Roles of telomeres and telomerase in cancer, and advances in telomerase-targeted therapies.
Telomeres maintain genomic integrity in normal cells, and their progressive shortening during successive cell divisions induces chromosomal instability. In the large majority of cancer cells, telomere length is maintained by telomerase. Thus, telomere length and telomerase activity are crucial for cancer initiation and the survival of tumors. Several pathways that regulate telomere length have been identified, and genome-scale studies have helped in mapping genes that are involved in telomere length control. Additionally, genomic screening for recurrent human telomerase gene hTERT promoter mutations and mutations in genes involved in the alternative lengthening of telomeres pathway, such as ATRX and DAXX, has elucidated how these genomic changes contribute to the activation of telomere maintenance mechanisms in cancer cells. Attempts have also been made to develop telomere length- and telomerase-based diagnostic tools and anticancer therapeutics. Recent efforts have revealed key aspects of telomerase assembly, intracellular trafficking and recruitment to telomeres for completing DNA synthesis, which may provide novel targets for the development of anticancer agents. Here, we summarize telomere organization and function and its role in oncogenesis. We also highlight genomic mutations that lead to reactivation of telomerase, and mechanisms of telomerase reconstitution and trafficking that shed light on its function in cancer initiation and tumor development. Additionally, recent advances in the clinical development of telomerase inhibitors, as well as potential novel targets, will be summarized.
Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, 21589, Kingdom of Saudi Arabia.
Mohammad A
MA
Jafri
Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, 21589, Kingdom of Saudi Arabia.
Shakeel A
SA
Ansari
Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, 21589, Kingdom of Saudi Arabia.
Mohammed H
MH
Alqahtani
Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, 21589, Kingdom of Saudi Arabia. jerry.shay@utsouthwestern.edu.|Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, 75390, USA. jerry.shay@utsouthwestern.edu.
Jerry W
JW
Shay
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D056970:Co-Repressor Proteins; D004265:DNA Helicases / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D018832:Molecular Chaperones; D009154:Mutation; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D011401:Promoter Regions, Genetic; D019098:Telomerase / Q000037:antagonists & inhibitors / Q000235:genetics; D016615:Telomere / Q000187:drug effects / Q000502:physiology*; D059505:Telomere Homeostasis; D000075924:X-linked Nuclear Protein
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D056970:Co-Repressor Proteins; C106985:DAXX protein, human; D004791:Enzyme Inhibitors; D018832:Molecular Chaperones; D009687:Nuclear Proteins; C509186:TERT protein, human; D019098:Telomerase; D004265:DNA Helicases; C092332:ATRX protein, human; D000075924:X-linked Nuclear Protein