Telomerase action

An enzyme that uses an RNA template to add DNA to the ends of chromosomes. Telomerase is normally active only in stem cells and those cells giving rise to sperm and egg, but telomerase also undergoes activation when cells become cancerous. In the latter case, telomerase action allows transformed cells to replicate without a limit, a process termed immortalization . 

The anthraquinone derivative (2) represents the first example from 1997, with numerous others following in rapid succession, including the dibenzo-phenanthroline derivatives and tri-substituted acridines (3), which were reported to inhibit telomerase action in tumour cell lines with IC50 values of up to 28 and 60 nM, respectively. The tri-substituted acridines (3) were developed from the simple acridine (4) on the basis of structure-based design principles to maximise the quadruplex binding affinity. Thus, inhibition of telomerase by these compounds appears to be correlated to selective stabilisation of the human DNA quadruplex structure. Tetra-(A-methyl-4-pyridyl)-porphyrins... 

Fig. 13.11. Telomerase action. The RNA present in telomerase base-pairs with the overhanging 3 -end of telomeres and extends it by acting both as a template and a reverse transcriptase. After copying a small number of repeats, the complex moves down to the 3 -end of the overhang and repeats the process.

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. 

Figure 3 Schematic outline of telomeres and telomerase action.

Although proteins and nucleic acids have well-separated functions in many instances, they also work intimately together in specific complexes containing both nucleic acid and protein. Some nucleoprotein complexes are very stable, some are transitory, and others have an intermediate stability. The protein component may provide a structural support for the nucleic acid, but in many cases, the two types of molecule both contribute directly to the function of the complex. Although cases of enzyme action by pure RNA molecules are rare, RNA molecules often act catalytically in nucleoprotein complexes. The chromosome was the first nucleoprotein complex to be discovered and is discussed first. Ribosomes have been studied intensively for many years and contain most of the RNA in the cell. More recently, nucleoprotein structures such as telomerase, spliceosomes, and signal-recognition particles have illustrated the versatility of nucleoprotein complexes. 

Blackburn, E.H. Telomeres and telomerase their mechanisms of action and the effects of altering their functions. FEBS Lett, 579,2005, 859-862. 

Termination and telomere The binding of the replication termination protein (Tus protein) to the terminus region (x locus) in prokaryotic chromosome impedes the progression of the replication fork and terminates DNA replication. In eukaryotes, the linear chromosomes terminate with telomeres by the action of telomerase. 

An important prediction is the expectation of a delay in the actions of telomerase inhibitors. Because sufficient telomere shortening needs to occur for senescence and crisis to be induced, the effects of telomerase inhibition will be observed only after the treated cancer cells have done sufficient number of cell divisions [2, 37]. Because of their delayed action, telomerase inhibitors are not going to be useful as a primary line of treatment. But to block the regrowth of residual disease after standard therapy, these inhibitors should be most valuable (Fig. 2). To produce recurrent tumors, surviving cancer cells need to undergo massive numbers of cell divisions. In the presence of a telomerase inhibitor, the... 

In view of their reduction potential, flavonoids have also been shown to interact with enzymes either unspecifically or specifically and modify their activity through reduction of metals in the active center. Of particular interest, because of their role in inflammatory conditions, is the reductive inactivation of lipoxygenases, cyclo-oxygenases, myeloperoxidase, and xanthine oxidase. In view of prooxidant activity of the enzymes, their inhibition by polyphenols may be regarded as an indirect antioxidation action. The list of enzymatic activities inhibited by flavonoids and other polyphenols also include phospholipase A2, protein kinases, metalloproteinases, drug metabolism enzymes, and telomerase, as reviewed elsewhere (Frade et al, 2005). 

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