Telomerase RNA Component
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Telomerase RNA component, also known as TR, TER or TERC, is an
ncRNA A non-coding RNA (ncRNA) is a functional RNA molecule that is not translated into a protein. The DNA sequence from which a functional non-coding RNA is transcribed is often called an RNA gene. Abundant and functionally important types of non-co ...
found in
eukaryotes The eukaryotes ( ) constitute the domain of Eukaryota or Eukarya, organisms whose cells have a membrane-bound nucleus. All animals, plants, fungi, seaweeds, and many unicellular organisms are eukaryotes. They constitute a major group of ...
that is a component of
telomerase 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 euka ...
, the enzyme used to extend
telomeres A telomere (; ) is a region of repetitive nucleotide sequences associated with specialized proteins at the ends of linear chromosomes (see Sequences). Telomeres are a widespread genetic feature most commonly found in eukaryotes. In most, if not ...
. TERC serves as a template for telomere replication (
reverse transcription A reverse transcriptase (RT) is an enzyme used to convert RNA genome to DNA, a process termed reverse transcription. Reverse transcriptases are used by viruses such as HIV and hepatitis B virus, hepatitis B to replicate their genomes, by retrot ...
) by telomerase. Telomerase RNAs differ greatly in sequence and structure between vertebrates, ciliates and yeasts, but they share a 5'
pseudoknot __NOTOC__ A pseudoknot is a nucleic acid secondary structure containing at least two stem-loop structures in which half of one stem is intercalated between the two halves of another stem. The pseudoknot was first recognized in the turnip yellow ...
structure close to the template sequence. The vertebrate telomerase RNAs have a 3' H/ACA
snoRNA 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, t ...
-like domain.


Structure

TERC is a
Long non-coding RNA Long non-coding RNAs (long ncRNAs, lncRNA) 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 mic ...
(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. TERC has extensive secondary structural features over 4 principal conserved domains. The core domain, the largest domain at the 5’ end of TERC, contains the CUAAC
Telomere A telomere (; ) is a region of repetitive nucleotide sequences associated with specialized proteins at the ends of linear chromosomes (see #Sequences, Sequences). Telomeres are a widespread genetic feature most commonly found in eukaryotes. In ...
template sequence. Its secondary structure consists of a large loop containing the template sequence, a P1 loop-closing helix, and a P2/P3
pseudoknot __NOTOC__ A pseudoknot is a nucleic acid secondary structure containing at least two stem-loop structures in which half of one stem is intercalated between the two halves of another stem. The pseudoknot was first recognized in the turnip yellow ...
. The core domain and CR4/CR5 conserved domain associate with
TERT Tert may refer to: * ''tert''-, a chemical descriptor prefix used to designate tertiary atoms in molecules * Telomerase reverse transcriptase Telomerase reverse transcriptase (abbreviated to TERT, or hTERT in humans) is a catalytic subunit of t ...
, and are the only domains of TERC necessary for in vitro catalytic activity of telomerase. The 3’ end of TERC consists of a conserved H/ACA domain, a 2 hairpin structure connected by a single-stranded hinge and bordered on the 3’ end by a single-stranded ACA sequence. The H/ACA domain binds
Dyskerin H/ACA ribonucleoprotein complex subunit 4 is a protein that in humans is encoded by the gene ''DKC1''. Dyskerin is a pseudouridine synthase enzyme which is part of the TruB family of enzymes. Dyskerin is an L-shaped protein of 514 residues ...
, GAR1, NOP10, NHP2, to form an H/ACA RNP complex. The conserved CR7 domain is also localized at the 3’ end of TERC, and contains a 3nt CAB (
Cajal body Cajal bodies (CBs), also coiled bodies, are spherical nuclear bodies of 0.3–1.0 μm in diameter found in the nucleus of proliferative cells like embryonic cells and tumor cells, or metabolically active cells like neurons. CBs are membra ...
Localisation) box which binds TCAB1.


Function

Telomerase is a ribonucleoprotein polymerase that maintains telomere ends by addition of the telomere repeat TTAGGG. This repeat does vary across
eukaryote The eukaryotes ( ) constitute the Domain (biology), domain of Eukaryota or Eukarya, organisms whose Cell (biology), cells have a membrane-bound cell nucleus, nucleus. All animals, plants, Fungus, fungi, seaweeds, and many unicellular organisms ...
s (see the table on the
telomere A telomere (; ) is a region of repetitive nucleotide sequences associated with specialized proteins at the ends of linear chromosomes (see #Sequences, Sequences). Telomeres are a widespread genetic feature most commonly found in eukaryotes. In ...
article for a complete list). The enzyme consists of a protein component (
TERT Tert may refer to: * ''tert''-, a chemical descriptor prefix used to designate tertiary atoms in molecules * Telomerase reverse transcriptase Telomerase reverse transcriptase (abbreviated to TERT, or hTERT in humans) is a catalytic subunit of t ...
) with
reverse transcriptase A reverse transcriptase (RT) is an enzyme used to convert RNA genome to DNA, a process termed reverse transcription. Reverse transcriptases are used by viruses such as HIV and hepatitis B to replicate their genomes, by retrotransposon mobi ...
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 Senescence () or biological aging is the gradual deterioration of Function (biology), functional characteristics in living organisms. Whole organism senescence involves an increase in mortality rate, death rates or a decrease in fecundity with ...
, as it is normally repressed in postnatal
somatic cell In cellular biology, a somatic cell (), or vegetal cell, is any biological cell forming the body of a multicellular organism other than a gamete, germ cell, gametocyte or undifferentiated stem cell. Somatic cells compose the body of an organism ...
s resulting in progressive shortening of telomeres. Deregulation of telomerase expression in somatic cells may be involved in
oncogenesis Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abno ...
. Studies in mice suggest that telomerase also participates in chromosomal repair, since ''de novo'' synthesis of telomere repeats may occur at double-stranded breaks.
Homologs Homologous chromosomes or homologs are a set of one maternal and one paternal chromosome that pair up with each other inside a cell during meiosis. Homologs have the same genes in the same loci, where they provide points along each chromosome th ...
of TERC can also be found in the Gallid herpes viruses. The core domain of TERC contains the
RNA Ribonucleic acid (RNA) is a polymeric molecule that is essential for most biological functions, either by performing the function itself (non-coding RNA) or by forming a template for the production of proteins (messenger RNA). RNA and deoxyrib ...
template from which
TERT Tert may refer to: * ''tert''-, a chemical descriptor prefix used to designate tertiary atoms in molecules * Telomerase reverse transcriptase Telomerase reverse transcriptase (abbreviated to TERT, or hTERT in humans) is a catalytic subunit of t ...
synthesizes TTAGGG telomeric repeats. Unlike in other RNPs, in
telomerase 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 euka ...
, the protein
TERT Tert may refer to: * ''tert''-, a chemical descriptor prefix used to designate tertiary atoms in molecules * Telomerase reverse transcriptase Telomerase reverse transcriptase (abbreviated to TERT, or hTERT in humans) is a catalytic subunit of t ...
is catalytic while the
lncRNA Long non-coding RNAs (long ncRNAs, lncRNA) 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 mic ...
TERC is structural, rather than acting as a
ribozyme Ribozymes (ribonucleic acid enzymes) are RNA molecules that have the ability to Catalysis, catalyze specific biochemical reactions, including RNA splicing in gene expression, similar to the action of protein enzymes. The 1982 discovery of ribozy ...
. The core region of TERC and
TERT Tert may refer to: * ''tert''-, a chemical descriptor prefix used to designate tertiary atoms in molecules * Telomerase reverse transcriptase Telomerase reverse transcriptase (abbreviated to TERT, or hTERT in humans) is a catalytic subunit of t ...
are sufficient to reconstitute catalytic telomerase activity in vitro. The H/ACA domain of TERC recruits the
Dyskerin H/ACA ribonucleoprotein complex subunit 4 is a protein that in humans is encoded by the gene ''DKC1''. Dyskerin is a pseudouridine synthase enzyme which is part of the TruB family of enzymes. Dyskerin is an L-shaped protein of 514 residues ...
complex (
DKC1 H/ACA ribonucleoprotein complex subunit 4 is a protein that in humans is encoded by the gene ''DKC1''. Dyskerin is a pseudouridine synthase enzyme which is part of the TruB family of enzymes. Dyskerin is an L-shaped protein of 514 residues ...
, GAR1, NOP10, NHP2), which stabilises TERC, increasing telomerase complex formation and overall catalytic activity. The CR7 domain binds TCAB1, which localizes telomerase to
cajal bodies Cajal bodies (CBs), also coiled bodies, are spherical nuclear bodies of 0.3–1.0 μm in diameter found in the nucleus of proliferative cells like embryonic cells and tumor cells, or metabolically active cells like neurons. CBs are membrane- ...
, further increasing telomerase catalytic activity. TERC is ubiquitously expressed, even in cells lacking telomerase activity and TERT expression. As a result, various TERT-independent functional roles of TERC have been proposed. 14
genes In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
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 TYRO protein tyrosine kinase-binding protein is an adapter protein that in humans is encoded by the ''TYROBP'' gene. Function This gene encodes a transmembrane signaling polypeptide which contains an immunoreceptor tyrosine-based activation m ...
, Usp16 stimulates the
NF-κB Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a family of transcription factor protein complexes that controls transcription (genetics), transcription of DNA, cytokine production and cell survival. NF-κB is found i ...
pathway, resulting in increased expression and secretion of inflammatory
cytokines Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...
.


Biosynthesis

Unlike most lncRNAs which are assembled from
introns An intron is any Nucleic acid sequence, nucleotide sequence within a gene that is not expressed or operative in the final RNA product. The word ''intron'' is derived from the term ''intragenic region'', i.e., a region inside a gene."The notion of ...
by the
spliceosome A spliceosome is a large ribonucleoprotein (RNP) complex found primarily within the nucleus of eukaryotic cells. The spliceosome is assembled from small nuclear RNAs ( snRNA) and numerous proteins. Small nuclear RNA (snRNA) molecules bind to sp ...
, hTR is directly transcribed from a dedicated promoter site located at genomic locus 3q26.2 by
RNA polymerase II RNA polymerase II (RNAP II and Pol II) is a Protein complex, multiprotein complex that Transcription (biology), transcribes DNA into precursors of messenger RNA (mRNA) and most small nuclear RNA (snRNA) and microRNA. It is one of the three RNA pol ...
. 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. 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 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. Function Exonucleolytic degradation of the poly(A) tail is ...
, and subsequent 3’-5’ exoribonucleolytic degradation. Extended hTR transcripts are also degraded by the RNA exosome. The 5’ ends of hTR transcripts are also additionally processed. TGS-1
hypermethylation Methylation, in the chemical sciences, is the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These terms ...
the 5'-methylguanosine cap to an N2,2,7 trimethylguanosine (TMG) cap, which inhibits hTR maturation. Binding of the
Dyskerin H/ACA ribonucleoprotein complex subunit 4 is a protein that in humans is encoded by the gene ''DKC1''. Dyskerin is a pseudouridine synthase enzyme which is part of the TruB family of enzymes. Dyskerin is an L-shaped protein of 514 residues ...
complex to transcribed H/ACA domains of hTR during transcription promotes termination of transcription. 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 biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mitosi ...
in the TERC genomic locus have been associated with a variety of
degenerative diseases Degenerative disease is the result of a continuous process based on degenerative cell changes, affecting tissues or organs, which will increasingly deteriorate over time. In neurodegenerative diseases, cells of the central nervous system stop wor ...
. Mutations in TERC have been associated with
dyskeratosis congenita 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, an ...
,
idiopathic pulmonary fibrosis Idiopathic pulmonary fibrosis (IPF) synonymous with cryptogenic fibrosing alveolitis is a rare, progressive illness of the respiratory system, characterized by the thickening and stiffening of lung tissue, associated with the formation of scar ...
,
aplastic anemia Aplastic anemia (AA) is a severe hematologic condition in which the body fails to make blood cells in sufficient numbers. Normally, blood cells are produced in the bone marrow by stem cells that reside there, but patients with aplastic anemia ...
, and
myelodysplasia A myelodysplastic syndrome (MDS) is one of a group of cancers in which blood cells in the bone marrow do not mature, and as a result, do not develop into healthy blood cells. Early on, no symptoms typically are seen. Later, symptoms may includ ...
. Overexpression and improper regulation of TERC have been associated with a variety of
cancers Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...
. Upregulation of hTR is widely observed in patients with precancerous cervical phenotype as a result of
HPV Human papillomavirus infection (HPV infection) is caused by a DNA virus from the ''Papillomaviridae'' family. Many HPV infections cause no symptoms and 90% resolve spontaneously within two years. In some cases, an HPV infection persists and ...
infection. Overexpression of TERC enhances MDV-mediated
oncogenesis Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abno ...
, and is observed in
gastric carcinoma Stomach cancer, also known as gastric cancer, is a malignant tumor of the stomach. It is a cancer that develops in the lining of the stomach. Most cases of stomach cancers are gastric carcinomas, which can be divided into a number of subtypes ...
. Overexpression of TERC is also observed in inflammatory conditions such as
Type II diabetes Type 2 diabetes (T2D), formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent ...
and
multiple sclerosis Multiple sclerosis (MS) is an autoimmune disease resulting in damage to myelinthe insulating covers of nerve cellsin the brain and spinal cord. As a demyelinating disease, MS disrupts the nervous system's ability to Action potential, transmit ...
, due to TERC-mediated activation of the
NF-κB Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a family of transcription factor protein complexes that controls transcription (genetics), transcription of DNA, cytokine production and cell survival. NF-κB is found i ...
inflammatory pathway. TERC has been implicated as protective in
osteoporosis Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to more porous bone, and consequent increase in Bone fracture, fracture risk. It is the most common reason f ...
, with its increased expression arresting the rate of
osteogenesis Osteoblasts (from the Greek language, Greek combining forms for "bone", ὀστέο-, ''osteo-'' and βλαστάνω, ''blastanō'' "germinate") are cell (biology), cells with a single Cell nucleus, nucleus that synthesize bone. However, in the p ...
. Due to its overexpression in a range of cancer phenotypes, TERC has been investigated as a potential
cancer biomarker A cancer biomarker refers to a substance or process that is indicative of the presence of cancer in the body. A biomarker may be a molecule secreted by a tumor or a specific response of the body to the presence of cancer. genetics, Genetic, epige ...
. It was found to be an effective biomarker of lung squamous cell carcinoma (LUSC).


References


Further reading

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External links


GeneReviews/NCBI/NIH/UW entry on Dyskeratosis Congenita

GeneReviews/NCBI/NIH/UW entry on Pulmonary Fibrosis, Familial

EntrezGene page for TERC
* * * {{DNA replication Non-coding RNA Telomere-related genes