Disease relevance of Telomere

• Moreover, elevated levels of chromosomal aberrations were detected, including telomeric end-to-end fusions, a signature of telomere dysfunction [1].
• 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 [2].
• These compound mutants showed increased telomere erosion and genomic instability, yet they experienced a substantial elimination of T-cell lymphomas associated with Atm deficiency [3].
• Together, these results are consistent with the model that although telomere dysfunction provokes chromosomal aberrations that initiate carcinogenesis, telomerase-mediated telomere maintenance enables such initiated cells to efficiently achieve a fully malignant endpoint, including metastasis [4].
• To investigate how telomerase activity and the differentiation state of germ cell tumors are related, telomerase activities and telomere lengths were measured in benign testicular tissues, germ cell cancers, and mature or immature teratomas [5].

Psychiatry related information on Telomere

• Analysis of many families with linked DNA markers has provided support for the Huntington's disease (HD) gene being close to the telomere on the short arm of chromosome 4 [6].
• Tissue-specific alternate splicing of human telomerase reverse transcriptase (hTERT) influences telomere lengths during human development [7].
• These results, in conjunction with historical cytogenetic data, suggest that a putative growth control locus lies distal to the thymidine kinase (Tk1) gene, near the telomere [8].

High impact information on Telomere

• Here we discuss the details of telomerase and its regulation by the telomere [9].
• This regulation can take place at the telomere terminus, involving single-stranded DNA-binding proteins (POT1 in humans and Cdc13 in budding yeast), which have been proposed to contribute to the recruitment of telomerase and may also regulate the extent or frequency of elongation [9].
• Telomerase is a ribonucleoprotein polymerase that specifically elongates telomeres [10].
• A simple mechanism in which a mobile promoter moves between telomeres has been rendered unlikely by the demonstration that two telomeric transcription units can be simultaneously active when one of them is interrupted by a large DNA insertion.(ABSTRACT TRUNCATED AT 400 WORDS)[11]
• Deletion of BUD32 or other KEOPS components leads to short telomeres and a failure to add telomeres de novo to DNA double-strand breaks [12].

Chemical compound and disease context of Telomere

• Phage N15 telomere resolution. Target requirements for recognition and processing by the protelomerase [13].
• PCa-precursor lesions (prostatic intraepithelial neoplasia) also displayed decreased levels of 14-3-3sigma expression in luminal cells, which are known to contain shortened telomeres [14].
• Prevention of critical telomere shortening by oestradiol in human normal hepatic cultured cells and carbon tetrachloride induced rat liver fibrosis [15].
• After exposure to cisplatin as single dose or continuous treatment, we found no loss of telomeres in either SHSY5Y neuroblastoma cells (telomere length, approximately 4 kbp), HeLa 229 cells (telomere length, 20 kbp) or in the acute lymphoblastic T cell line 1301 (telomere length, approximately 80 kbp) [16].
• Treatment of a human hepatoma cell line HepG2 with a low concentration of compound E gradually reduced the telomere length, indicating that this compound was able to inhibit telomerase in living cells as well as in vitro [17].

Biological context of Telomere

• The t-loop structure of mammalian telomeres is thought to repress nonhomologous end joining (NHEJ) at natural chromosome ends [18].
• Together, these observations support the view that telomerase and telomere structure are dynamically regulated in normal human cells and that telomere length alone is unlikely to trigger entry into replicative senescence [19].
• Expression of telomerase prevents overhang loss, suggesting that this enzyme prevents senescence by maintaining proper telomere structure [20].
• However, telomerase is not detectable in most normal somatic cells; this corresponds to the gradual telomere loss observed with each cell division [21].
• In wild-type cells, elimination of a telomere caused a RAD9-mediated cell cycle arrest, indicating that telomeres help cells to distinguish intact chromosomes from damaged DNA [22].

Anatomical context of Telomere

• Some immortalized human cell lines and some tumours maintain their telomeres in the absence of any detectable telomerase activity by a mechanism referred to as alternative lengthening of telomeres (ALT) [23].
• Telomere length is maintained, by the presence of telomerase activity, in the vast majority of primary tumours and stem cells, suggesting that telomere maintenance is essential for cellular immortalization [24].
• Telomerase is expressed and telomere length is maintained in human germ cells and the great majority of primary human tumours [21].
• Telomerase is present in both normal and AT lymphocytes and so neither telomere shortening nor telomeric fusions can be explained by the absence of telomerase [25].
• I have identified an activity in crude HeLa cell extracts that satisfies the requirements for a human telomere terminal transferase or telomerase [26].

Associations of Telomere with chemical compounds

• Here we report physical linkage of three mouse PAR probes: DXYHgu1, DXYMov15 and (TTAGGG)n. Steroid sulphatase (Sts) maps distal to these probes, indicating that there is an internal array of the telomere sequence (TTAGGG)n in the PAR [27].
• Single-stranded complex guanine-rich DNA sequences from chromosomal telomeres and elsewhere can associate to form stable parallel four-stranded structures termed G4-DNA by a process that is anomalously dependent on the particular alkali metal cation that is present [28].
• Here we report that histone H3 is required for full repression at yeast telomeres and at partially disabled silent mating loci, and that the acetylatable lysine residues of H3 play an important role in silencing [29].
• Mutations in the conserved acetyl-CoA binding motif of Sas2p are shown to disrupt the ability of Sas2p to mediate the silencing at HML and telomeres, providing evidence for an important role for the acetyltransferase activity of the SAS complex in silencing [30].
• The B. burgdorferi telomere resolvase ResT generates the hairpin telomeres from replication intermediates in a reaction with mechanistic similarities to that catalyzed by type IB topoisomerases and tyrosine recombinases [31].

Gene context of Telomere

• Moreover, telomerase inhibition in human tumour cell lines using dominant-negative versions of TERT leads to telomere shortening and cell death [32].
• Immunofluorescence studies with antibodies against RAP1 and SIR3 demonstrate that the H3 and H4 N-termini are required for the association of SIR3 with telomeric chromatin and the perinuclear positioning of yeast telomeres [33].
• In addition, normal telomere length can be restored by expressing a Cdc13-Est1p hybrid protein [34].
• Accompanying the continual telomere shortening, the growth rate of Terc-deficient ES cells was gradually reduced after more than 300 divisions [24].
• MEC1-dependent redistribution of the Sir3 silencing protein from telomeres to DNA double-strand breaks [35].

Analytical, diagnostic and therapeutic context of Telomere

• Using immunofluorescence labeling, electron microscopy, and chromatin immunoprecipitation assays, RAD51D was shown to localize to the telomeres of both meiotic and somatic cells [1].
• Indirect immunofluorescence demonstrated the presence of RAD50 and MRE11 at interphase telomeres [36].
• Microarray analysis revealed that HTZ1-activated genes cluster near telomeres [37].
• We used the yeast two-hybrid assay to show that Hdf1 interacts with Sir4, which is involved in transcriptional silencing at telomeres and HM loci [38].
• Confocal microscopy shows that the release of telomerase to the nucleoplasm from sequestration at nucleolar sites is enhanced at the expected time of telomere replication [39].

References