telomere maintenance

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.

Pathology: Telomere maintenance anomalies

There are at least three human diseases that are associated with germ-line mutations of the genes encoding the two essential components of telomerase, TERT and TERC.

Heterozygous mutations of these genes have been described for patients with dyskeratosis congenita, bone marrow failure and idiopathic pulmonary fibrosis.

The spectrum of mutations in TERT and TERC varies for these diseases and may in part explain the clinical differences observed.

Environmental insults and genetic modifiers that accelerate telomere shortening and increase cell turnover may exaggerate the effects of telomerase haploinsufficiency, contributing to the variability of age of onset as well as tissue-specific organ pathology.

A central still unanswered question is whether telomerase dysfunction and short telomeres are a much more prominent factor than previously suspected in other adult-onset, age-related diseases.

See also

 cellular senescence
 cellular immortalization

Reviews

 Garcia CK, Wright WE, Shay JW. Human diseases of telomerase dysfunction: insights into tissue aging. Nucleic Acids Res. 2007;35(22):7406-16. PMID: 17913752

 Johnson JE, Broccoli D. Telomere maintenance in sarcomas. Curr Opin Oncol. 2007 Jul;19(4):377-82. PMID: 17545803

 Stewart SA. Telomere maintenance and tumorigenesis: an "ALT"ernative road. Curr Mol Med. 2005 Mar;5(2):253-7. PMID: 15974880

 Slijepcevic P. Is there a link between telomere maintenance and radiosensitivity? Radiat Res. 2004 Jan;161(1):82-6. PMID: 14680393

 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

 Wong JMY, Collins K: Telomere maintenance and disease. Lancet 362:983, 2003.

 Stewart SA, Weinberg RA: Senescence: does it all happen at the ends? Oncogene 21:627, 2002.

References

Shachar R, Ungar L, Kupiec M, Ruppin E, Sharan R. A systems-level approach to mapping the telomere length maintenance gene circuitry.Mol Syst Biol. 2008;4:172. .PMID: 18319724