Telomerase RNA component

Last updated
TERC
PDB 1ymo EBI.png
Identifiers
Aliases TERC , DKCA1, PFBMFT2, SCARNA19, TR, TRC3, hTR, Telomerase RNA component, TER
External IDs OMIM: 602322 GeneCards: TERC
Orthologs
SpeciesHumanMouse
Entrez

7012

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Ensembl

ENSG00000277925

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UniProt

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a

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RefSeq (mRNA)

n/a

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RefSeq (protein)

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Location (UCSC) Chr 3: 169.76 – 169.77 Mb n/a
PubMed search [2] n/a
Wikidata
View/Edit Human
Vertebrate telomerase RNA
RF00024-rscape.svg
Identifiers
SymbolTelomerase-vert
Rfam RF00024
Other data
RNA type Gene
Domain(s) Eukaryote; Virus
PDB structures PDBe
Ciliate telomerase RNA
RF00025-rscape.svg
Identifiers
SymbolTelomerase-cil
Rfam RF00025
Other data
RNA type Gene
Domain(s) Eukaryote
PDB structures PDBe
Saccharomyces cerevisiae telomerase RNA
RF01050-rscape.svg
Identifiers
SymbolSacc_telomerase
Rfam RF01050
Other data
RNA type Gene
Domain(s) Eukaryote
PDB structures PDBe

Telomerase RNA component, also known as TR, TER or TERC, is an ncRNA found in eukaryotes that is a component of telomerase, the enzyme used to extend telomeres. [3] [4] TERC serves as a template for telomere replication (reverse transcription) by telomerase. Telomerase RNAs differ greatly in sequence and structure between vertebrates, ciliates and yeasts, but they share a 5' pseudoknot structure close to the template sequence. The vertebrate telomerase RNAs have a 3' H/ACA snoRNA-like domain. [5] [6] [7]

Contents

Structure

TERC is a Long non-coding RNA (lncRNA) ranging in length from ~150nt in ciliates to 400-600nt in vertebrates, and 1,300nt in yeast (Alnafakh). Mature human TERC (hTR) is 451nt in length. [8] TERC has extensive secondary structural features over 4 principal conserved domains. [9] The core domain, the largest domain at the 5’ end of TERC, contains the CUAAC Telomere template sequence. Its secondary structure consists of a large loop containing the template sequence, a P1 loop-closing helix, and a P2/P3 pseudoknot. [10] The core domain and CR4/CR5 conserved domain associate with TERT, and are the only domains of TERC necessary for in vitro catalytic activity of telomerase. [11] The 3’ end of TERC consists of a conserved H/ACA domain, [10] a 2 hairpin structure connected by a single-stranded hinge and bordered on the 3’ end by a single-stranded ACA sequence. [8] The H/ACA domain binds Dyskerin, GAR1, NOP10, NHP2, to form an H/ACA RNP complex. [10] The conserved CR7 domain is also localized at the 3’ end of TERC, and contains a 3nt CAB (Cajal body Localisation) box which binds TCAB1. [10]

Illustration: hTR and associated proteins of Telomerase complex Illustration - hTR and associated proteins of telomerase complex.png
Illustration: hTR and associated proteins of Telomerase complex

Function

Telomerase is a ribonucleoprotein polymerase that maintains telomere ends by addition of the telomere repeat TTAGGG. This repeat does vary across eukaryotes (see the table on the telomere article for a complete list). The enzyme consists of a protein component (TERT) with reverse transcriptase activity, and an RNA component, encoded by this gene, that serves as a template for the telomere repeat. CCCUAA found near position 50 of the vertebrate TERC sequence acts as the template. Telomerase expression plays a role in cellular senescence, as it is normally repressed in postnatal somatic cells resulting in progressive shortening of telomeres. Deregulation of telomerase expression in somatic cells may be involved in oncogenesis. Studies in mice suggest that telomerase also participates in chromosomal repair, since de novo synthesis of telomere repeats may occur at double-stranded breaks. [12] Homologs of TERC can also be found in the Gallid herpes viruses. [13]

The core domain of TERC contains the RNA template from which TERT synthesizes TTAGGG telomeric repeats. [10] Unlike in other RNPs, in telomerase, the protein TERT is catalytic while the lncRNA TERC is structural, rather than acting as a ribozyme. [14] The core region of TERC and TERT are sufficient to reconstitute catalytic telomerase activity in vitro. [10] [11] The H/ACA domain of TERC recruits the Dyskerin complex (DKC1, GAR1, NOP10, NHP2), which stabilises TERC, increasing telomerase complex formation and overall catalytic activity. [10] The CR7 domain binds TCAB1, which localizes telomerase to cajal bodies, further increasing telomerase catalytic activity. [10] TERC is ubiquitously expressed, even in cells lacking telomerase activity and TERT expression. [15] As a result, various TERT-independent functional roles of TERC have been proposed. 14 genes containing a TERC binding motif are directly transcriptionally regulated by TERC through RNA-DNA triplex formation-mediated increase of expression. TERC-mediated upregulation of Lin37, Trpg1l, tyrobp, Usp16 stimulates the NF-κB pathway, resulting in increased expression and secretion of inflammatory cytokines. [16]

Biosynthesis

Unlike most lncRNAs which are assembled from introns by the spliceosome, hTR is directly transcribed from a dedicated promoter site [8] located at genomic locus 3q26.2 [17] by RNA polymerase II. [8] Mature hTR is 451nt in length, but approximately 1/3 of cellular hTR transcripts at steady state have ~10nt genomically encoded 3’ tails. The majority of those extended hTR species have additional oligo-A 3’ extension. [8] Processing of immature 3’-tailed hTR to mature 451nt hTR can be accomplished by direct 3’-5’ exoribonucleolytic degradation or by an indirect pathway of oligoadenylation by PAPD5, removal of 3’ oligo-A tail by the 3’-5’ RNA exonuclease PARN, and subsequent 3’-5’ exoribonucleolytic degradation. [8] Extended hTR transcripts are also degraded by the RNA exosome. [8]

The 5’ ends of hTR transcripts are also additionally processed. TGS-1 hypermethylation the 5'-methylguanosine cap to an N2,2,7 trimethylguanosine (TMG) cap, which inhibits hTR maturation. [18] Binding of the Dyskerin complex to transcribed H/ACA domains of hTR during transcription promotes termination of transcription. [8] Control of the relative rates of these various competing pathways that activate or inhibit hTR maturation is a crucial element of regulation of overall telomerase activity.

Clinical Significance

Loss of function mutations in the TERC genomic locus have been associated with a variety of degenerative diseases. Mutations in TERC have been associated with dyskeratosis congenita, [19] idiopathic pulmonary fibrosis, [20] aplastic anemia, and myelodysplasia. [10] Overexpression and improper regulation of TERC have been associated with a variety of cancers. Upregulation of hTR is widely observed in patients with precancerous cervical phenotype as a result of HPV infection. [21] Overexpression of TERC enhances MDV-mediated oncogenesis, [22] and is observed in gastric carcinoma. [23] Overexpression of TERC is also observed in inflammatory conditions such as Type II diabetes and multiple sclerosis, due to TERC-mediated activation of the NF-κB inflammatory pathway. [16]

TERC has been implicated as protective in osteoporosis, with its increased expression arresting the rate of osteogenesis. [24] Due to its overexpression in a range of cancer phenotypes, TERC has been investigated as a potential cancer biomarker. It was found to be an effective biomarker of lung squamous cell carcinoma (LUSC). [25]

Related Research Articles

<span class="mw-page-title-main">Telomere</span> Region of repetitive nucleotide sequences on chromosomes

A telomere is a region of repetitive nucleotide sequences associated with specialized proteins at the ends of linear chromosomes. Telomeres are a widespread genetic feature most commonly found in eukaryotes. In most, if not all species possessing them, they protect the terminal regions of chromosomal DNA from progressive degradation and ensure the integrity of linear chromosomes by preventing DNA repair systems from mistaking the very ends of the DNA strand for a double-strand break.

<span class="mw-page-title-main">Telomerase</span> Telomere-restoring protein active in the most rapidly dividing cells

Telomerase, also called terminal transferase, is a ribonucleoprotein that adds a species-dependent telomere repeat sequence to the 3' end of telomeres. A telomere is a region of repetitive sequences at each end of the chromosomes of most eukaryotes. Telomeres protect the end of the chromosome from DNA damage or from fusion with neighbouring chromosomes. The fruit fly Drosophila melanogaster lacks telomerase, but instead uses retrotransposons to maintain telomeres.

<span class="mw-page-title-main">Dyskeratosis congenita</span> Medical condition

Dyskeratosis congenita (DKC), also known as Zinsser-Engman-Cole syndrome, is a rare progressive congenital disorder with a highly variable phenotype. The entity was classically defined by the triad of abnormal skin pigmentation, nail dystrophy, and leukoplakia of the oral mucosa, and MDS/AML, but these components do not always occur. DKC is characterized by short telomeres. Some of the manifestations resemble premature ageing and cognitive impairment can be a feature. The disease initially mainly affects the skin, but a major consequence is progressive bone marrow failure which occurs in over 80%, causing early mortality.

Small nuclear RNA (snRNA) is a class of small RNA molecules that are found within the splicing speckles and Cajal bodies of the cell nucleus in eukaryotic cells. The length of an average snRNA is approximately 150 nucleotides. They are transcribed by either RNA polymerase II or RNA polymerase III. Their primary function is in the processing of pre-messenger RNA (hnRNA) in the nucleus. They have also been shown to aid in the regulation of transcription factors or RNA polymerase II, and maintaining the telomeres.

In molecular biology, small nucleolar RNAs (snoRNAs) are a class of small RNA molecules that primarily guide chemical modifications of other RNAs, mainly ribosomal RNAs, transfer RNAs and small nuclear RNAs. There are two main classes of snoRNA, the C/D box snoRNAs, which are associated with methylation, and the H/ACA box snoRNAs, which are associated with pseudouridylation. SnoRNAs are commonly referred to as guide RNAs but should not be confused with the guide RNAs that direct RNA editing in trypanosomes or the guide RNAs (gRNAs) used by Cas9 for CRISPR gene editing.

<span class="mw-page-title-main">Carol W. Greider</span> American molecular biologist and Nobel laureate

Carolyn Widney Greider is an American molecular biologist and Nobel laureate. She joined the University of California, Santa Cruz as a Distinguished Professor in the department of molecular, cell, and developmental biology in October 2020.

<span class="mw-page-title-main">Telomerase reverse transcriptase</span> Catalytic subunit of the enzyme telomerase

Telomerase reverse transcriptase 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.

<span class="mw-page-title-main">Dyskerin</span> Protein

H/ACA ribonucleoprotein complex subunit 4 is a protein that in humans is encoded by the gene DKC1.

<span class="mw-page-title-main">Poly(A)-specific ribonuclease</span> Protein-coding gene in the species Homo sapiens

Poly(A)-specific ribonuclease (PARN), also known as polyadenylate-specific ribonuclease or deadenylating nuclease (DAN), is an enzyme that in humans is encoded by the PARN gene.

<span class="mw-page-title-main">POT1</span> Protein-coding gene in the species Homo sapiens

Protection of telomeres protein 1 is a protein that in humans is encoded by the POT1 gene.

<span class="mw-page-title-main">TINF2</span> Protein-coding gene in the species Homo sapiens

TERF1-interacting nuclear factor 2 is a protein that in humans is encoded by the TINF2 gene. TINF2 is a component of the shelterin protein complex found at the end of telomeres.

<span class="mw-page-title-main">ACD (gene)</span> Protein-coding gene in the species Homo sapiens

Adrenocortical dysplasia protein homolog is a protein that in humans is encoded by the ACD gene.

<span class="mw-page-title-main">TEP1</span> Protein-coding gene in the species Homo sapiens

Telomerase protein component 1 is an enzyme that in humans is encoded by the TEP1 gene.

<span class="mw-page-title-main">SMG6</span> Protein-coding gene in the species Homo sapiens

Telomerase-binding protein EST1A is an enzyme that in humans is encoded by the SMG6 gene on chromosome 17. It is ubiquitously expressed in many tissues and cell types. The C-terminus of the EST1A protein contains a PilT N-terminus (PIN) domain. This structure for this domain has been determined by X-ray crystallography. SMG6 functions to bind single-stranded DNA in telomere maintenance and single-stranded RNA in nonsense-mediated mRNA decay (NMD). The SMG6 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.

<span class="mw-page-title-main">PINX1</span> Protein-coding gene in the species Homo sapiens

PIN2/TERF1-interacting telomerase inhibitor 1, also known as PINX1, is a human gene. PINX1 is also known as PIN2 interacting protein 1. PINX1 is a telomerase inhibitor and a possible tumor suppressor.

<span class="mw-page-title-main">Sierra Sciences</span> Biotechnology company

Sierra Sciences, LLC is a biotechnology company founded by William H. Andrews, former director of molecular biology at Geron Corporation. Andrews founded Sierra Sciences in 1999 in Reno, Nevada with the goal of preventing and/or reversing cellular senescence, and ultimately curing diseases associated with human aging, including the aging process itself.

<span class="mw-page-title-main">Long non-coding RNA</span> Non-protein coding transcripts longer than 200 nucleotides

Long non-coding RNAs are a type of RNA, generally defined as transcripts more than 200 nucleotides that are not translated into protein. This arbitrary limit distinguishes long ncRNAs from small non-coding RNAs, such as microRNAs (miRNAs), small interfering RNAs (siRNAs), Piwi-interacting RNAs (piRNAs), small nucleolar RNAs (snoRNAs), and other short RNAs. Given that some lncRNAs have been reported to have the potential to encode small proteins or micro-peptides, the latest definition of lncRNA is a class of RNA molecules of over 200 nucleotides that have no or limited coding capacity. Long intervening/intergenic noncoding RNAs (lincRNAs) are sequences of lncRNA which do not overlap protein-coding genes.

William Henry Andrews is an American molecular biologist and gerontologist whose career is centered on searching for a cure for human aging. Andrews is the founder and president of the biotechnology company Sierra Sciences. In the 1990s, he led the team at Geron Corporation that was the first to successfully identify the genes for human enzyme telomerase. This enzyme is responsible for preventing telomeres from shortening in human primordial germ cells.

<span class="mw-page-title-main">WRAP53</span> Protein-coding gene in the species Homo sapiens

WRAP53 is a gene implicated in cancer development. The name was coined in 2009 to describe the dual role of this gene, encoding both an antisense RNA that regulates the p53 tumor suppressor and a protein involved in DNA repair, telomere elongation and maintenance of nuclear organelles Cajal bodies.

<span class="mw-page-title-main">Hoyeraal–Hreidarsson syndrome</span> Medical condition

Hoyeraal–Hreidasson syndrome is a very rare multisystem X-linked recessive disorder characterized by excessively short telomeres and is considered a severe form of dyskeratosis congenita. Being an X-linked disorder, Hoyeraal–Hreidasson syndrome primarily affects males. Patients typically present in early childhood with cerebellar hypoplasia, immunodeficiency, progressive bone marrow failure, and intrauterine growth restriction. The primary cause of death in Hoyeraal–Hreidasson syndrome is bone marrow failure, but mortality from cancer and pulmonary fibrosis is also significant.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000277925 - Ensembl, May 2017
  2. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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  4. ↑ Jády BE, Richard P, Bertrand E, Kiss T (February 2006). "Cell cycle-dependent recruitment of telomerase RNA and Cajal bodies to human telomeres". Molecular Biology of the Cell. 17 (2): 944–54. doi:10.1091/mbc.E05-09-0904. PMC   1356602 . PMID   16319170.
  5. ↑ McCormick-Graham M, Romero DP (April 1995). "Ciliate telomerase RNA structural features". Nucleic Acids Research. 23 (7): 1091–7. doi:10.1093/nar/23.7.1091. PMC   306816 . PMID   7739888.
  6. ↑ Lingner J, Hendrick LL, Cech TR (August 1994). "Telomerase RNAs of different ciliates have a common secondary structure and a permuted template". Genes & Development. 8 (16): 1984–98. doi: 10.1101/gad.8.16.1984 . PMID   7958872.
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  8. 1 2 3 4 5 6 7 8 Roake CM, Chen L, Chakravarthy AL, Ferrell JE, Raffa GD, Artandi SE (May 2019). "Disruption of Telomerase RNA Maturation Kinetics Precipitates Disease". Molecular Cell. 74 (4): 688–700.e3. doi:10.1016/j.molcel.2019.02.033. PMC   6525023 . PMID   30930056.
  9. ↑ Alnafakh RA, Adishesh M, Button L, Saretzki G, Hapangama DK (2019). "Telomerase and Telomeres in Endometrial Cancer". Frontiers in Oncology. 9: 344. doi: 10.3389/fonc.2019.00344 . PMC   6533802 . PMID   31157162.
  10. 1 2 3 4 5 6 7 8 9 Zhang Q, Kim NK, Feigon J (December 2011). "Architecture of human telomerase RNA". Proceedings of the National Academy of Sciences of the United States of America. 108 (51): 20325–32. Bibcode:2011PNAS..10820325Z. doi: 10.1073/pnas.1100279108 . PMC   3251123 . PMID   21844345.
  11. 1 2 Webb CJ, Zakian VA (August 2016). "Telomerase RNA is more than a DNA template". RNA Biology. 13 (8): 683–9. doi:10.1080/15476286.2016.1191725. PMC   4993324 . PMID   27245259.
  12. ↑ "Entrez Gene: TERC telomerase RNA component".
  13. ↑ Fragnet L, Kut E, Rasschaert D (June 2005). "Comparative functional study of the viral telomerase RNA based on natural mutations". The Journal of Biological Chemistry. 280 (25): 23502–15. doi: 10.1074/jbc.M501163200 . PMID   15811851. S2CID   24301693.
  14. ↑ Wang Y, Sušac L, Feigon J (December 2019). "Structural Biology of Telomerase". Cold Spring Harbor Perspectives in Biology. 11 (12): a032383. doi:10.1101/cshperspect.a032383. PMC   6886448 . PMID   31451513.
  15. ↑ Shay JW, Wright WE (May 2019). "Telomeres and telomerase: three decades of progress". Nature Reviews Genetics. 20 (5): 299–309. doi:10.1038/s41576-019-0099-1. PMID   30760854. S2CID   61156603.
  16. 1 2 Liu H, Yang Y, Ge Y, Liu J, Zhao Y (September 2019). "TERC promotes cellular inflammatory response independent of telomerase". Nucleic Acids Research. 47 (15): 8084–8095. doi:10.1093/nar/gkz584. PMC   6735767 . PMID   31294790.
  17. ↑ "OMIM Entry - * 602322 - TELOMERASE RNA COMPONENT; TERC". www.omim.org. Retrieved 2020-03-02.
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  19. ↑ Rich RR (2018-01-13). Clinical immunology : principles and practice (Fifth ed.). [St. Louis, Mo.] ISBN   978-0-7020-7039-6. OCLC   1023865227.{{cite book}}: CS1 maint: location missing publisher (link)
  20. ↑ Swigris JJ, Brown KK (2018-07-25). Idiopathic pulmonary fibrosis. St. Louis. ISBN   978-0-323-54432-0. OCLC   1053744041.{{cite book}}: CS1 maint: location missing publisher (link)
  21. ↑ Liu Y, Fan P, Yang Y, Xu C, Huang Y, Li D, et al. (November 2019). "Human papillomavirus and human telomerase RNA component gene in cervical cancer progression". Scientific Reports. 9 (1): 15926. Bibcode:2019NatSR...915926L. doi:10.1038/s41598-019-52195-5. PMC   6828729 . PMID   31685833.
  22. ↑ Kheimar A, Trimpert J, Groenke N, Kaufer BB (March 2019). "Overexpression of cellular telomerase RNA enhances virus-induced cancer formation". Oncogene. 38 (10): 1778–1786. doi:10.1038/s41388-018-0544-1. PMID   30846849. S2CID   53085869.
  23. ↑ Heine B, Hummel M, Demel G, Stein H (June 1998). "Demonstration of constant upregulation of the telomerase RNA component in human gastric carcinomas using in situ hybridization". The Journal of Pathology. 185 (2): 139–44. doi:10.1002/(SICI)1096-9896(199806)185:2<139::AID-PATH79>3.0.CO;2-L. PMID   9713339. S2CID   21966828.
  24. ↑ Gao GC, Yang DW, Liu W (January 2020). "LncRNA TERC alleviates the progression of osteoporosis by absorbing miRNA-217 to upregulate RUNX2". European Review for Medical and Pharmacological Sciences. 24 (2): 526–534. doi:10.26355/eurrev_202001_20029. PMID   32016954. S2CID   211024218.
  25. ↑ Storti CB, de Oliveira RA, de Carvalho M, Hasimoto EN, Cataneo DC, Cataneo AJ, et al. (February 2020). "Telomere-associated genes and telomeric lncRNAs are biomarker candidates in lung squamous cell carcinoma (LUSC)". Experimental and Molecular Pathology. 112: 104354. doi:10.1016/j.yexmp.2019.104354. PMID   31837325. S2CID   209385638.

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