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50-868: TERC may refer to: Telomerase RNA component , a human gene. TERC (Cambridge, Massachusetts) , a nonprofit research and development organization in Cambridge, Massachusetts, the developers of the Investigations in Numbers, Data, and Space mathematics curriculum " Investigations " or TERC, a K–5 mathematics curriculum, developed at TERC (Cambridge, Massachusetts) Technical Education Research Centers (TERC) CSIRO Tropical Ecosystems Research Centre Terrestrial Environment Research Center . A research center at University of Tsukuba . Thermal Enclosure Rater Checklist A standard for achieving green building certification in
100-426: A n/a n/a n/a n/a n/a 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 . 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
150-430: A 5' pseudoknot structure close to the template sequence. The vertebrate telomerase RNAs have a 3' H/ACA snoRNA -like domain. 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. TERC has extensive secondary structural features over 4 principal conserved domains. The core domain,
200-497: A T-loop. G-quadruplexes present an obstacle for enzymes such as DNA-polymerases and are thus thought to be involved in the regulation of replication and transcription. Many organisms have a ribonucleoprotein enzyme called telomerase, which carries out the task of adding repetitive nucleotide sequences to the ends of the DNA. Telomerase "replenishes" the telomere "cap" and requires no ATP. In most multicellular eukaryotic organisms, telomerase
250-506: A T-loop. This loop is analogous to a knot, which stabilizes the telomere, and prevents the telomere ends from being recognized as breakpoints by the DNA repair machinery. Should non-homologous end joining occur at the telomeric ends, chromosomal fusion would result. The T-loop is maintained by several proteins, collectively referred to as the shelterin complex. In humans, the shelterin complex consists of six proteins identified as TRF1 , TRF2 , TIN2 , POT1 , TPP1 , and RAP1 . In many species,
300-474: 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 . Unlike most lncRNAs which are assembled from introns by the spliceosome , hTR is directly transcribed from
350-615: A cell replicates until the loss reaches a critical level, at which point cell division ends. According to his theory of marginotomy, DNA sequences at the ends of telomeres are represented by tandem repeats, which create a buffer that determines the number of divisions that a certain cell clone can undergo. Furthermore, it was predicted that a specialized DNA polymerase (originally called a tandem-DNA-polymerase) could extend telomeres in immortal tissues such as germ line, cancer cells and stem cells. It also followed from this hypothesis that organisms with circular genome, such as bacteria, do not have
400-471: 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. Telomerase is a ribonucleoprotein polymerase that maintains telomere ends by addition of
450-518: A dedicated promoter site located at genomic locus 3q26.2 by RNA polymerase II . 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
500-574: A group of scientists organized at Geron Corporation by Geron's founder Michael D. West , that tied telomere shortening with the Hayflick limit. The cloning of the catalytic component of telomerase enabled experiments to test whether the expression of telomerase at levels sufficient to prevent telomere shortening was capable of immortalizing human cells. Telomerase was demonstrated in a 1998 publication in Science to be capable of extending cell lifespan, and now
550-492: A major influence on telomere shortening in vivo . There is a multitude of ways in which oxidative stress, mediated by reactive oxygen species (ROS), can lead to DNA damage; however, it is yet unclear whether the elevated rate in telomeres is brought about by their inherent susceptibility or a diminished activity of DNA repair systems in these regions. Despite widespread agreement of the findings, widespread flaws regarding measurement and sampling have been pointed out; for example,
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#1732868918036600-439: 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 . Homologs of TERC can also be found in
650-703: A suspected species and tissue dependency of oxidative damage to telomeres is said to be insufficiently accounted for. Population-based studies have indicated an interaction between anti-oxidant intake and telomere length. In the Long Island Breast Cancer Study Project (LIBCSP), authors found a moderate increase in breast cancer risk among women with the shortest telomeres and lower dietary intake of beta carotene, vitamin C or E. These results suggest that cancer risk due to telomere shortening may interact with other mechanisms of DNA damage, specifically oxidative stress. Although telomeres shorten during
700-405: A variety of cancers . 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 and multiple sclerosis , due to TERC-mediated activation of
750-446: 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 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
800-404: Is active only in germ cells , some types of stem cells such as embryonic stem cells , and certain white blood cells . Telomerase can be reactivated and telomeres reset back to an embryonic state by somatic cell nuclear transfer . The steady shortening of telomeres with each replication in somatic (body) cells may have a role in senescence and in the prevention of cancer . This is because
850-502: Is dominated by cross-sectional and correlational studies, which makes causal interpretation problematic. A 2020 review argued that the relationship between psychosocial stress and telomere length appears strongest for stress experienced in utero or early life. The phenomenon of limited cellular division was first observed by Leonard Hayflick , and is now referred to as the Hayflick limit . Significant discoveries were subsequently made by
900-454: Is essential for telomere maintenance and capping. Multiple proteins binding single- and double-stranded telomere DNA have been identified. These function in both telomere maintenance and capping. Telomeres form large loop structures called telomere loops, or T-loops. Here, the single-stranded DNA curls around in a long circle, stabilized by telomere-binding proteins . At the very end of the T-loop,
950-645: Is the Terminal Restriction Fragment (TRF) southern blot. There is a Web-based Analyser of the Length of Telomeres ( WALTER ), software processing the TRF pictures. A Real-Time PCR assay for telomere length involves determining the Telomere-to-Single Copy Gene (T/S) ratio, which is demonstrated to be proportional to the average telomere length in a cell. Tools have also been developed to estimate
1000-473: Is used to quantify the length of telomeres in human white blood cells. A semi-automated method for measuring the average length of telomeres with Flow FISH was published in Nature Protocols in 2006. While multiple companies offer telomere length measurement services, the utility of these measurements for widespread clinical or personal use has been questioned. Nobel Prize winner Elizabeth Blackburn , who
1050-409: Is variable among taxa and linked to the method used for estimating telomere length. In contrast, the available information shows no sex differences in telomere length across vertebrates. Phylogeny and life history traits such as body size or the pace of life can also affect telomere dynamics. For example, it has been described across species of birds and mammals. In 2019, a meta-analysis confirmed that
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#17328689180361100-526: Is well-recognized as capable of immortalizing human somatic cells. Two studies on long-lived seabirds demonstrate that the role of telomeres is far from being understood. In 2003, scientists observed that the telomeres of Leach's storm-petrel ( Oceanodroma leucorhoa ) seem to lengthen with chronological age, the first observed instance of such behaviour of telomeres. A study reported that telomere length of different mammalian species correlates inversely rather than directly with lifespan, and concluded that
1150-527: The Dyskerin complex ( DKC1 , 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 containing
1200-469: The Energy Star home rating program. UC Davis Tahoe Environmental Research Center (TERC). A non-profit organization that conducts research on Lake Tahoe and educated the public on environmental issues at Lake Tahoe Topics referred to by the same term [REDACTED] This disambiguation page lists articles associated with the title TERC . If an internal link led you here, you may wish to change
1250-568: The Gallid herpes viruses . The core domain of TERC contains the RNA template from which TERT synthesizes TTAGGG telomeric repeats. Unlike in other RNPs, in telomerase , the protein TERT is catalytic while the lncRNA TERC is structural, rather than acting as a ribozyme . The core region of TERC and TERT are sufficient to reconstitute catalytic telomerase activity in vitro. The H/ACA domain of TERC recruits
1300-575: The NF-κB 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). Telomere A telomere ( / ˈ t ɛ l ə m ɪər , ˈ t iː l ə -/ ; from Ancient Greek τέλος ( télos ) 'end' and μέρος ( méros ) 'part')
1350-481: The 3'-end of the template (corresponding to the potential 5'-end of the lagging-strand). Originally it was believed that the last primer would sit at the very end of the template, thus, once removed, the DNA-polymerase that substitutes primers with DNA (DNA-Pol δ in eukaryotes) would be unable to synthesize the "replacement DNA" from the 5'-end of the lagging strand so that the template nucleotides previously paired to
1400-539: The 3’-5’ RNA exonuclease PARN , 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 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
1450-400: The contribution of telomere length to lifespan remains controversial. There is little evidence that, in humans, telomere length is a significant biomarker of normal aging with respect to important cognitive and physical abilities. Experimentally verified and predicted telomere sequence motifs from more than 9000 species are collected in research community curated database TeloBase . Some of
1500-429: The end replication problem and therefore do not age. Olovnikov suggested that in germline cells, cells of vegetatively propagated organisms, and immortal cell populations such as most cancer cell lines, an enzyme might be activated to prevent the shortening of DNA termini with each cell division. In 1975–1977, Elizabeth Blackburn , working as a postdoctoral fellow at Yale University with Joseph G. Gall , discovered
1550-407: The eukaryotic chromosomes in structure and function. The known structures of bacterial telomeres take the form of proteins bound to the ends of linear chromosomes, or hairpin loops of single-stranded DNA at the ends of the linear chromosomes. At the very 3'-end of the telomere there is a 300 base pair overhang which can invade the double-stranded portion of the telomere forming a structure known as
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1600-516: The experimentally verified telomere nucleotide sequences are also listed in Telomerase Database website (see nucleic acid notation for letter representations). Preliminary research indicates that disease risk in aging may be associated with telomere shortening, senescent cells , or SASP ( senescence-associated secretory phenotype ). Several techniques are currently employed to assess average telomere length in eukaryotic cells. One method
1650-472: 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 . 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. The 3’ end of TERC consists of
1700-536: The last primer would not be replicated. It has since been questioned whether the last lagging strand primer is placed exactly at the 3'-end of the template and it was demonstrated that it is rather synthesized at a distance of about 70–100 nucleotides which is consistent with the finding that DNA in cultured human cell is shortened by 50–100 base pairs per cell division . If coding sequences are degraded in this process, potentially vital genetic code would be lost. Telomeres are non-coding, repetitive sequences located at
1750-413: The length of telomere from whole genome sequencing (WGS) experiments. Amongst these are TelSeq, Telomerecat and telomereHunter. Length estimation from WGS typically works by differentiating telomere sequencing reads and then inferring the length of telomere that produced that number of reads. These methods have been shown to correlate with preexisting methods of estimation such as PCR and TRF. Flow-FISH
1800-595: The lifetime of an individual, it is telomere shortening-rate rather than telomere length that is associated with the lifespan of a species. Critically short telomeres trigger a DNA damage response and cellular senescence . Mice have much longer telomeres, but a greatly accelerated telomere shortening-rate and greatly reduced lifespan compared to humans and elephants. Telomere shortening is associated with aging, mortality, and aging-related diseases in experimental animals. Although many factors can affect human lifespan, such as smoking, diet, and exercise, as persons approach
1850-409: The link to point directly to the intended article. Retrieved from " https://en.wikipedia.org/w/index.php?title=TERC&oldid=1065812480 " Category : Disambiguation pages Hidden categories: Short description is different from Wikidata All article disambiguation pages All disambiguation pages Telomerase RNA component n/a ENSG00000277925 n/a n
1900-411: The parent strands. This is a consequence of its unidirectional mode of DNA synthesis: it can only attach new nucleotides to an existing 3'-end (that is, synthesis progresses 5'-3') and thus it requires a primer to initiate replication. On the leading strand (oriented 5'-3' within the replication fork), DNA-polymerase continuously replicates from the point of initiation all the way to the strand's end with
1950-499: The presence of a protective cap, which he coined "telomeres", from the Greek telos (end) and meros (part). In the early 1970s, Soviet theorist Alexey Olovnikov first recognized that chromosomes could not completely replicate their ends; this is known as the "end replication problem". Building on this, and accommodating Leonard Hayflick 's idea of limited somatic cell division, Olovnikov suggested that DNA sequences are lost every time
2000-445: The primer (made of RNA ) then being excised and substituted by DNA. The lagging strand, however, is oriented 3'-5' with respect to the replication fork so continuous replication by DNA-polymerase is impossible, which necessitates discontinuous replication involving the repeated synthesis of primers further 5' of the site of initiation (see lagging strand replication ). The last primer to be involved in lagging-strand replication sits near
2050-552: The relative rates of these various competing pathways that activate or inhibit hTR maturation is a crucial element of regulation of overall telomerase activity. 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 , idiopathic pulmonary fibrosis , aplastic anemia , and myelodysplasia . Overexpression and improper regulation of TERC have been associated with
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2100-495: The sequence repeats are enriched in guanine , e.g. TTAGGG in vertebrates , which allows the formation of G-quadruplexes , a special conformation of DNA involving non-Watson-Crick base pairing. There are different subtypes depending on the involvement of single- or double-stranded DNA, among other things. There is evidence for the 3'-overhang in ciliates (that possess telomere repeats similar to those found in vertebrates ) to form such G-quadruplexes that accommodate it, rather than
2150-435: The single-stranded telomere DNA is held onto a region of double-stranded DNA by the telomere strand disrupting the double-helical DNA, and base pairing to one of the two strands. This triple-stranded structure is called a displacement loop or D-loop. Apart from the end replication problem, in vitro studies have shown that telomeres accumulate damage due to oxidative stress and that oxidative stress-mediated DNA damage has
2200-430: 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
2250-560: The telomeres act as a sort of time-delay "fuse", eventually running out after a certain number of cell divisions and resulting in the eventual loss of vital genetic information from the cell's chromosome with future divisions. Telomere length varies greatly between species, from approximately 300 base pairs in yeast to many kilobases in humans, and usually is composed of arrays of guanine -rich, six- to eight-base-pair-long repeats. Eukaryotic telomeres normally terminate with 3′ single-stranded-DNA overhang ranging from 75 to 300 bases, which
2300-682: The termini of linear chromosomes to act as buffers for those coding sequences further behind. They "cap" the end-sequences and are progressively degraded in the process of DNA replication. The "end replication problem" is exclusive to linear chromosomes as circular chromosomes do not have ends lying without reach of DNA-polymerases. Most prokaryotes , relying on circular chromosomes, accordingly do not possess telomeres. A small fraction of bacterial chromosomes (such as those in Streptomyces , Agrobacterium , and Borrelia ), however, are linear and possess telomeres, which are very different from those of
2350-463: The unusual nature of telomeres, with their simple repeated DNA sequences composing chromosome ends. Blackburn, Carol Greider , and Jack Szostak were awarded the 2009 Nobel Prize in Physiology or Medicine for the discovery of how chromosomes are protected by telomeres and the enzyme telomerase . During DNA replication, DNA polymerase cannot replicate the sequences present at the 3' ends of
2400-434: The upper limit of human life expectancy , longer telomeres may be associated with lifespan. Meta-analyses found that increased perceived psychological stress was associated with a small decrease in telomere length—but that these associations attenuate to no significant association when accounting for publication bias . The literature concerning telomeres as integrative biomarkers of exposure to stress and adversity
2450-442: The very ends of the DNA strand for a double-strand break . The existence of a special structure at the ends of chromosomes was independently proposed in 1938 by Hermann Joseph Muller , studying the fruit fly Drosophila melanogaster , and in 1939 by Barbara McClintock , working with maize. Muller observed that the ends of irradiated fruit fly chromosomes did not present alterations such as deletions or inversions. He hypothesized
2500-565: Was co-founder of one company, promoted the clinical utility of telomere length measures. During the last two decades, eco-evolutionary studies have investigated the relevance of life-history traits and environmental conditions on telomeres of wildlife. Most of these studies have been conducted in endotherms , i.e. birds and mammals. They have provided evidence for the inheritance of telomere length; however, heritability estimates vary greatly within and among species. Age and telomere length often negatively correlate in vertebrates, but this decline
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