A Mechanistic Framework for Telomerase Kinetics Identifies New Opportunities for Therapeutic Interventions

A Mechanistic Framework for Telomerase Kinetics Identifies New Opportunities for Therapeutic Interventions

Bibliographic Details
Main Author: Hernandez-Sanchez, Wilnelly
Language:English
Published: Case Western Reserve University School of Graduate Studies / OhioLINK 2020
Subjects:
Pharmacology
Biochemistry
Oncology
Online Access:http://rave.ohiolink.edu/etdc/view?acc_num=case1586191570745256
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spelling ndltd-OhioLink-oai-etd.ohiolink.edu-case15861915707452562021-08-03T07:14:07Z A Mechanistic Framework for Telomerase Kinetics Identifies New Opportunities for Therapeutic Interventions Hernandez-Sanchez, Wilnelly Pharmacology Biochemistry Oncology Since DNA replication mechanisms are unable to extend the extreme ends of the lagging strand, a portion of genetic material is lost during each cell division. To compensate for this loss, the ends of all linear chromosomes contain repetitive DNA sequences called telomeres. A specialized enzyme called telomerase is responsible for the synthesis of telomere DNA and is essential for the retention of genomic material during continuous cellular division. Alterations to telomerase genes are associated with a range of diseases, including cancer, dyskeratosis congenita, aplastic anemia, and idiopathic pulmonary fibrosis. Whereas telomerase activity is undetectable in healthy adult somatic cells, it is upregulated in 90% of all metastatic tumor cells. This upregulation allows cancer cells to proliferate indefinitely by avoiding senescence. Because of the selective expression of telomerase in cancer cells, it is a well-recognized cancer target. Thus, it is crucial for cancer researchers to understand the fundamental and molecular processes related to telomerase activity in healthy and diseased states. Insights from the findings in this study could guide the development of new mechanisms for the therapeutic regulation of telomerase function.The telomerase catalytic cycle involves the tight coordination of four sequential enzymatic reactions that are repeated in a highly processive manner. In this thesis, I explore how the telomerase catalytic cycle is altered in the presence of deoxynucleotides (dNTPs). Our kinetic approach revealed that telomerase nucleotide addition and processivity could be regulated by native nucleotide (dATP, dTTP, dGTP, and dCTP) concentrations. These results highlight a novel mode of regulation that could potentially modulate telomerase polymerization and processivity by controlling the concentrations of nucleotide pools.I also explore the impairment of telomerase catalytic activity in the presence of a novel dATP analog. Kinetic and mechanistic characterizations performed with this novel inhibitor, 5-methylcarboxylate indole triphosphate (5-MeCITP), revealed that this analog binds the telomerase active site, resulting in the displacement of the RNA template from the active site. These findings show that 5-MeCITP is capable of inhibiting nucleotide incorporation and telomere lengthening in cancer cells, which ultimately results in telomere shortening and senescence. 2020-06-01 English text Case Western Reserve University School of Graduate Studies / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=case1586191570745256 http://rave.ohiolink.edu/etdc/view?acc_num=case1586191570745256 restricted--full text unavailable until 2022-05-17 This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.
collection NDLTD
language English
sources NDLTD
topic Pharmacology
Biochemistry
Oncology
spellingShingle Pharmacology
Biochemistry
Oncology
Hernandez-Sanchez, Wilnelly
A Mechanistic Framework for Telomerase Kinetics Identifies New Opportunities for Therapeutic Interventions
author Hernandez-Sanchez, Wilnelly
author_facet Hernandez-Sanchez, Wilnelly
author_sort Hernandez-Sanchez, Wilnelly
title A Mechanistic Framework for Telomerase Kinetics Identifies New Opportunities for Therapeutic Interventions
title_short A Mechanistic Framework for Telomerase Kinetics Identifies New Opportunities for Therapeutic Interventions
title_full A Mechanistic Framework for Telomerase Kinetics Identifies New Opportunities for Therapeutic Interventions
title_fullStr A Mechanistic Framework for Telomerase Kinetics Identifies New Opportunities for Therapeutic Interventions
title_full_unstemmed A Mechanistic Framework for Telomerase Kinetics Identifies New Opportunities for Therapeutic Interventions
title_sort mechanistic framework for telomerase kinetics identifies new opportunities for therapeutic interventions
publisher Case Western Reserve University School of Graduate Studies / OhioLINK
publishDate 2020
url http://rave.ohiolink.edu/etdc/view?acc_num=case1586191570745256
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AT hernandezsanchezwilnelly mechanisticframeworkfortelomerasekineticsidentifiesnewopportunitiesfortherapeuticinterventions
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