View source for Telomerase

{{short description|Telomere-restoring protein active in the most rapidly dividing cells}}
{{Primary sources|date = June 2015}}
[[File:Tibolium castaneum TERT structure.png|thumb|Telomerase catalytic subunit TERT of ''[[Tribolium castaneum]]'' (Red flour beetle), bound to putative RNA template and telomeric DNA (PDB [http://www.rcsb.org/pdb/explore/explore.do?structureId=3KYL 3KYL])]]
[[File:Telomerase illustration.jpg|thumb|A conceptual diagram showing the protein component of telomerase (TERT) in grey and the RNA component (TR) in yellow]]

'''Telomerase''', also called '''terminal transferase''',<ref>{{Cite web |url=http://www4.utsouthwestern.edu/cellbio/shay-wright/intro/facts/sw_facts.html |title=What are telomeres and telomerase? |access-date=2014-05-30 |archive-date=2014-05-30 |archive-url=https://web.archive.org/web/20140530062120/http://www4.utsouthwestern.edu/cellbio/shay-wright/intro/facts/sw_facts.html }}</ref> is a [[ribonucleoprotein]] that adds a species-dependent [[Telomere#Sequences|telomere repeat sequence]] to the [[Directionality (molecular biology)#3.27-end|3']] end of [[telomere]]s. A telomere is a region of repetitive [[Sequence (biology)|sequences]] at each end of the [[chromosome]]s of most [[eukaryote]]s. Telomeres protect the end of the chromosome from [[DNA damage (naturally occurring)|DNA damage]] or from fusion with neighbouring chromosomes. The fruit fly ''[[Drosophila melanogaster]]'' lacks telomerase, but instead uses [[retrotransposon]]s to maintain telomeres.<ref name="pmid21821789">{{cite journal | vauthors=Pardue ML, DeBaryshe PG | title=Retrotransposons that maintain chromosome ends | journal=[[Proceedings of the National Academy of Sciences of the United States of America|PNAS]]  | volume=108 | issue=51 | pages=20317–24 | year=2011 | doi = 10.1073/pnas.1100278108 | pmc = 3251079 | pmid=21821789| doi-access=free }}</ref>

Telomerase is a [[reverse transcriptase]] [[enzyme]] that carries its own [[Telomerase RNA component|RNA molecule]] (e.g., with the sequence 3′-[[Cytosine|C]]CC[[Adenine|A]]A[[Uracil|U]]CCC-5′ in ''[[Trypanosoma brucei]]'')<ref name="pmid10097086">{{cite journal | vauthors = Cano MI, Dungan JM, Agabian N, Blackburn EH | title = Telomerase in kinetoplastid parasitic protozoa | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 96 | issue = 7 | pages = 3616–21 | date = March 1999 | pmid = 10097086 | pmc = 22343 | doi = 10.1073/pnas.96.7.3616| bibcode = 1999PNAS...96.3616C | doi-access = free }}</ref> which is used as a template when it elongates telomeres. Telomerase is active in [[gamete]]s and most [[cancer]] cells, but is normally absent in most [[somatic cell]]s.

==History==
The existence of a compensatory mechanism for telomere shortening was first found by Soviet biologist [[Alexey Olovnikov]] in 1973,<ref name="pmid4754905">{{cite journal | vauthors = Olovnikov AM | title = A theory of marginotomy. The incomplete copying of template margin in enzymic synthesis of polynucleotides and biological significance of the phenomenon | journal = Journal of Theoretical Biology | volume = 41 | issue = 1 | pages = 181–90 | date = September 1973 | pmid = 4754905 | doi = 10.1016/0022-5193(73)90198-7 | bibcode = 1973JThBi..41..181O }}</ref> who also suggested the telomere hypothesis of [[aging]] and the telomere's connections to cancer and perhaps some neurodegenerative diseases.<ref name="pmid16247010" />

Telomerase in the [[ciliate]] ''[[Tetrahymena]]'' was discovered by [[Carol W. Greider]] and [[Elizabeth Blackburn]] in 1984.<ref name="pmid3907856">{{cite journal |vauthors=Greider CW, Blackburn EH | title = Identification of a specific telomere terminal transferase activity in Tetrahymena extracts | journal = Cell | volume = 43 | issue = 2 Pt 1 | pages = 405–13 |date=December 1985 | pmid = 3907856 | doi = 10.1016/0092-8674(85)90170-9 | doi-access = free }}</ref> Together with [[Jack W. Szostak]], Greider and Blackburn were awarded the 2009 [[Nobel Prize]] in [[Nobel Prize in Physiology or Medicine|Physiology or Medicine]] for their discovery.<ref name="Nobel_Prize_2003">{{cite web | url =  http://nobelprize.org/nobel_prizes/medicine/laureates/2009/press.html | title = The Nobel Prize in Physiology or Medicine 2009 | date = 2009-10-05 | access-date = 2010-10-23 | publisher = The Nobel Foundation }}</ref> Later the [[Cryogenic electron microscopy|cryo-EM]] structure of telomerase was first reported in ''T. thermophila'', to be followed a few years later by the cryo-EM structure of telomerase in humans.<ref name="pmid31451513">{{cite journal | vauthors = Wang Y, Sušac L, Feigon J | title = Structural Biology of Telomerase | journal = [[Cold Spring Harbor Laboratory Press#Journals|Cold Spring Harbor Perspectives in Biology]] | volume = 11 | issue=12 | article-number = a032383 | date=2019 | doi = 10.1101/cshperspect.a032383 | pmc=6886448 | pmid = 31451513}}</ref>

The role of telomeres and telomerase in [[cellular aging|cell aging]] and [[cancer]] was established by scientists at [[biotechnology]] company [[Geron Corporation|Geron]] with the cloning of the [[RNA]] and catalytic components of human telomerase<ref>{{cite journal |vauthors=Feng J, Funk WD, Wang SS, Weinrich SL, Avilion AA, Chiu CP, Adams RR, Chang E, Allsopp RC, Yu J | title = The RNA component of human telomerase | journal = Science | volume = 269 | issue = 5228 | pages = 1236–41 |date=September 1995 | pmid = 7544491 | doi = 10.1126/science.7544491| bibcode = 1995Sci...269.1236F | s2cid = 9440710 }}</ref> and the development of a [[polymerase chain reaction]] (PCR) based assay for telomerase activity called the TRAP assay, which surveys telomerase activity in multiple types of cancer.<ref>{{cite journal | vauthors = Kim NW, Piatyszek MA, Prowse KR, Harley CB, West MD, Ho PL, Coviello GM, Wright WE, Weinrich SL, Shay JW | title = Specific association of human telomerase activity with immortal cells and cancer | journal = Science | volume = 266 | issue = 5193 | pages = 2011–5 | date = December 1994 | pmid = 7605428 | doi = 10.1126/science.7605428 | bibcode = 1994Sci...266.2011K | s2cid = 11965342 }}</ref>

The [[negative stain]] electron microscopy (EM) structures of human and ''Tetrahymena'' telomerases were characterized in 2013.<ref>{{cite journal | vauthors = Sauerwald A, Sandin S, Cristofari G, Scheres SH, Lingner J, Rhodes D | title = Structure of active dimeric human telomerase | journal = Nature Structural & Molecular Biology | volume = 20 | issue = 4 | pages = 454–60 | date = April 2013 | pmid = 23474713 | doi = 10.1038/nsmb.2530 | pmc = 3785136 }}</ref><ref>{{cite journal | vauthors = Jiang J, Miracco EJ, Hong K, Eckert B, Chan H, Cash DD, Min B, Zhou ZH, Collins K, Feigon J | title = The architecture of Tetrahymena telomerase holoenzyme | journal = Nature | volume = 496 | issue = 7444 | pages = 187–92 | date = April 2013 | pmid = 23552895 | doi = 10.1038/nature12062 | pmc = 3817743 | bibcode = 2013Natur.496..187J }}</ref> Two years later, the first cryo-electron microscopy ([[cryo-EM]]) structure of telomerase holoenzyme (''Tetrahymena'') was determined.<ref>{{cite journal | vauthors = Jiang J, Chan H, Cash DD, Miracco EJ, Ogorzalek Loo RR, Upton HE, Cascio D, O'Brien Johnson R, Collins K, Loo JA, Zhou ZH, Feigon J | title = Structure of Tetrahymena telomerase reveals previously unknown subunits, functions, and interactions | journal = Science | volume = 350 | issue = 6260 | article-number = aab4070 | date = October 2015 | pmid = 26472759 | doi = 10.1126/science.aab4070 | pmc = 4687456 }}</ref> In 2018, the structure of human telomerase was determined through cryo-EM by UC Berkeley scientists.<ref>{{cite journal | vauthors = Nguyen TH, Tam J, Wu RA, Greber BJ, Toso D, Nogales E, Collins K | title = Cryo-EM structure of substrate-bound human telomerase holoenzyme | language = En | journal = Nature | volume = 557 | issue = 7704 | pages = 190–195 | date = May 2018 | pmid = 29695869 | pmc = 6223129 | doi = 10.1038/s41586-018-0062-x | bibcode = 2018Natur.557..190N }}</ref>

==Human telomerase structure==

Human telomerase complex consists of two [[molecules]] each of human [[telomerase reverse transcriptase]] (TERT, 1132 [[amino acids]]),<ref>{{Cite journal |last1=Jansson |first1=Linnea I. |last2=Stone |first2=Michael D. |date=2019-09-03 |title=Single-Molecule Analysis of Reverse Transcriptase Enzymes |journal=Cold Spring Harbor Perspectives in Biology |volume=11 |issue=9 |article-number=a032458 |doi=10.1101/cshperspect.a032458 |issn=1943-0264 |pmc=6719600 |pmid=31481455}}</ref> [[Telomerase RNA component|Telomerase RNA]] (TR or TERC, 452 nucleotides), and [[dyskerin]] (DKC1).<ref name="pmid17395830">{{cite journal |vauthors=Cohen S, Graham M, Lovrecz G, Bache N, Robinson P, Reddel R |title=Protein composition of catalytically active human telomerase from immortal cells |journal=[[Science (journal)|Science]] |volume=315 |issue=5820 |pages=1850–3 |year=2007 |pmid=17395830 |doi=10.1126/science.1138596|bibcode=2007Sci...315.1850C |s2cid=36658925 }}</ref><ref>{{Cite journal |last1=Verma |first1=Amit Kumar |last2=Singh |first2=Prithvi |last3=Al-Saeed |first3=Fatimah A. |last4=Ahmed |first4=Ahmed Ezzat |last5=Kumar |first5=Sunil |last6=Kumar |first6=Ashok |last7=Dev |first7=Kapil |last8=Dohare |first8=Ravins |date=2022-12-01 |title=Unravelling the role of telomere shortening with ageing and their potential association with diabetes, cancer, and related lifestyle factors |url=https://www.sciencedirect.com/science/article/abs/pii/S0040816622001975 |journal=Tissue and Cell |volume=79 |article-number=101925 |doi=10.1016/j.tice.2022.101925 |pmid=36137363 |issn=0040-8166|url-access=subscription }}</ref>

[[File:Working principle of telomerase.png|thumb|400px|An image illustrating how telomerase elongates telomere ends progressively]]

The protein consists of four [[Conserved sequence|conserved domains]] (RNA-Binding Domain (TRBD), fingers, palm and thumb), organized into a "right hand" ring configuration that shares common features with [[retroviral]] reverse transcriptases, viral [[RNA replicase]]s and [[bacteriophage]] B-family DNA polymerases.<ref>Gillis AJ, Schuller AP, Skordalakes E. Structure of the Tribolium castaneum telomerase catalytic subunit TERT. Nature. 2008 Oct 2;455(7213):633-7</ref><ref>Mitchell M, Gillis A, Futahashi M, Fujiwara H, Skordalakes E. Structural basis for telomerase catalytic subunit TERT binding to RNA template and telomeric DNA. Nat Struct Mol Biol. 2010 Apr;17(4):513-8</ref>

TERT proteins from many eukaryotes have been sequenced.<ref>NCBI - [https://web.archive.org/web/20180522122802/https://www.ncbi.nlm.nih.gov/protein?cmd=DetailsSearch&term=telomerase+reverse+transcriptase&log$=activity telomerase reverse transcriptase]</ref>

==Mechanism==
<!-- Image with unknown copyright status removed: [[Image:telomerase.jpg|thumb|250 px|Telomerase extending telomeres]] -->

The [[shelterin]] protein [[ACD (gene)|TPP1]] is both necessary and sufficient to recruit the telomerase enzyme to telomeres, and is the only shelterin protein in direct contact with telomerase.<ref name="pmid33482595">{{cite journal | vauthors = Grill S, Nandakumar J | title = Molecular mechanisms of telomere biology disorders | journal = [[Journal of Biological Chemistry]] | volume = 296 | article-number = 100064 | date=2021 | doi = 10.1074/jbc.REV120.014017  |doi-access=free | pmc=7948428 | pmid = 33482595}}</ref>

By using TERC, TERT can add a six-nucleotide repeating sequence, 5'-[[Thymidine|T]]TA[[Guanine|G]]GG (in vertebrates; the sequence differs in other organisms) to the 3' strand of chromosomes. These TTAGGG repeats (with their various protein binding partners) are called telomeres. The template region of TERC is 3'-CAAUCCCAAUC-5'.<ref name="pmid12384594">{{cite journal |vauthors=Gavory G, Farrow M, Balasubramanian S | title = Minimum length requirement of the alignment domain of human telomerase RNA to sustain catalytic activity in vitro | journal = Nucleic Acids Res. | volume = 30 | issue = 20 | pages = 4470–80 |date=October 2002 | pmid = 12384594 | pmc = 137139 | doi = 10.1093/nar/gkf575 }}</ref>

Telomerase can bind the first few nucleotides of the template to the last telomere sequence on the chromosome, add a new telomere repeat (5'-GGTTAG-3') sequence, let go, realign the new 3'-end of telomere to the template, and repeat the process. Telomerase reverses [[Telomere#Shortening|telomere shortening]].

==Clinical implications==

===Aging===
Telomerase restores short bits of DNA known as [[telomeres]], which are otherwise shortened after repeated division of a cell via [[mitosis]].

In normal circumstances, where telomerase is absent, if a cell divides recursively, at some point the progeny reach their [[Hayflick limit]],<ref>{{cite journal |vauthors=Hayflick L, Moorhead PS |title=The serial cultivation of human diploid cell strains |journal=Exp Cell Res |volume=25 |pages=585–621 |year=1961 |pmid=13905658 |doi=10.1016/0014-4827(61)90192-6 |issue=3}}</ref> which is believed to be between 50 and 70 cell divisions. At the limit the cells become senescent and [[cell division]] stops.<ref>Siegel, L (2013). [http://learn.genetics.utah.edu/content/begin/traits/telomeres Are Telomeres the Key to Aging and Cancer?] {{webarchive|url=https://web.archive.org/web/20131201021609/http://learn.genetics.utah.edu/content/begin/traits/telomeres/ |date=2013-12-01 }} The University of Utah. Retrieved 30 September 2013</ref> Telomerase allows each offspring to replace the lost bit of DNA, allowing the cell line to divide without ever reaching the limit. This same unbounded growth is a feature of [[cancer|cancerous growth]].<ref name="pmid21376230">{{cite journal |vauthors=Hanahan D, Weinberg RA| title = Hallmarks of cancer: the next generation | journal = Cell | volume = 144 | issue = 5 | pages = 646–74 |date=March 2011 | pmid = 21376230 | doi = 10.1016/j.cell.2011.02.013 | doi-access = free }}</ref>

[[Embryonic stem cells]] express telomerase, which allows them to divide repeatedly and form the individual. In adults, telomerase is highly expressed only in cells that need to divide regularly, especially in male [[sperm cell]]s,<ref>{{cite journal | vauthors = Fice HE, Robaire B | title = Telomere Dynamics Throughout Spermatogenesis | journal = Genes | volume = 10 | issue = 7 | page = 525 | date = July 2019 | pmid = 31336906 | pmc = 6678359 | doi = 10.3390/genes10070525 | doi-access = free }}</ref> but also in [[epidermis|epidermal cells]],<ref name="pmid8692840 ">{{cite journal | vauthors = Härle-Bachor C, Boukamp P | title = Telomerase activity in the regenerative basal layer of the epidermis inhuman skin and in immortal and carcinoma-derived skin keratinocytes | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 93 | issue = 13 | pages = 6476–6481 | date = June 1996 | pmid = 8692840 | pmc = 39048 | doi = 10.1073/pnas.93.13.6476 | doi-access = free | bibcode = 1996PNAS...93.6476H }}</ref> in activated [[T cell]]<ref name="pmid21395382">{{cite journal | vauthors = Barsov EV | title = Telomerase and primary T cells: biology and immortalization for adoptive immunotherapy | journal = Immunotherapy | volume = 3 | issue = 3 | pages = 407–421 | date = March 2011 | pmid = 21395382 | pmc = 3120014 | doi = 10.2217/imt.10.107 }}</ref> and [[B cell]]<ref name="pmid19806612">{{cite journal | vauthors = Bougel S, Renaud S, Braunschweig R, Loukinov D, Morse HC, Bosman FT, Lobanenkov V, Benhattar J | display-authors = 6 | title = PAX5 activates the transcription of the human telomerase reverse transcriptase gene in B cells | journal = The Journal of Pathology | volume = 220 | issue = 1 | pages = 87–96 | date = January 2010 | pmid = 19806612 | pmc = 3422366 | doi = 10.1002/path.2620 }}</ref> [[lymphocyte]]s, as well as in certain [[adult stem cells]], but in the great majority of cases [[Somatic (biology)|somatic]] cells do not express telomerase.<ref>{{cite journal | vauthors = Cong YS, Wright WE, Shay JW | title = Human telomerase and its regulation | journal = Microbiology and Molecular Biology Reviews | volume = 66 | issue = 3 | pages = 407–25, table of contents | date = September 2002 | pmid = 12208997 | pmc = 120798 | doi = 10.1128/MMBR.66.3.407-425.2002 }}</ref>

A comparative biology study of mammalian telomeres indicated that telomere length of some mammalian species correlates inversely, rather than directly, with lifespan, and concluded that the contribution of telomere length to lifespan is unresolved.<ref>{{cite journal | vauthors = Gomes NM, Ryder OA, Houck ML, Charter SJ, Walker W, Forsyth NR, Austad SN, Venditti C, Pagel M, Shay JW, Wright WE | title = Comparative biology of mammalian telomeres: hypotheses on ancestral states and the roles of telomeres in longevity determination | journal = Aging Cell | volume = 10 | issue = 5 | pages = 761–8 | date = October 2011 | pmid = 21518243 | pmc = 3387546 | doi = 10.1111/j.1474-9726.2011.00718.x }}</ref>  Telomere shortening does not occur with age in some [[postmitotic]] tissues, such as in the rat brain.<ref>{{cite journal | vauthors = Cherif H, Tarry JL, Ozanne SE, Hales CN | title = Ageing and telomeres: a study into organ- and gender-specific telomere shortening | journal = Nucleic Acids Research | volume = 31 | issue = 5 | pages = 1576–83 | date = March 2003 | pmid = 12595567 | pmc = 149817 | doi = 10.1093/nar/gkg208 }}</ref> In humans, skeletal muscle telomere lengths remain stable from ages 23 –74.<ref>{{cite journal | vauthors = Renault V, Thornell LE, Eriksson PO, Butler-Browne G, Mouly V, Thorne LE | title = Regenerative potential of human skeletal muscle during aging | journal = Aging Cell | volume = 1 | issue = 2 | pages = 132–9 | date = December 2002 | pmid = 12882343 | doi = 10.1046/j.1474-9728.2002.00017.x | doi-access = free }}</ref> In baboon skeletal muscle, which consists of fully [[Cellular differentiation|differentiated]] postmitotic cells, less than 3% of [[myonuclei]] contain damaged telomeres and this percentage does not increase with age.<ref>{{cite journal | vauthors = Jeyapalan JC, Ferreira M, Sedivy JM, Herbig U | title = Accumulation of senescent cells in mitotic tissue of aging primates | journal = Mechanisms of Ageing and Development | volume = 128 | issue = 1 | pages = 36–44 | date = January 2007 | pmid = 17116315 | pmc = 3654105 | doi = 10.1016/j.mad.2006.11.008 }}</ref> Thus, telomere shortening does not appear to be a major factor in the aging of the differentiated cells of brain or skeletal muscle. In human liver, [[cholangiocytes]] and [[hepatocytes]] show no age-related telomere shortening.<ref>{{cite journal | vauthors = Verma S, Tachtatzis P, Penrhyn-Lowe S, Scarpini C, Jurk D, Von Zglinicki T, Coleman N, Alexander GJ | title = Sustained telomere length in hepatocytes and cholangiocytes with increasing age in normal liver | journal = Hepatology | volume = 56 | issue = 4 | pages = 1510–20 | date = October 2012 | pmid = 22504828 | doi = 10.1002/hep.25787 | s2cid = 25965027 | doi-access = free }}</ref> Another study found little evidence that, in humans, telomere length is a significant [[biomarker]] of normal aging with respect to important cognitive and physical abilities.<ref>{{cite journal | vauthors = Harris SE, Martin-Ruiz C, von Zglinicki T, Starr JM, Deary IJ | s2cid = 10309423 | title = Telomere length and aging biomarkers in 70-year-olds: the Lothian Birth Cohort 1936 | journal = Neurobiology of Aging | volume = 33 | issue = 7 | pages = 1486.e3–8 | date = July 2012 | pmid = 21194798 | doi = 10.1016/j.neurobiolaging.2010.11.013 }}</ref>

Some experiments have raised questions on whether telomerase can be used as an [[anti-aging therapy]], namely, the fact that mice with elevated levels of telomerase have higher cancer incidence and hence do not live longer.<ref name="pmid15312299">{{cite journal |vauthors=de Magalhães JP, Toussaint O | title = Telomeres and telomerase: a modern fountain of youth? | journal = Rejuvenation Res | volume = 7 | issue = 2 | pages = 126–33 | year = 2004 | pmid = 15312299 | doi = 10.1089/1549168041553044 | citeseerx = 10.1.1.318.8027 }}</ref> On the other hand, one study showed that activating telomerase in cancer-resistant mice by overexpressing its catalytic subunit extended lifespan.<ref name="pmid19013273">{{cite journal |vauthors=Tomás-Loba A, Flores I, Fernández-Marcos PJ, Cayuela ML, Maraver A, Tejera A, Borrás C, Matheu A, Klatt P, Flores JM, Viña J, Serrano M, Blasco MA | s2cid = 14753825 | title = Telomerase reverse transcriptase delays aging in cancer-resistant mice | journal = Cell | volume = 135 | issue = 4 | pages = 609–22 |date=November 2008 | pmid = 19013273 | doi = 10.1016/j.cell.2008.09.034 | doi-access = free }}</ref> A study found that long-lived subjects inherited a hyperactive version of telomerase.<ref name="pmid19915151">{{cite journal |vauthors=Atzmon G, Cho M, Cawthon RM, Budagov T, Katz M, Yang X, Siegel G, Bergman A, Huffman DM, Schechter CB, Wright WE, Shay JW, Barzilai N, Govindaraju DR, Suh Y | title = Genetic variation in human telomerase is associated with telomere length in Ashkenazi centenarians | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 107 | issue = Suppl 1 | pages = 1710–7 |date=January 2010 | pmid = 19915151 | pmc = 2868292 | doi = 10.1073/pnas.0906191106 |  doi-access = free }}
* {{lay source |template = web|url = http://www.livescience.com/health/091112-anti-aging-telomeres.html|title = One Key Found for Living to 100|date= November 12, 2009 |website = LiveScience }}</ref>

====Premature aging====
Premature aging syndromes including [[Werner syndrome]], [[Progeria]], [[Ataxia telangiectasia]], Ataxia-telangiectasia like disorder, [[Bloom syndrome]], [[Fanconi anemia]] and [[Nijmegen breakage syndrome]] are associated with short telomeres.<ref name="pmid16136653">{{cite journal | vauthors = Blasco MA | s2cid = 14828121 | title = Telomeres and human disease: ageing, cancer and beyond | journal = Nature Reviews. Genetics | volume = 6 | issue = 8 | pages = 611–22 | date = August 2005 | pmid = 16136653 | doi = 10.1038/nrg1656 }}</ref> However, the genes that have mutated in these diseases all have roles in the [[DNA repair|repair of DNA damage]] and the increased DNA damage may, itself, be a factor in the premature aging (see [[DNA damage theory of aging]]). An additional role in maintaining telomere length is an active area of investigation.

===Cancer===
''In vitro,'' when cells approach the [[Hayflick limit]], the time to senescence can be extended by inactivating the [[tumor suppressor gene|tumor suppressor]] proteins [[p53]] and [[Retinoblastoma protein]] (pRb).<ref name=":0">{{cite journal | vauthors = Akincilar SC, Unal B, Tergaonkar V | title = Reactivation of telomerase in cancer | journal = Cellular and Molecular Life Sciences | volume = 73 | issue = 8 | pages = 1659–1670 | date = April 2016 | pmid = 26846696 | pmc = 4805692 | doi = 10.1007/s00018-016-2146-9 }}</ref> [[Cell (biology)|Cell]]s that have been so-altered eventually undergo an event termed a "crisis" when the majority of the cells in the culture die. Sometimes, a cell does not stop dividing once it reaches a crisis. In a typical situation, the telomeres are shortened<ref>{{cite book| vauthors = Skloot R |title=The Immortal Life of Henrietta Lacks |year=2010 |publisher=Broadway Paperbacks |location=New York |isbn=978-1-4000-5218-9|pages=[https://archive.org/details/unset0000unse_h0q7/page/216 216, 217] |url= https://archive.org/details/unset0000unse_h0q7/page/216 }}</ref> and chromosomal integrity declines with every subsequent cell division. Exposed chromosome ends are interpreted as double-stranded breaks (DSB) in DNA; such damage is usually [[DNA repair|repaired]] by reattaching the broken ends together. When the cell does this due to telomere-shortening, the ends of different chromosomes can be attached to each other. This solves the problem of lacking telomeres, but during cell division [[anaphase]], the fused chromosomes are randomly ripped apart, causing many [[mutation]]s and chromosomal abnormalities. As this process continues, the cell's genome becomes unstable. Eventually, either fatal damage is done to the cell's chromosomes (killing it via [[apoptosis]]), or an additional mutation that activates telomerase occurs.<ref name=":0" />

With telomerase activation some types of cells and their offspring become [[Biological immortality|immortal]] (bypass the [[Hayflick limit]]), thus avoiding cell death as long as the conditions for their duplication are met. Many [[cancer cell]]s are considered 'immortal' because telomerase activity allows them to live much longer than any other somatic cell, which, combined with uncontrollable cell proliferation<ref>Dr. Todd Hennessey, 2016 University at Buffalo</ref> is why they can form [[tumor]]s. A good example of immortal cancer cells is [[HeLa cell]]s, which have been used in laboratories as a model [[cell line]] since 1951.

While this method of modelling human cancer in cell culture is effective and has been used for many years by scientists, it is also very imprecise. The exact changes that allow for the formation of the [[tumorigenic]] [[Cloning|clone]]s in the above-described experiment are not clear. Scientists addressed this question by the serial introduction of multiple mutations present in a variety of human cancers. This has led to the identification of mutation combinations that form tumorigenic cells in a variety of cell types. While the combination varies by cell type, the following alterations are required in all cases: TERT activation, loss of p53 pathway function, loss of pRb pathway function, activation of the [[Ras subfamily|Ras]] or [[C-myc|myc]] [[proto-oncogenes]], and aberration of the [[Protein phosphatase 2]] (PP2A).<ref>{{cite journal | vauthors = Grech G, Baldacchino S, Saliba C, Grixti MP, Gauci R, Petroni V, Fenech AG, Scerri C | display-authors = 6 | title = Deregulation of the protein phosphatase 2A, PP2A in cancer: complexity and therapeutic options | journal = Tumour Biology | volume = 37 | issue = 9 | pages = 11691–11700 | date = September 2016 | pmid = 27444275 | doi = 10.1007/s13277-016-5145-4 | s2cid = 24784814 }}</ref> That is to say, the cell has an activated telomerase, eliminating the process of death by chromosome instability or loss, absence of apoptosis-induction pathways, and continued [[mitosis]] activation.

This model of [[cancer]] in cell culture accurately describes the role of telomerase in actual human tumors. Telomerase activation has been observed in ~90% of all human tumors,<ref name="pmid9282118">{{cite journal | vauthors = Shay JW, Bacchetti S | title = A survey of telomerase activity in human cancer | journal = European Journal of Cancer | volume = 33 | issue = 5 | pages = 787–91 | date = April 1997 | pmid = 9282118 | doi = 10.1016/S0959-8049(97)00062-2 }}</ref> suggesting that the immortality conferred by telomerase plays a key role in cancer development. Of the tumors without TERT activation,<ref name="pmid7556065">{{cite journal | vauthors = Bryan TM, Englezou A, Gupta J, Bacchetti S, Reddel RR | title = Telomere elongation in immortal human cells without detectable telomerase activity | journal = The EMBO Journal | volume = 14 | issue = 17 | pages = 4240–8 | date = September 1995 | pmid = 7556065 | pmc = 394507 | doi =  10.1002/j.1460-2075.1995.tb00098.x}}</ref> most employ a separate pathway to maintain telomere length termed [[Alternative Lengthening of Telomeres]] (ALT).<ref name="pmid11850785">{{cite journal | vauthors = Henson JD, Neumann AA, Yeager TR, Reddel RR | title = Alternative lengthening of telomeres in mammalian cells | journal = Oncogene | volume = 21 | issue = 4 | pages = 598–610 | date = January 2002 | pmid = 11850785 | doi = 10.1038/sj.onc.1205058 | doi-access = free }}</ref> The presence of this alternative pathway was first described in an SV40 virus-transformed human cell line, and based on the dynamics of the changes in telomere length, was proposed to result through [[Genetic recombination|recombination]].<ref>{{cite journal |last1=Murnane |first1=John P. |last2=Sabatier |first2=Laure |last3=Marder |first3=Brad A. |last4=Morgan |first4=William F. |title=Telomere dynamics in an immortal human cell line |journal=EMBO Journal |date=1994 |volume=13 |issue=17 |pages=4953–4962 |doi=10.1002/j.1460-2075.1995.tb00098.x |pmid=7556065 |pmc=394507 }}</ref> However, the exact mechanism remains unclear.

[[Elizabeth Blackburn]] ''et al.'', identified the upregulation of 70 genes known or suspected in cancer growth and spread through the body, and the activation of [[glycolysis]], which enables cancer cells to rapidly use sugar to facilitate their programmed growth rate (roughly the growth rate of a fetus).<ref name="pmid15680963">{{cite journal | vauthors = Blackburn EH | title = Telomeres and telomerase: their mechanisms of action and the effects of altering their functions | journal = FEBS Letters | volume = 579 | issue = 4 | pages = 859–862 | date = February 2005 | pmid = 15680963 | doi = 10.1016/j.febslet.2004.11.036 | bibcode = 2005FEBSL.579..859B | doi-access = free }}</ref>

Approaches to controlling telomerase and telomeres for cancer therapy include [[gene therapy]], [[cancer immunotherapy|immunotherapy]], small-molecule and signal pathway inhibitors.<ref name="Tian 2013" />

====Drugs====
The ability to maintain functional [[telomeres]] may be one mechanism that allows [[cancer cells]] to grow ''in vitro'' for decades.<ref name="Griffiths2008">{{cite book| vauthors = Griffiths AJ, Wesslet SR, Carroll SB, Doebley J |title=Introduction to Genetic Analysis|url={{google books |plainurl=y |id=MsFkrBY2-5AC}}|year=2008|publisher=W. H. Freeman|isbn=978-0-7167-6887-6}}</ref> Telomerase activity is necessary to preserve many cancer types and is inactive in [[somatic cells]], creating the possibility that telomerase inhibition could selectively repress cancer cell growth with minimal side effects.<ref name="pmid23295993">{{cite journal | vauthors = Williams SC | title = No end in sight for telomerase-targeted cancer drugs | journal = Nature Medicine | volume = 19 | issue = 1 | page = 6 | date = January 2013 | pmid = 23295993 | doi = 10.1038/nm0113-6 | s2cid = 12232531 | doi-access = free }}</ref> If a drug can inhibit telomerase in cancer cells, the telomeres of successive generations will progressively shorten, limiting tumor growth.<ref name="pmid12488618">{{cite journal | vauthors = Blasco MA | title = Telomeres in Cancer Therapy | journal = Journal of Biomedicine & Biotechnology | volume = 1 | issue = 1 | pages = 3–4 | date = 2001 | pmid = 12488618 | pmc = 79678 | doi = 10.1155/S1110724301000109 | doi-access = free }}</ref>

Telomerase is a good [[biomarker]] for cancer detection because most human cancer cells express high levels of it. Telomerase activity can be identified by its catalytic protein domain ([[hTERT]]). {{clarify span|This|date=September 2015}} is the [[rate-limiting step]] in telomerase activity. It is associated with many cancer types. Various cancer cells and [[fibroblasts]] transformed with hTERT [[cDNA]] have high telomerase activity, while somatic cells do not. Cells testing positive for hTERT have positive nuclear signals. Epithelial stem cell tissue and its early daughter cells are the only noncancerous cells in which hTERT can be detected. Since hTERT expression is dependent only on the number of tumor cells within a sample, the amount of hTERT indicates the severity of cancer.<ref name="Shay">{{cite journal | vauthors = Shay JW, Zou Y, Hiyama E, Wright WE | title = Telomerase and cancer | journal = Human Molecular Genetics | volume = 10 | issue = 7 | pages = 677–85 | date = April 2001 | pmid = 11257099 | doi = 10.1093/hmg/10.7.677 | doi-access = free }}</ref>

The expression of hTERT can also be used to distinguish [[benign tumors]] from [[malignant tumors]]. Malignant tumors have higher hTERT expression than benign tumors. Real-time [[reverse transcription polymerase chain reaction]] (RT-PCR) quantifying hTERT expression in various tumor samples verified this varying expression.<ref name="Gul">{{cite journal | vauthors = Gül I, Dündar O, Bodur S, Tunca Y, Tütüncü L | title = The status of telomerase enzyme activity in benign and malignant gynaecologic pathologies | journal = Balkan Medical Journal | volume = 30 | issue = 3 | pages = 287–92 | date = September 2013 | pmid = 25207121 | pmc = 4115914 | doi = 10.5152/balkanmedj.2013.7328 }}</ref>
[[File:Immuntherap.jpg|thumb|Figure 4:A) Tumor cells expressing hTERT will actively degrade some of the protein and process for presenting. The major histocompatibility complex 1(MHC1), can then present the hTERT epitote. CD8- T cells that have antigen-specific T cell receptors against hTERT will then bind to the presented epitote. B) As a result of the antigenic binding, the T cells will release cytotoxins, which can be absorbed by the affected cell. C) These cytotoxins induce multiple proteases and result in apoptosis (or cell death).]]
The lack of telomerase does not affect cell growth until the telomeres are short enough to cause cells to "die or undergo growth arrest". However, inhibiting telomerase alone is not enough to destroy large tumors. It must be combined with surgery, [[radiation treatment|radiation]], [[chemotherapy]] or immunotherapy.<ref name="Shay" />

Cells may reduce their telomere length by only 50-252 base pairs per cell division, which can lead to a long [[lag phase]].<ref name="Saret">{{cite journal | vauthors = Saretzki G | title = Telomerase inhibition as cancer therapy | journal = Cancer Letters | volume = 194 | issue = 2 | pages = 209–19 | date = May 2003 | pmid = 12757979 | doi = 10.1016/s0304-3835(02)00708-5 }}</ref><ref name="Stoyanov">{{cite journal | vauthors = Stoyanov V | year = 2009 | title = T-loop deletion factor showing speeding aging of Homo telomere diversity and evolution  | journal = Rejuvenation Research | volume = 12 | issue = 1| page = 52 }}</ref>

A telomerase activator [[TA-65]] is commercially available and is claimed to delay aging and to provide relief from certain disease conditions.<ref>{{cite journal | vauthors = Fernandez ML, Thomas MS, Lemos BS, DiMarco DM, Missimer A, Melough M, Chun OK, Murillo AG, Alyousef HM, Medina-Vera I | display-authors = 6 | title = TA-65, A Telomerase Activator improves Cardiovascular Markers in Patients with Metabolic Syndrome | journal = Current Pharmaceutical Design | volume = 24 | issue = 17 | pages = 1905–1911 | year = 2018 | pmid = 29546832 | doi = 10.2174/1381612824666180316114832 | s2cid = 3892746 }}</ref><ref>{{cite journal | vauthors = Harley CB, Liu W, Blasco M, Vera E, Andrews WH, Briggs LA, Raffaele JM | title = A natural product telomerase activator as part of a health maintenance program | journal = Rejuvenation Research | volume = 14 | issue = 1 | pages = 45–56 | date = February 2011 | pmid = 20822369 | pmc = 3045570 | doi = 10.1089/rej.2010.1085 }}</ref><ref>{{cite journal | vauthors = Salvador L, Singaravelu G, Harley CB, Flom P, Suram A, Raffaele JM | title = A Natural Product Telomerase Activator Lengthens Telomeres in Humans: A Randomized, Double Blind, and Placebo Controlled Study | journal = Rejuvenation Research | volume = 19 | issue = 6 | pages = 478–484 | date = December 2016 | pmid = 26950204 | pmc = 5178008 | doi = 10.1089/rej.2015.1793 }}</ref><ref>{{cite journal | vauthors = Harley CB, Liu W, Flom PL, Raffaele JM | title = A natural product telomerase activator as part of a health maintenance program: metabolic and cardiovascular response | journal = Rejuvenation Research | volume = 16 | issue = 5 | pages = 386–395 | date = October 2013 | pmid = 23808324 | doi = 10.1089/rej.2013.1430 }}</ref><ref>{{cite journal | vauthors = Hoffmann J, Richardson G, Haendeler J, Altschmied J, Andrés V, Spyridopoulos I | title = Telomerase as a Therapeutic Target in Cardiovascular Disease | journal = Arteriosclerosis, Thrombosis, and Vascular Biology | volume = 41 | issue = 3 | pages = 1047–1061 | date = March 2021 | pmid = 33504179 | doi = 10.1161/ATVBAHA.120.315695 | s2cid = 231753311 | doi-access = free }}</ref> This formulation contains a molecule called [[cycloastragenol]] derived from a legume Astragalus membranaceus. Several other compounds have been found to increase telomerase activity: [[Centella asiatica]] extract&nbsp;8.8-fold, [[oleanolic acid]]&nbsp;5.9-fold, [[Astragalus (plant)|astragalus]] extract&nbsp;4.3-fold, TA-65&nbsp;2.2-fold, and [[maslinic acid]]&nbsp;2-fold.<ref name="pmid31485647">{{cite journal | vauthors = Tsoukalas D, Fragkiadaki P, Calina D | title=Discovery of potent telomerase activators: Unfolding new therapeutic and anti-aging perspectives | journal=Molecular Medicine Reports | volume=20 | issue=4 | pages=3701–3708 | year=2019 | doi= 10.3892/mmr.2019.10614 | pmc=6755196 | pmid=31485647}}</ref>

====Immunotherapy====

[[Immunotherapy]] successfully treats some kinds of cancer, such as [[melanoma]]. This treatment involves manipulating a human's [[immune system]] to destroy cancerous cells. Humans have two major [[antigen]] identifying [[lymphocyte]]s: [[CD8]]+ [[cytotoxic T-lymphocytes]] (CTL) and [[CD4]]+ [[T helper cell|helper T-lymphocytes]] that can destroy cells. Antigen receptors on CTL can bind to a 9-10 [[amino acid]] chain that is presented by the [[major histocompatibility complex]] (MHC) as in Figure 4.  HTERT is a potential target antigen. Immunotargeting should result in relatively few side effects since hTERT expression is associated only with telomerase and is not essential in almost all somatic cells.<ref name="Patel">{{cite journal | vauthors = Patel KP, Vonderheide RH | title = Telomerase as a tumor-associated antigen for cancer immunotherapy | journal = Cytotechnology | volume = 45 | issue = 1–2 | pages = 91–9 | date = June 2004 | pmid = 19003246 | pmc = 3449959 | doi = 10.1007/s10616-004-5132-2 }}</ref> GV1001 uses this pathway.<ref name="Tian 2013" /> Experimental drug and [[vaccine]] therapies targeting active telomerase have been tested in [[mouse model]]s, and [[clinical trial]]s have begun. One drug, [[imetelstat]], is being clinically researched as a means of interfering with telomerase in cancer cells.<ref>{{Cite news|url = http://www.modernhealthcare.com/article/20150902/NEWS/150909967|title = Experimental blood disorder therapy shows promise in new studies | vauthors = Johnson SR | name-list-style = vanc |date = 2 September 2015 |work = Modern Healthcare }}</ref> Most of the harmful cancer-related effects of telomerase are dependent on an intact RNA template. [[Cancer stem cell]]s that use an alternative method of telomere maintenance are still killed when telomerase's RNA template is blocked or damaged.

====Telomerase Vaccines====
Two telomerase vaccines have been developed: [[GRNVAC1]] and [[GV1001]]. GRNVAC1 isolates [[dendritic cells]] and the RNA that codes for the telomerase protein and puts them back into the patient to make [[cytotoxic]] T cells that kill the telomerase-active cells. GV1001 is a peptide from the active site of hTERT and is recognized by the immune system that reacts by killing the telomerase-active cells.<ref name="Tian 2013">{{cite journal | vauthors = Tian X, Chen B, Liu X | s2cid = 20560225 | title = Telomere and telomerase as targets for cancer therapy | journal = Applied Biochemistry and Biotechnology | volume = 160 | issue = 5 | pages = 1460–72 | date = March 2010 | pmid = 19412578 | doi = 10.1007/s12010-009-8633-9 }}</ref>

====Targeted apoptosis====
[[File:Antisenseoligonucleotide.jpg|thumb|Figure 5: A) Human telomerase RNA (hTR) is present in the cell and can be targeted. B) 2-5 anti-hTR oligonucleotides is a specialized antisense oligo that can bind to the telomerase RNA. C) Once bound, the 2-5 anti-hTR oligonucleotide recruits RNase L to the sequence. Once recruited, the RNase L creates a single cleavage in the RNA (D) and causes dissociation of the RNA sequence.]]
Another independent approach is to use [[2'-5'-oligoadenylate synthase|oligoadenylated]] anti-telomerase antisense [[oligonucleotides]] and [[ribozymes]] to target telomerase RNA, leading to the dissociation of the RNA and to [[apoptosis]] (Figure 5). The fast induction of apoptosis through antisense binding may be a good alternative to the slower telomere shortening.<ref name="Saret" />

==== Small interfering RNA (siRNA) ====
[[Small interfering RNA|siRNAs]] are small RNA molecules that induce the sequence-specific degradation of other RNAs. siRNA treatment can function similar to traditional [[gene therapy]] by destroying the [[mRNA]] products of particular genes, and therefore preventing the expression of those genes. A 2012 study found that targeting TERC with an siRNA reduced telomerase activity by more than 50% and resulted in decreased viability of immortal cancer cells.<ref>{{cite journal | vauthors = Chen M, Xing LN | title = siRNA-mediated inhibition of hTERC enhances radiosensitivity of cervical cancer | journal = Asian Pacific Journal of Cancer Prevention | volume = 13 | issue = 12 | pages = 5975–9 | pmid = 23464388 | doi = 10.7314/apjcp.2012.13.12.5975 | year = 2012 | doi-access = free }}</ref> Treatment with both the siRNA and radiation caused a greater reduction in tumor size in mice than treatment with radiation alone, suggesting that targeting telomerase could be a way to increase the efficacy of radiation in treating radiation-resistant tumors.

===Heart disease, diabetes and quality of life===

Blackburn also discovered that mothers caring for very sick children have shorter telomeres when they report that their emotional stress is at a maximum and that telomerase was active at the site of blockages in [[coronary artery]] tissue, possibly accelerating heart attacks.

In 2009, it was shown that the amount of telomerase activity significantly increased following [[psychological stress]]. Across the sample of patients telomerase activity in [[peripheral blood mononuclear cell]]s increased by 18% one hour after the end of the stress.<ref name="pmid20018236">{{cite journal | vauthors = Epel ES, Lin J, Dhabhar FS, Wolkowitz OM, Puterman E, Karan L, Blackburn EH | title = Dynamics of telomerase activity in response to acute psychological stress | journal = Brain, Behavior, and Immunity | volume = 24 | issue = 4 | pages = 531–9 | date = May 2010 | pmid = 20018236 | pmc = 2856774 | doi = 10.1016/j.bbi.2009.11.018 }}</ref>

A study in 2010 found that there was "significantly greater" telomerase activity in participants than controls after a three-month meditation retreat.<ref>{{cite journal | vauthors = Jacobs TL, Epel ES, Lin J, Blackburn EH, Wolkowitz OM, Bridwell DA, Zanesco AP, Aichele SR, Sahdra BK, MacLean KA, King BG, Shaver PR, Rosenberg EL, Ferrer E, Wallace BA, Saron CD | s2cid = 4890811 | title = Intensive meditation training, immune cell telomerase activity, and psychological mediators | journal = Psychoneuroendocrinology | volume = 36 | issue = 5 | pages = 664–81 | date = June 2011 | pmid = 21035949 | doi = 10.1016/j.psyneuen.2010.09.010 }}</ref>

Telomerase deficiency has been linked to [[diabetes]] mellitus and impaired [[insulin]] secretion in mice, due to loss of [[Beta cell|pancreatic insulin-producing cell]]s.<ref>{{cite journal | vauthors = Kuhlow D, Florian S, von Figura G, Weimer S, Schulz N, Petzke KJ, Zarse K, Pfeiffer AF, Rudolph KL, Ristow M | title = Telomerase deficiency impairs glucose metabolism and insulin secretion | journal = Aging | volume = 2 | issue = 10 | pages = 650–8 | date = October 2010 | pmid = 20876939 | pmc = 2993795 | doi = 10.18632/aging.100200 | url = https://www.aging-us.com/article/100200/text | author-link = Michael Ristow }}</ref>

===Rare human diseases===
Mutations in TERT have been implicated in predisposing patients to [[aplastic anemia]], a disorder in which the [[bone marrow]] fails to produce blood cells, in 2005.<ref name="pmid15814878">{{cite journal | vauthors = Yamaguchi H, Calado RT, Ly H, Kajigaya S, Baerlocher GM, Chanock SJ, Lansdorp PM, Young NS | title = Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia | journal = The New England Journal of Medicine | volume = 352 | issue = 14 | pages = 1413–24 | date = April 2005 | pmid = 15814878 | doi = 10.1056/NEJMoa042980 | doi-access = free }}</ref>

[[Cri du chat syndrome]] (CdCS) is a complex disorder involving the loss of the distal portion of the short arm of [[chromosome 5]]. TERT is located in the deleted region, and loss of one copy of TERT has been suggested as a cause or contributing factor of this disease.<ref name="pmid12629597">{{cite journal | vauthors = Zhang A, Zheng C, Hou M, Lindvall C, Li KJ, Erlandsson F, Björkholm M, Gruber A, Blennow E, Xu D | title = Deletion of the telomerase reverse transcriptase gene and haploinsufficiency of telomere maintenance in Cri du chat syndrome | journal = American Journal of Human Genetics | volume = 72 | issue = 4 | pages = 940–8 | date = April 2003 | pmid = 12629597 | pmc = 1180356 | doi = 10.1086/374565 }}</ref>

[[Dyskeratosis congenita]] (DC) is a disease of the [[bone marrow]] that can be caused by some mutations in the telomerase subunits.<ref name="pmid17625368">{{cite journal | vauthors = Yamaguchi H | title = Mutations of telomerase complex genes linked to bone marrow failures | journal = Journal of Nippon Medical School | volume = 74 | issue = 3 | pages = 202–9 | date = June 2007 | pmid = 17625368 | doi = 10.1272/jnms.74.202 | doi-access = free }}</ref> In the DC cases, about 35% cases are [[Sex linkage|X-linked]]-[[Dominance (genetics)|recessive]] on the DKC1 locus<ref name="pmid9590285">{{cite journal | vauthors = Heiss NS, Knight SW, Vulliamy TJ, Klauck SM, Wiemann S, Mason PJ, Poustka A, Dokal I | s2cid = 205342127 | title = X-linked dyskeratosis congenita is caused by mutations in a highly conserved gene with putative nucleolar functions | journal = Nature Genetics | volume = 19 | issue = 1 | pages = 32–8 | date = May 1998 | pmid = 9590285 | doi = 10.1038/ng0598-32 }}</ref> and 5% cases are [[autosome|autosomal]] dominant on the TERT<ref name="pmid15885610">{{cite journal | vauthors = Vulliamy TJ, Walne A, Baskaradas A, Mason PJ, Marrone A, Dokal I | title = Mutations in the reverse transcriptase component of telomerase (TERT) in patients with bone marrow failure | journal = Blood Cells, Molecules & Diseases | volume = 34 | issue = 3 | pages = 257–63 | year = 2005 | pmid = 15885610 | doi = 10.1016/j.bcmd.2004.12.008 }}</ref> and TERC<ref name="pmid11574891">{{cite journal | vauthors = Vulliamy T, Marrone A, Goldman F, Dearlove A, Bessler M, Mason PJ, Dokal I | s2cid = 4348062 | title = The RNA component of telomerase is mutated in autosomal dominant dyskeratosis congenita | journal = Nature | volume = 413 | issue = 6854 | pages = 432–5 | date = September 2001 | pmid = 11574891 | doi = 10.1038/35096585 | bibcode = 2001Natur.413..432V }}</ref> loci.

Patients with DC have severe bone marrow failure manifesting as abnormal [[skin pigmentation]], [[leucoplakia]] (a white thickening of the oral mucosa) and [[nail dystrophy]], as well as a variety of other symptoms.  Individuals with either TERC or DKC1 mutations have shorter telomeres and defective telomerase activity ''in vitro'' versus other individuals of the same age.<ref name="pmid15917199">{{cite journal | vauthors = Marrone A, Walne A, Dokal I | title = Dyskeratosis congenita: telomerase, telomeres and anticipation | journal = Current Opinion in Genetics & Development | volume = 15 | issue = 3 | pages = 249–57 | date = June 2005 | pmid = 15917199 | doi = 10.1016/j.gde.2005.04.004 }}</ref>

In one family autosomal dominant DC was linked to a [[heterozygous]] TERT mutation.<ref name="pmid16247010">{{cite journal | vauthors = Armanios M, Chen JL, Chang YP, Brodsky RA, Hawkins A, Griffin CA, Eshleman JR, Cohen AR, Chakravarti A, Hamosh A, Greider CW | title = Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenita | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 102 | issue = 44 | pages = 15960–4 | date = November 2005 | pmid = 16247010 | pmc = 1276104 | doi = 10.1073/pnas.0508124102 | bibcode = 2005PNAS..10215960A | doi-access = free }}</ref> These patients also exhibited an increased rate of telomere-shortening, and [[genetic anticipation]] (i.e., the DC phenotype worsened with each generation).

== TERT Splice Variants ==

{{Empty section|date=April 2023}}

== See also ==
* [[DNA repair]]
* [[Imetelstat]]
* [[TA-65]]
* [[Telomere]]
* [[Epitalon]]

== References ==
{{Reflist|32em}}

== Further reading ==
* ''The Immortal Cell'', by [[Michael D. West]], [[Doubleday (publisher)|Doubleday]] (2003) {{ISBN|978-0-385-50928-2}}

== External links ==
* [[Gene Ontology]]: {{GO|GO:0003720|label=telomerase activity}}
* [https://www.genecards.org/cgi-bin/carddisp.pl?gene=TERT&keywords=Telomerase Human telomerase reverse transcriptase (TERT) gene on genecards.org]
* [http://telomerase.asu.edu/ The Telomerase Database - A Web-based tool for telomerase research] {{Webarchive|url=https://web.archive.org/web/20210419093842/http://telomerase.asu.edu/ |date=2021-04-19 }}
* [https://web.archive.org/web/20110805081152/http://www.mun.ca/biochem/courses/3107/images/telomerase_model.gif Three-dimensional model of telomerase] at [[Memorial University of Newfoundland|MUN]]
* [https://www.ibiology.org/genetics-and-gene-regulation/telomerase/ Elizabeth Blackburn's Seminars: Telomeres and Telomerase]
* {{MeshName|Telomerase}}
* {{PDBe-KB2|O14746|Human Telomerase reverse transcriptase}}
* {{PDBe-KB2|Q0QHL8|Tribolium castaneum Telomerase reverse transcriptase}}

{{DNA replication}}
{{Ribonucleoproteins}}
{{Kinases}}
{{Enzymes}}
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[[Category:Ribonucleoproteins]]
[[Category:Aging-related enzymes]]
[[Category:Anti-aging substances]]
[[Category:DNA replication]]
[[Category:EC 2.7.7]]
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[[Category:Telomere-related proteins]]