Telomerase-Related Proteins

Abstract

The ends of all eukaryotic chromosomes are protected by specialized nucleoprotein complexes called telomeres. When functional and intact, telomeres prevent end-to-end fusions, inappropriate DNA repair mechanisms, and DNA degradation. Often referred to as biological clocks, telomeres are repeatedly shortened during each replication cycle due to incomplete replication by DNA polymerases. When critically short, telomeres become dysfunctional or uncapped, losing their higher-order structures and ability to protect the chromosome, an event referred to as the “end-replication problem.” This telomere instability prompts cells to enter a growth arrest state and trigger DNA damage responses (DDRs) such as cellular senescence and apoptosis. In addition, due the guanine rich properties of telomeric DNA, they can form intramolecular G-quadruplexes, four-stranded DNA structures that are stabilized by the stacking of guanine residues in a planar arrangement. However, the functional roles of telomeric G-quadruplexes are not understood. In cancer cells, telomere length is maintained by telomerase, a ribonucleoprotein enzyme complex with reverse transcriptase activity, which adds TTAGGG repeats to the 3’ telomere end. Telomerase is comprised of two sub-units: hTERT, the catalytic component of telomerase, and hTR, an RNA template complementary to the 3’ overhang. While telomerase is generally inactive in normal somatic cells, early studies demonstrated that telomerase is overexpressed in more than 85 % of cancers, and its activity is believed to be a requirement for malignant cells to achieve immortality. Hence, telomerase and the telomere components which regulate it have been regarded as near-universal cancer targets and have become an active focus of cancer researchers. Currently, telomere-based targets are being tested as potential diagnostic and prognostic markers of cancers.