POT1 (Protection of Telomeres)

Maintain telomere integrity with one or more oligonucleotide/oligosaccharide binding folds

(OB folds) only telomeric protein that binds telomere ssDNA. Loss of function of POT1 (POT1
knockout) trigger damage response pathway inititated by protein kinase ATR (ataxia
telangiectasia related). Both TPP1 and POT1 are critical for regulating telomere length.

TPP1 (Tripeptidyl Peptidase)

Interacts with both TIN2 and POT1. Major POT1-interacting protein. OB fold is required for
telomerase recruitment. TRF1-TIN2-TPP1-POT1 association illustrates an important pathway
through which signals are communicated along a telomere.
In the absence of telomerase activity telomeres progressively shorten. Telomerase activity is
absent in most normal human somatic cells because of the lack of expression of TERT; TERC is
usually present. On the other hand most mouse cells have telomerase activity (Blasco, 2005)
Without telomerase, telomere shortening eventually limits the growth of cells, either by
senescence, in cells with intact cell cycle checkpoints (a G1 cell cycle block), or by crisis in cells
with inactivated checkpoints (telomeric end-to-end fusions cause chromosome breakage and
mitotic catastrophe) (Shay and Wright, 2007).Expression of TERT in cells that otherwise lack
telomerase activity causes cells to bypass senescence and crisis, and such cells are usually
termed “immortalized.”

Telomerase inhibitors have been touted as a novel cancer specific therapy, as most tumor
cells have high expression of telomerase, whereas most normal somatic cells express low or
undetectable levels of telomerase. Continued proliferation of tumor cells requires activation of
telomerase to maintain chromosomal stability and extend life span, because telomerase elongates
telomere length and rewinds the cellular mitotic clock. Conversely, shortening of telomeres by
inhibition of telomerase activity induces growth arrest (senescence) and apoptosis in tumor cells.
Moreover, it has been reported that inhibition of telomerase increases the susceptibility of tumor
cells to apoptosis induced by anticancer agents. Thus, telomerase inhibitors could be used as an
adjuvant with conventional therapy. However, there are also several potential limitations of
telomerase inhibition as a therapeutic strategy. For example, there is a lag phase between
telomerase inhibition and telomere shortening, with growth arrest and cell death. In this review,
we will discuss the basic biology of telomeres and telomerase as a platform for the development
of treatments based upon inhibition of telomerase activity.

The sodium salt of imetelstat, a synthetic lipid-conjugated, 13-mer oligonucleotide N3' P5'-
thio-phosphoramidate with potential antineoplastic activity. Complementary to the template
region of telomerase RNA (hTR), imetelstat acts as a competitive enzyme inhibitor that binds
and blocks the active site of the enzyme (a "telomerase template antagonist"), a mechanism of
action which differs from that for the antisense oligonucleotide-mediated inhibition of
telomerase activity through telomerase mRNA binding. Inhibition of telomerase activity in tumor
cells by imetelstat results in telomere shortening, which leads to cell cycle arrest or apoptosis.

Telomerase, also called telomere terminal transferase, is an enzyme made of protein and

RNA subunits that elongates chromosomes by adding TTAGGG sequences to the end of existing
chromosomes. Because these somatic cells do not regularly use telomerase, they age. The result
of aging cells is an aging body.

ADVANTAGES:

Normal human ageing could be slowed by reawakening the enzyme in cells where it has ceased
working drugs that ramp up telomerase activity are worth pursuing as a potential treatment for
rare disorders characterized by premature ageing and perhaps even for more common age-related
conditions potential to produce unlimited quantities of normal human cells of virtually any tissue
type genetic engineering of telomerase-immortalized cells could lead to the development of cell-
based therapies for certain genetic disorders.

Other areas of cell engineering that may be possible in the future including:

 unlimited supply of pancreatic islet cells that are glucose responsive for the treatment of
diabetes
 rejuvenating the endothelial lining of blood vessels
 regeneration of bone marrow stem cells
 in retinal treatment of macular degeneration
(age-related blindness)
DISADVANTAGES:
 Some normal cells may be affected by telomerase
 Needs further investigation