Two types of telomere maintenance mechanisms (TMMs) have been described in human tumors: telomerase activation and alternative lengthening of telomeres (ALT).

The vast majority of epithelial tumors rely on telomerase activation. Many mesenchymal tumors rely also on ALT for telomere maintenance.

Telomeres

Telomeres, which define the ends of chromosomes, consist of short, tandemly repeated DNA sequences loosely conserved in eukaryotes. Telomerase is a ribonucleoprotein complex ( we only show a few of the components in this illustration) which in vitro recognizes a single-stranded G-rich telomere primer and adds multiple telomeric repeats to its 3-prime end by using an RNA template.

Human telomeres consist of many kilobases of (TTAGGG)n together with various associated proteins. Small amounts of these terminal sequences are lost from the tips of the chromosomes during each S phase because of incomplete DNA replication, but de novo addition of TTAGGG repeats by the enzyme telomerase compensates for this loss.

Telomerase

Telomerase may also have a role in de novo formation of telomeres. Telomerase has been identified in many cultured cell lines and actively dividing cell types. The active reverse transcriptase component has been identified in teh TERT protein. The presence of this factor determines the availability of the telomerase function.

The TERT protein has a high turnover rate and its expression is regulated by factors that promote growth (c-MYC, v-k-ras, Bcl-2 and E6) and inhibiting factors (RB and p53) that promote cell death or that block cell division.

Regulation of active telomerase

It appears that the regulation of active telomerase has many levels and can be inhibited by TEP1 not releasing TERT or by TRF1 which binds the end repeats and prevents access to the chromosome ends. Additional modulation is due to phosphorlyation by PKC and AKT or dephophorylation by PP2A.

Telomere length in humans is partly controlled by a feedback mechanism in which telomere elongation by telomerase is limited by the accumulation of the TRF1 complex at chromosome ends. TRF1 itself can be inhibited by the poly(ADP-ribose) polymerase (PARP) activity of its interacting partner tankyrase 1, which abolishes its DNA binding activity in vitro and removes the TRF1 complex from telomeres in vivo.

Features

 cellular senescence
 cellular immortalization

References

 Chakhparonian M, Wellinger RJ. Telomere maintenance and DNA replication: how closely are these two connected? Trends Genet. 2003 Aug;19(8):439-46. PMID: #12902162#