Telomerase Signaling

The extended growth potential of cancer cells is critically dependent upon the maintenance of functional telomeres, which are sections of DNA occurring at the ends of each chromosome in a eukaryotic cell. Telomeres consist of highly repetitive sequences of DNA that do not code for proteins, but function as caps to keep chromosomes from fusing together. In order to divide, a normal cell has to replicate the entire DNA in its chromosomes. However, the last few bases on the telomere are not copied with each round of DNA replication as a cell ages, which results in telomere shortening with each round of cell division. At one point, cells stop going through cell division, and this halt in growth is triggered by genes that are activated in response to DNA damage such as p53. A telomere that becomes too short no longer protects the chromosome from DNA damage. Cell replication is stopped and the cell is forced into senescence.Telomeric structural proteins fall into two general groups: those that bind telomeric DNA directly, and those that interact, directly or indirectly, with the telomeric DNA-binding proteins. Some telomeric DNA-binding proteins bind single-stranded telomeric DNA and others bind duplex telomeric DNA. The telomerase ribonucleoprotein enzyme complex binds the protruding single-stranded end of the G-rich telomeric DNA strand in order to extend it and make up for the loss of terminal sequences resulting from normal semi-conservative DNA replication. Telomerase synthesizes its species-specific telomeric repeat sequence by elongating a DNA primer. It has two essential components, the RNA component TERC and a catalytic subunit TERT. TERC acts in concert to elongate telomeres by reading from the RNA template sequence carried by the RNA subunit and synthesizing a complementary DNA strand.The expression of the TERT catalytic subunit is upregulated by growth factors such as EGF via the Ras-Raf-MEK-ERK pathway, while it is downregulated by inhibiting factors that promote apoptosis or block cell division such as p53, p21CIP1, E2F and HDAC. Post-translational signaling events acting directly on TERT also play a role in regulation of telomerase activity, such as activation of TERT by AKT and HSP90 and inhibition of TERT by c-Abl, where the phosphorylation state of TERT modulates the catalytic activity of telomerase. Additional molecules that regulate the activity of hTERC-hTERT and the maintenance of telomere structure include TRF1,Tankyrase, TIN-2 and RAP1. These proteins interact with the telomere and regulate the opening and closing of the free telomere end and access to the telomere by other protein complexes including the telomerase components.