Telomere capping

Short-term and massive apoptosis were also observed from the interference of the telomere-capping function of telomerase when hTERT or hTR are modified by mutations.The observation that BRACO-19 causes chromosome end-to-end fusions associated with the appearance of pl6-associated senescence led to the proposal that G-quadruplex ligands mostly act to disrupt the telomere structure.Such telomeric dysfunction was also observed in cell lines treated with RHSP4 or with 307A and in cell lines resistant to 12459 with typical images of telophase bridges" (Figure 4). 

Figure 6 Proposed role of hTERT overexpression in resistant JFD18 cell line to control telomere cappingf The telomere length increase and hTERT overexpression stabilize telomere-capping alterations induced by 12459 in JED 18 resistant cells. Transfection of JFD18 by DN-hTERT reduces the telomere length and restores sensitivity to the short-term effects of 12459. In parental cells, DN-hTERT transfection does not change the sensitivity to 12459, indicating that the short effect of the G-quadruplex ligand is independent of telomerase activity...

Interestingly, the (co)telomers used behave as further potential telogens for subsequent telomerizations, and all of them can be end-capped with ethylene (E). 

A human Estl ortholog, ESTIA, is associated with most or all active telomerase in human cell extracts and is involved, either directly or indirectly, in chromosome end-capping and telomere elongation [24, 25]. Another yeast subunit, Est3p, is similarly important for activity in vivo but not in vitro, with its specific function unknown. 

EXAMPLE 8.11 Telomerase is not expressed in somatic cells in mammals. This explains why they exhibit senescence. When grown in culture, they only divide a limited number of times before they die. After each cell division the telomeres become shorter to the extent they are unable to be capped. The resulting chromosomal instability leads to cell death. 

Telomeres are essential structures that cap the ends of linear chromosomes. Human telomeres are made of a simple DNA repeat, (TTAGGG)n [1,2]. These repeats serve as anchor for the recruitment of sequence-specific DNA-binding... 

G4 quadruplex in telomeres and in oncogenes. Barbara McClintock is cited for credit in the first description of capping eukaryotic chromosomes (in plant cells) for protection from ds-DNA breakage fusion catastrophes [370, 371]. 

DNA propellers. The a-mitochondriate Giardia is one of the most ancestral eukaryote. It has two telomeric G4 sequences a propeller-type parallel-stranded one with three G-tetrads, and a basket type anti-parallel-stranded one with two G-tetrads. Components of the G-quadruplexes can be readily exchanged by a cut and paste principle the chromosomal ends are kept capped [388]. The giardia genome is packed with retrotransposons (both LTR-, and non-LTR-types). The non-LTR-types are LINEs (long interspersed nuclear elements) with a single ORF... 

Comment. There is an eclat difference between telomere replacement in unicellular eukaryotes (like the ciliates) and somatic cells of multicellular hosts (like the mammals). The ciliates immediately cap with telomeres their chromosome ends after each cell division, whereas the chromosome ends of somatic cells in multicellular hosts remain uncapped, and steadily shorten with each cell division (approx 50 bp per cell divisions). These somatic cells of multicellular hosts undergo senescence and die, at which time stem cells may (or may not) replace them. The tetrahymena cells are rejuvenated and escape senescence due to constant telomere repairs. In that, unicellular eukaryotes (example the ciliates) resemble malignantly transformed somatic cells of the multicellular hosts, except that telomerase action is constitutive (irreversible) in the latter, whereas it can accelerate (at conjugation) and decelerate (after conjugation) in the former. 

How are the telomere ends treated in the trypanosoma cells rapidly (close to constitutively) replicating in liquid media While the mammalian blood stream form of the parasite may revert to that one residing in the insect vector (simulating trans-speciation) and virulence (mouse pathogenicity) may decline upon prolonged in vitro cultivation, the speed of replication is retained the telomeres are capped after each cell division [1287]. Unicellular life forms are able to sustain re-capped... 

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