Disease relevance of TERC

• Disease anticipation is associated with progressive telomere shortening in families with dyskeratosis congenita due to mutations in TERC [1].
• Mutations in TERC, encoding the RNA component of telomerase, have been found in autosomal dominant dyskeratosis congenita (DC) and aplastic anemia (AA) [2].
• Mutations of the human telomerase RNA gene (TERC) in aplastic anemia and myelodysplastic syndrome [3].
• Because of the possibility that TERC mutations might underlie seemingly acquired forms of bone marrow failure, we examined blood samples from a large number of patients with aplastic anemia (AA), paroxysmal nocturnal hemoglobinuria (PNH), and myelodysplasia (MDS) [3].
• Invasive cervical carcinomas almost invariably carry extra copies of chromosome arm 3q, resulting in a gain of the human telomerase gene (TERC) [4].

Psychiatry related information on TERC

• We used a radioactive in situ method to study expression of the RNA component of human telomerase (hTR) during normal human development and differentiation using archival tissues [5].

High impact information on TERC

• Subtelomeric DNA methylation is also decreased in conjunction with telomere shortening in Terc(-/-) mice [6].
• Reconstitution of human telomerase with the template RNA component hTR and the catalytic protein subunit hTRT [7].
• Dyskerin is also associated with telomerase RNA (hTR), which contains a H/ACA consensus sequence [8].
• Affected members of this family have an 821-base-pair deletion on chromosome 3q that removes the 3' 74 bases of hTR [8].
• Human cell lines that expressed hTR mutated in the template region generated the predicted mutant telomerase activity [9].

Chemical compound and disease context of TERC

• Also, using digoxigenin-labeled probes, we measured the in situ expression of human telomerase RNA component (hTR) in paired oral squamous cell carcinomas (OSCC) and adjacent non-cancerous matched tissue (NCMT) [10].
• MATERIALS AND METHODS: The TRF, TA and hTR of 11 human ovarian cancer cell lines and 2 cisplatin-resistant ovarian cancer cell lines were determined by genomic Southern blotting, a telomeric repeat amplification protocol and reverse transcription-polymerase chain reaction [11].
• The RNA expression levels of human catalytic subunit (TERT) and the RNA subunit (TR) of telomerase were analysed after treatment with the agonists of the membrane receptor (S 20098) and the nuclear receptor (CGP 52608) for melatonin in the MCF-7 human breast tumor cell line [12].

Biological context of TERC

• Telomeres are equally short in all individuals carrying the TERC gene deletion irrespective of their age [13].
• Here, we report a patient with DKC who inherited 2 distinct TERC sequence variants from her parents; a deletion (216_229del) in one and a point mutation (37A>G) in the other allele of the TERC gene [14].
• Interphase nuclei prepared from archival material of 12 primary cervical adenocarcinomas, eight of which were human papillomavirus positive, were hybridised with a triple colour probe set specific for centromeres of chromosomes 3 and 7 and the TERC gene [15].
• Telomerase is composed of a protein catalytic subunit and an RNA (hTR or TERC) component, both of which are critical for holoenzyme activity [16].
• But the TA other than telomere elongation (TERC independent) is crucial to initiate or restore melanoma cell proliferation [17].

Anatomical context of TERC

• Autosomal dominant dyskeratosis congenita (AD DC), a rare inherited bone marrow failure syndrome, is caused by mutations in TERC, the RNA component of telomerase [13].
• Our analysis shows that peripheral blood cells from family members haploinsufficient for TERC have very short telomeres [13].
• Expression of TERC and TLP1 was observed in all normal chorionic villi, as well as in trophoblastic diseases, and various cell lines irrespective of telomerase activity [18].
• While hTR is ubiquitously expressed, hTERT is normally restricted to germ cells and certain stem cells, but both are often deregulated during tumorigenesis [19].
• Telomerase activity immunoprecipitated from the reticulocyte lysate contained hTR and recombinant TP2 [20].

Associations of TERC with chemical compounds

• We also observed a significant reduction in TR, the RNA telomerase subunit, mRNA expression at physiological concentrations of melatonin (1 nm) [21].
• The products synthesized by human telomerase do not contain the nucleotide cytosine, which is encoded by an hTR residue 2 nucleotides (nt) 5' of the template boundary [22].
• As methylation might be involved in hTERC silencing, we examined the methylation pattern in all samples by direct sequencing and methylation-specific single stand conformation analysis after bisulfite modification. hTERC methylation was never observed, neither in normal nor in tumor tissues [23].
• CpG dinucleotides in the 5'-untranslated region of hTR were completely unmethylated from -204 to -3 and mosaically methylated from -290 to -272, irrespective of the atypism [24].
• The exposed RNA template of hTR is an ideal target for antisense oligonucleotides (As-ODN); while recent findings indicate all-trans retinoid acid (ATRA) could effectively inhibit the expression of catalytic subunit-hTERT [25].

Physical interactions of TERC

• Our results also identified two distinct regions of hTR that can independently bind hTERT in vitro [26].
• Potential telomerase-associated proteins that bind hTR were also identified using a UV cross-linking assay [27].
• RESULTS: Here we show using chromatin immunoprecipitation that mdm2 specifically binds the hTR promoter in vivo [28].
• Human Ku70/80 interacts directly with hTR, the RNA component of human telomerase [29].

Regulatory relationships of TERC

• However, the transcription rate of hTR is greatly increased in cells expressing endogenous hTERT, suggesting some overlap in transcriptional regulatory control [30].
• Dyskerin expression influences the level of ribosomal RNA pseudo-uridylation and telomerase RNA component in human breast cancer [31].
• Reverse transcriptase polymerase chain reaction analysis revealed that TP1 was ubiquitously expressed. hTR was found in all malignant (100%) and in 13/28 (46%) benign PCs [32].
• Retrovirus-mediated expression of p21WAF1 stopped the growth of all these cell types, but expression of wt p53 did not affect the cells' growth properties. p21WAF1 also downregulated human telomerase RNA component mRNA expression in HaCaT cells [33].
• These results indicate that the T3-bound TR inhibits the transcription of cyclin D1 through the Tcf/Lef-1 site, which is positively regulated by the Wnt-signaling pathway [34].

Other interactions of TERC

• The 5' half of hTR comprises the pseudoknot (core) domain, which includes the RNA template for telomere synthesis and a highly conserved pseudoknot that is required for telomerase activity [35].
• Dyskerin mRNA levels were highly variable and directly associated with both telomerase RNA component levels and rRNA pseudo-uridylation [31].
• Neither IGF-1 nor PHA altered hTR expression [36].
• The hTR/GAPDH mRNA ratio and hTR mRNA/total RNA in superficial tumor were significantly lower than in invasive bladder tumor [37].
• RT-PCR analysis was used for the detection of hTR, hTERT, and PGM1 (as a housekeeping) genes expression [38].

Analytical, diagnostic and therapeutic context of TERC

• This provided the rationale for the development of a multicolor fluorescence in situ hybridization (FISH) probe set as a diagnostic tool for the direct detection of TERC gains in Pap smears [4].
• RT-PCR analyses revealed that hTR and TP I mRNA were constitutively expressed both in tumor and in normal tissues [39].
• Our study conclusively demonstrates that antisense hTR effectively inhibits the growth of human glioma cells in vitro and in vivo and, thus, may be potentially used for gene therapy of malignant gliomas and other cancers [40].
• The levels of human telomerase RNA component (hTERC) also increased approximately 2.7-fold at 5 days after treatment [41].
• Telomerase activity was determined with ELISA, and its subunits human telomerase reverse transcriptase (hTERT) and human telomerase RNA (hTR) by RT-PCR [42].

References