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Telomerase

Telomeres are repetitive DNA sequences at chromosome ends that are bound by a protective protein complex known as shelterin, which prevents them from eliciting a DNA damage response (DDR). They shorten with each cell division due in part to the end-replication problem, an inability of the DNA replication machinery to fully replicate DNA ends. Nevertheless, telomerase expression in stem cells is not sufficient to prevent progressive telomere shortening associated with increasing age. Almost all human cancers present activation of telomerase as a hallmark, most likely as a mechanism to allow unlimited cell proliferation of tumor cells. Short telomeres could be recognized as DNA double strand (dsDNA) breaks, a deleterious DNA aberration that results in a strong activation of DNA damage repair (DDR) pathways. With an intact DDR and active checkpoints, cells with dsDNA breaks activate a multitude of signaling cascades which conclude in p53 and tumor suppressor activation. This cascade of events culminates in activation of anti-proliferation signals. In addition to the canonical role of telomerase in maintaining telomeres, telomerase overexpression has also been shown to influence the regulation of the Wnt pathway, although the physiological relevance and mechanism of this regulation is still debated. Telomerase expression in a background of high levels of tumor suppressors or in aged organisms seems to prevent its expected pro-cancer activity and yet it still functions as an anti-aging factor.

References

1.Bernardes de Jesus B,et al. Trends Genet. 2013;29(9):513–520.

Cell Cycle/DNA Damage

ABC(12) AChR(42) Antifolate(10) ATM/ATR(24) Aurora Kinase(46) CLK(15) c-Myc(22) DHFR(7) DNA Alkylator(33) DNA gyrase(10) DNA Repair Protein(21) DNA/RNA Synthesis(141) DNA-PK(13) GPR(66) HDAC(138) Hec1/Nek2(9) Integrin(55) LIM Kinase (LIMK)(7) Mps1/TTK(2) Nucleoside Antimetabolite/Analog(48) Other Targets(4) PAK(11) PARP(50) PLK(19) Potassium Channel(107) RAD51(1) Rho(10) ROCK(29) Telomerase(9) Topoisomerase(61) Wee1(4)