Telomerase Activity in Cancer Cells

INTRODUCTION

Telomerase is a ribonucleoprotein complex, which is made of a reverse transcriptase enzyme subunit and a long non-coding RNA which contains the template sequence for telomere synthesis. Telomeres are specialized DNA-protein complexes found at the end of all linear chromosomes. These telomeres in human somatic cells are slowly cut off and shortened after each replication cycle due to, in which some experts believe is oxidative stress of the telomeres. Telomerase is the enzyme responsible for lengthening/maintaining the telomeres that are shortening after each replication. Telomeres are there to protect chromosome ends from being recognized as damaged DNA by DNA damage responses (DDRs). There are certain lengths to where the telomere is too short and it is known as the "critical length". At this critical length most cells become "replicative" senescence cells. Once a cell reaches senescence the cell intelligently stops dividing before the DNA is exposed and there is a high risk of developing cancers and mutations within. The amount of times the cell can divide before becoming a senescent cell is called the "Hayflick" limit, named after the American anatomist Leonard Hayflick, and it is around 60 divisions.

hTERT GENE'S IMPORTANCE

The hTERT gene, human telomerase reverse transcriptase, is significantly expressed in approximately 90% of all human cancers. This gene encodes telomerase production for the cell. In a normal functioning cell, this hTERT gene is silenced. With the upregulating of the hTERT gene, the telomerase enzyme is produced constantly in cancer cells, meaning constant replacement of the telomeres, so as the cell can replicate uncontrollably without a stopping point. This is how most cancers get this ability. The hTERT promoter region is GC rich and lacks both a TATA and CAAT sequence which is popular in both eukaryotic and prokaryotic cells. There is a specific sequences in the hTERT promoter called an E-box (5'-CACGTC-3') and GC boxes (GGGCGG), that are important for both activation and repression of the hTERT gene. The list of up regulating substrates includes: c-MYC, SP1, E-26 Family Members, NF-kB, AP-2, and HIF-1. The down regulators include: p52, MAD, WT1, MZF-2, SIP1, and Menin.