Telomerase RNA component, also known as TR, TER or TERC, is an
ncRNA found in
eukaryotes
Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bact ...
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 e ...
, 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. Although there are different architectures, telomeres, in a broad sense, are a widespread genetic feature mos ...
.
TERC serves as a template for telomere
replication
Replication may refer to:
Science
* Replication (scientific method), one of the main principles of the scientific method, a.k.a. reproducibility
** Replication (statistics), the repetition of a test or complete experiment
** Replication crisi ...
(
reverse transcription
A reverse transcriptase (RT) is an enzyme used to generate complementary DNA (cDNA) from an RNA template, a process termed reverse transcription. Reverse transcriptases are used by viruses such as HIV and hepatitis B to replicate their genomes ...
) 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
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, ...
-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 mi ...
(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. Although there are different architectures, telomeres, in a broad sense, are a widespread genetic feature mo ...
template sequence. Its secondary structure consists of a large loop containing the template sequence, a P1 loop-closing helix, and a P2/P3
pseudoknot.
The core domain and CR4/CR5 conserved domain associate with
TERT
Telomerase reverse transcriptase (abbreviated to TERT, or hTERT in humans) is a catalytic subunit of the enzyme telomerase, which, together with the telomerase RNA component (TERC), comprises the most important unit of the telomerase complex.
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,
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 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
Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bact ...
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. Although there are different architectures, telomeres, in a broad sense, are a widespread genetic feature mo ...
article for a complete list). The enzyme consists of a protein component (
TERT
Telomerase reverse transcriptase (abbreviated to TERT, or hTERT in humans) is a catalytic subunit of the enzyme telomerase, which, together with the telomerase RNA component (TERC), comprises the most important unit of the telomerase complex.
T ...
) with
reverse transcriptase
A reverse transcriptase (RT) is an enzyme used to generate complementary DNA (cDNA) from an RNA template, a process termed reverse transcription. Reverse transcriptases are used by viruses such as HIV and hepatitis B to replicate their genomes, ...
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 functional characteristics in living organisms. The word ''senescence'' can refer to either cellular senescence or to senescence of the whole organism. Organismal senescence inv ...
, as it is normally repressed in postnatal
somatic cell
A somatic cell (from Ancient Greek σῶμα ''sôma'', meaning "body"), 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. Such cells co ...
s 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.
Homologs 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 essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...
template from which
TERT
Telomerase reverse transcriptase (abbreviated to TERT, or hTERT in humans) is a catalytic subunit of the enzyme telomerase, which, together with the telomerase RNA component (TERC), comprises the most important unit of the telomerase complex.
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 e ...
, the protein
TERT
Telomerase reverse transcriptase (abbreviated to TERT, or hTERT in humans) is a catalytic subunit of the enzyme telomerase, which, together with the telomerase RNA component (TERC), comprises the most important unit of the telomerase complex.
T ...
is catalytic while the
lncRNA TERC is structural, rather than acting as a
ribozyme
Ribozymes (ribonucleic acid enzymes) are RNA molecules that have the ability to catalyze specific biochemical reactions, including RNA splicing in gene expression, similar to the action of protein enzymes. The 1982 discovery of ribozymes demonst ...
. The core region of TERC and
TERT
Telomerase reverse transcriptase (abbreviated to TERT, or hTERT in humans) is a catalytic subunit of the enzyme telomerase, which, together with the telomerase RNA component (TERC), comprises the most important unit of the telomerase complex.
T ...
are sufficient to reconstitute catalytic telomerase activity in vitro.
The H/ACA domain of TERC recruits the
Dyskerin complex (
DKC1
H/ACA ribonucleoprotein complex subunit 4 is a protein that in humans is encoded by the gene ''DKC1''.
This gene is a member of the snoRNA, H/ACA snoRNPs (small nucleolar ribonucleoproteins) gene family. snoRNPs are involved in various aspects of ...
,
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, 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 (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
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
Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular ...
pathway, resulting in increased expression and secretion of inflammatory
cytokines.
Biosynthesis
Unlike most
lncRNAs
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 ...
which are assembled from
introns
An intron is any 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 the cistron .e., gene ...
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
In genetics, a promoter is a sequence of DNA to which proteins bind to initiate transcription of a single RNA transcript from the DNA downstream of the promoter. The RNA transcript may encode a protein (mRNA), or can have a function in and of i ...
located at genomic locus 3q26.2 by
RNA polymerase II
RNA polymerase II (RNAP II and Pol II) is a multiprotein complex that transcribes DNA into precursors of messenger RNA (mRNA) and most small nuclear RNA (snRNA) and microRNA. It is one of the three RNAP enzymes found in the nucleus of eukary ...
.
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, and subsequent 3’-5’ exoribonucleolytic degradation.
Extended hTR transcripts are also degraded by the RNA
exosome
Exosome may refer to:
* Exosome complex
The exosome complex (or PM/Scl complex, often just called the exosome) is a multi-protein intracellular complex capable of degrading various types of RNA (ribonucleic acid) molecules. Exosome complexes ...
.
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. Binding of the
Dyskerin 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. 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, and ...
,
idiopathic pulmonary fibrosis
Idiopathic pulmonary fibrosis (IPF), or (formerly) 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 tissue. It is ...
,
aplastic anemia
Aplastic anemia is a cancer in which the body fails to make blood cells in sufficient numbers. Blood cells are produced in the bone marrow by stem cells that reside there. Aplastic anemia causes a deficiency of all blood cell types: red blood ...
, and
myelodysplasia.
Overexpression and improper regulation of TERC have been associated with a variety of
cancers
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal ble ...
. Upregulation of hTR is widely observed in patients with precancerous cervical phenotype as a result of
HPV infection. Overexpression of TERC enhances
MDV-mediated
oncogenesis, and is observed in
gastric carcinoma. Overexpression of TERC is also observed in
inflammatory conditions such as
Type II diabetes
Type 2 diabetes, 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 urination, ...
and
multiple sclerosis, due to TERC-mediated activation of the
NF-κB
Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular ...
inflammatory pathway.
TERC has been implicated as protective in
osteoporosis, with its increased expression arresting the rate of
osteogenesis. 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).
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, FamilialEntrezGene page for TERC*
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{{DNA replication
Non-coding RNA
Telomere-related genes