THE ROLE OF TELOMERIC PROTEINS AND THEIR RELEVANCE AS TARGETS IN ANTI-CANCER THERAPY

Abstract

The telomere is a region of vital nucleoprotein structures at the terminal end of the
chromosome with 500- 3000 repeat sequences of TTAGGG. The shelterin and non-shelterin
complexes are telomere associated proteins. These proteins protect chromosome ends from
fusion and degradation. The non-shelterin complex of proteins is involved in DNA repair
while the shelterin complex of proteins is responsible for regulating telomere length.
Telomerase enzyme lengthens telomeres and in immortal cells it is activated. Approximately
90% of human cancers are telomerase positive. The inhibition of telomerase has been
considered a safer approach than the use of cytotoxic drugs in anti-cancer therapy. However,
the induction of delayed cell growth arrest via telomerase inhibition has been shown to be
slow. This is due to the fact that the replication rounds required are too many for it to be
effective. Induction of dissociation of shelterin proteins from telomeric DNA has been
considered a more efficacious approach based on gene silencing and mutation studies.
The loss of shelterin proteins such as the protection of telomeres 1 (POT 1) and telomere
repeat binding factor 2 (TRF 2) in cancer cells has been associated with apoptosis of the
tumour cells. Poly ADP ribose polymerase (PARP), a non-shelterin protein, is involved in
DNA repair. Drugs such as PJ-34 and 3-Aminobenzamide have been developed as PARP
inhibitors. Drugs that dissociate telomeric proteins from telomeric DNA are still under
clinical trials, they include Quarfloxin, C-1305 and Telomestatin. These drugs have low
cytotoxicity and are effective against tumours linked with dysfunction of DNA repair. The
level of cytotoxicity of a drug is vital in determining its efficacy. The cytotoxicity of cellcycle
inhibitors as anti-cancer medication motivated researchers to investigate telomeric
proteins as targets of anti-cancer intervention. The dissociation of shelterin proteins from
telomeric DNA and inhibition of non-shelterin proteins such as PARP and Tankyrase 1 and 2
have shown promising efficacy levels as anti-cancer therapy.