Telomerase as a clinical target: current strategies and potential applications.
Chromosome ends are capped by telomeres, protective DNA-protein complexes that distinguish natural ends from random DNA breaks. Telomeres erode with each successive cell division, and such divisions cease once telomeres become critically short. This proliferation limit is important as a tumor suppressive mechanism, but also contributes to the degenerative conditions associated with cellular aging. In cell types that require continuous renewal, transient expression of telomerase delays proliferation arrest by the de novo synthesis of telomere repeats. Data from our work and others' has shown that deficient telomerase activity has a negative impact on normal human physiology. In the bone marrow failure syndrome dyskeratosis congenita, telomerase enzyme deficiency leads to the premature shortening of telomeres. Premature telomere shortening most grievously affects tissues that have a rapid turnover, such as the hematopoietic and epithelial compartments. In the most severe cases, compromised renewal of hematopoietic stem cells leads to bone marrow failure and premature death. Telomerase activation/replacement shows potential as a therapy for telomere maintenance deficiency syndromes, and in tissue engineering for the degenerative conditions that are associated with normal aging. Conversely, clinical researchers are developing telomerase inhibition therapies to treat tumors, which overcome the short-telomere barrier to unrestricted proliferation by over-expressing telomerase.
Fleisig
Helen B
HB
Division of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada V6T 1Z3.
Wong
Judy M Y
JM
D000375:Aging / Q000502:physiology*; D000818:Animals; D000970:Antineoplastic Agents; D002455:Cell Division; D002875:Chromosomes / Q000648:ultrastructure*; D016147:Genes, Tumor Suppressor; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000628:therapy; D012091:Repetitive Sequences, Nucleic Acid; D019098:Telomerase / Q000648:ultrastructure*; D016615:Telomere / Q000502:physiology* / Q000648:ultrastructure
D000970:Antineoplastic Agents; D019098:Telomerase