TELOMERASE TARGETING IN CANCER

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e-ISSN: 2582-5208 International Research Journal of Modernization in Engineering Technology and Science Volume:02/Issue:10/ October -2020

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TELOMERASE TARGETING IN CANCER Hari Krishnan R*1 *1Student,

Department of Biotechnology, SRM institute of Science and Technology, Chennai, India.

ABSTRACT Telomerase is a terminal transferase ribonucleo protein that is responsible for maintaining telomere length. This is a feature of nearly 85% of the cancers where cell immortality is achieved by increased expression of telomerase enzyme responsible for the addition of telomere repeat sequences at the 3’ end of the chromosomes after every replication cycle thereby maintaining telomere length. Telomerase is generally active in germ cells and stem cells but is undetectable in normal cells. This makes telomerase inhibitors a potential target in cancer immunotherapy. The telomerase holoenzyme contains two major subunits, the telomerase reverse transcriptase (hTERT) which is the catalytical subunit, and the telomerase RNA (hTR) which provides a template RNA with its sequence complementary to the telomere repeat sequence (“5’-dTTAGGG-3’”). These two subunits are considered important in the telomerase inhibitors studies. Other telomerase inhibitor targets are tankyrase 1 and 2 which is responsible for telomere homeostasis, HSP 90 inhibitors, and 3’ telomere overhang sequence (T-oligos), etc. Inhibition of telomerase will lead to loss of telomeres in cancer cells thereby disabling its immortality feature and enabling replicative senescence and hence acting as a tumor suppressor mechanism. In this review paper, we discuss the recent advances in telomerase inhibition and focus on the future perspectives. Keywords: cell immortality, hTERT, immunotherapy, T-Oligos, replicative senescence.

I.

INTRODUCTION

Telomeres are DNA sequences consisting of hexameric 5′-TTAGGG-3′ tandem repeats capped at the ends of the eukaryotic chromosomes. During eukaryotic cell division, the telomeres shorten with each division as a result of the reduced expression of telomerase enzyme and after about 50 divisions the telomere length becomes critically shortened thereby inducing replicative senescence. The tandem repeats are associated with a complex protein called shelterin. Shelterin consists of six subunits, TRF1, TRF2, Rap1, TIN2, TPP1, and POT1 which binds to the telomere sequences to ensure stability [1]. Telomere prevents the ends of the chromosome to be misrecognized as DNA breaks thereby preventing DNA damage responses that lead to apoptosis and senescence.[2] Telomere shortening occurs due to a process known as ‘end replication problem’, where the DNA polymerase responsible for polymerization does not completely replicate the strand [3]. At some point when the telomere length reaches its threshold, the DNA damage repair system recognizes this as DNA breaks and activates the p53 pathway inducing apoptosis [4]. Telomerase expression is highly regulated from cell to cell, its activity is generally high in cells with proliferative potential like germ cells, self-renewing stem cells. In other tissues, telomerase is inactivated in the gestation stage. A major factor in the molecular basis of telomerase regulation is transcriptional and translational regulation of the hTERT catalytical domain. Due to its overexpression in cancer cells and minimal expression in normal cells, telomerase activity (TA) is considered to be a unique cancer biomarker. Telomerase activity is high in cancer cells during early tumorigenesis and procedures such as telomeric repeat amplification protocol (TRAP) assay is being used for cancer diagnosis as this method can detect trace amounts of this enzyme [5]. In less than 15% of cancers, telomere length is maintained by a homologous recombination-mediated mechanism called the ALT pathway. These cells replenish telomeres in a telomerase independent pathway and thereby are resistant to telomerase-based therapies.

II.

TARGETING hTERT and hTR

The telomerase reverse transcriptase (TERT) and the telomerase RNA(TR) are the two subunits of Telomerase which are responsible for telomere lengthening and telomerase activity (TA) thereby making

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