Disease relevance of Terc

• In successive generations of ApcMin Terc-/- mice, progressive telomere dysfunction led to an increase in initiated lesions (microscopic adenomas), yet a significant decline in the multiplicity and size of macroscopic adenomas [1].
• Telomere shortening in G2 and G5 Terc-/- mice was coupled with attenuation in cardiac myocyte proliferation, increased apoptosis and cardiac myocyte hypertrophy [2].
• Furthermore, pathology not observed in Terc mutants but similar to that observed in Werner syndrome and Bloom syndrome, such as bone loss, was observed [3].
• Late-generation Terc-/- mice show defects in proliferative tissues and a moderate increase in the incidence of spontaneous tumours in highly proliferative cell types (lymphomas, teratocarcinomas) [4].
• In contrast, similarly treated G5 Terc(-/-) mice with critically short telomeres did not develop tumors and died of acute toxicity to the small intestine [5].

High impact information on Terc

• To examine the dosage effect of telomerase, we generated a line of mTR+/- mice on the CAST/EiJ background, which has short telomeres [6].
• Cells from the fourth mTR-/- generation onward possessed chromosome ends lacking detectable telomere repeats, aneuploidy, and chromosomal abnormalities, including end-to-end fusions [7].
• The affected G5 mTR(-/)- mice show higher chromosomal damage and greater apoptosis than similarly irradiated wild-type controls [8].
• The IR-sensitive phenotype of G5 mTR(-/)- mice suggests that telomere function is one of the determinants of radiation sensitivity of whole animals [8].
• 60% of the irradiated G5 mTR(-/)- mice die of acute radiation toxicity in the gastrointestinal tract, lymphoid organs, and kidney [8].

Biological context of Terc

• To determine whether telomere shortening leads to a cardiac phenotype, we studied heart function in the telomerase knockout mouse, Terc-/-. We studied Terc-/- mice at the second, G2, and fifth, G5, generation [2].
• Finally, G5 Terc(-/-) hypersensitivity to MNU supports the notion that short telomeres interfere with proper DNA damage repair [5].
• Although a few transcripts are modulated specifically in Ku86- or Terc-deficient cells, the observed transcriptional response is mainly inductive and qualitatively similar for all three genotypes, with highest transcriptional induction observed in double mutant G3 Terc-/-/Ku86-/- cells compared with either single mutant [9].
• We show here that in meiotic chromosome ends of late generation Terc-/- mice telomeric TTAGGG repeats and the TRF1 telomere-binding protein are significantly reduced or below detection level [10].
• The influence of critical telomeric attrition, a well-known trigger of apoptosis and cell arrest, on sperm DNA fragmentation was studied in late-generation knockout mice for Terc, the RNA component of telomerase, as a model of choice [11].

Anatomical context of Terc

• Here, we report on genome-wide transcription in mouse G3 Terc-/-, Ku86-/- and G3 Terc-/-/Ku86-/- germ cells using high-density oligonucleotide microarrays [9].
• To examine chromosome instability in the absence of telomerase, we established mouse embryonic fibroblast (MEF) lines from late generation mTR-/- and wild-type animals and examined metaphases using telomere fluorescence in situ hybridization (FISH) and spectral karyotyping (SKY) [12].
• We have identified an alternative telomere maintenance mechanism in mouse embryonic stem cells lacking telomerase RNA unit (mTER) with amplification of non-telomeric sequences adjacent to existing short stretches of telomere repeats [13].
• Although late generation mTR-/- mice show defects in the hematopoietic system, they are viable to adulthood, only showing a decrease in viability in old age [14].
• Here, we show that a percentage of mTR-/- embryos do not develop normally and fail to close the neural tube, preferentially at the forebrain and midbrain [15].

Associations of Terc with chemical compounds

• Here, we use telomerase-deficient mice, Terc(-/-), to study the impact of telomerase abrogation in response to treatment with the alkylating agent N-Methyl-N-Nitrosourea (MNU), a potent carcinogen in the mouse [5].

Regulatory relationships of Terc

• The telomerase RNA component Terc is required for the tumour-promoting effects of Tert overexpression [16].
• The presence of critically short telomeres in late-generation Inv-MycERTAM x Terc-/- mice further reduced the skin lesion induced by Myc [17].
• We have also identified mTR mutants that are able to inhibit wild type telomerase in vivo [18].

Other interactions of Terc

• Here, we demonstrate that the telomerase RNA component Terc is necessary to mediate these effects of Tert overexpression [16].
• These findings highlight Terc as a target for telomerase-based anticancer therapies [16].
• The tumors in the Atm(-/-) mTR(-/-) iG6 mice showed increased apoptosis and anaphase bridges [19].

Analytical, diagnostic and therapeutic context of Terc

• Telomere dynamics, chromosomal instability, and cellular viability were studied in serial passages of mouse embryonic stem (ES) cells in which the telomerase RNA (mTER) gene was deleted [20].
• Expression of ribozymes and mTER at various time points were evaluated by quantitative real-time PCR [21].
• However, antibodies that reacted with mTR in A31 cells were not detected in both Western blot analyses and indirect immunofluorescence assay [22].

References