these novel therapies specifically targeting telomeres and telomerase will certainly bolster current therapeutic interventions and serve as a promising avenue to overcome the toxic side-effects of conventional cancer therapies in near future.
Also read: ATF4: A stress-responsive factor in mTORC1 signaling
Sources:
- Chan, S. R. W. L., & Blackburn, E. H. (2004). Telomeres and telomerase. Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences, 359(1441), 109–122. https://doi.org/10.1098/rstb.2003.1370
- Liu, T., Yuan, X., & Xu, D. (2016). Cancer-specific telomerase reverse transcriptase (Tert) promoter mutations: Biological and clinical implications. Genes, 7(7), 38. https://doi.org/10.3390/genes7070038
- Hu, C., Ni, Z., Li, B., Yong, X., Yang, X., Zhang, J., Zhang, D., Qin, Y., Jie, M., Dong, H., Li, S., He, F., & Yang, S. (2017). Htert promotes the invasion of gastric cancer cells by enhancing foxo3a ubiquitination and subsequent itgb1 upregulation. Gut, 66(1), 31–42. https://doi.org/10.1136/gutjnl-2015-309322
- Esquela-Kerscher, A., & Slack, F. J. (2006). Oncomirs—MicroRNAs with a role in cancer. Nature Reviews Cancer, 6(4), 259–269. https://doi.org/10.1038/nrc1840
- Schrank, Z., Khan, N., Osude, C., Singh, S., Miller, R., Merrick, C., Mabel, A., Kuckovic, A., & Puri, N. (2018). Oligonucleotides targeting telomeres and telomerase in cancer. Molecules, 23(9), 2267. https://doi.org/10.3390/molecules23092267
- Mizukoshi, E., & Kaneko, S. (2019). Telomerase-targeted cancer immunotherapy. International Journal of Molecular Sciences, 20(8), 1823. https://doi.org/10.3390/ijms20081823
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