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A persistent variant telomere sequence in a human pedigree

Hinchie, Angela M (2024) A persistent variant telomere sequence in a human pedigree. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

The telomere sequence, TTAGGG, is conserved across all vertebrates and plays an essential role in suppressing the DNA damage response by binding a set of proteins termed shelterin. Changes in the telomere sequence impair shelterin binding, initiate a DNA damage response, and are toxic to cells. We identified a family with a heterozygous variant in the telomere template sequence of telomerase, the enzyme responsible for telomere elongation, that led to a non-canonical telomere sequence. The variant was inherited across at least one generation and one family member is clinically normal despite ~9% of their telomeres converting to the novel sequence. The variant template disrupted telomerase repeat addition processivity and decreased the binding of the telomere-binding protein POT1 in vitro. Despite these disruptions, the sequence was readily incorporated into cellular chromosomes. While overexpression of the variant telomerase led to decreased cell proliferation and a DNA damage response, heterozygous expression of the variant appeared to be tolerated. Incorporation of a variant sequence prevented POT1-mediated inhibition of telomerase and promoted telomere lengthening, somewhat offsetting the defect in enzyme processivity. These findings demonstrate that the telomere sequence directly influences telomerase activity and identifies a novel mechanism by which telomeres that have incorporated a variant sequence are rapidly lengthened by creating highly extendable telomeres.

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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Hinchie, Angela Manh164@pitt.eduanh1640000-0002-4544-4735
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorAlder, Jonathan Kjalder@pitt.edu
Committee ChairOpresko, Patricia Lplo4@pitt.edu
Committee MemberVan Houten, Bennettvanhoutenb@upmc.edu
Committee MemberO'Sullivan, Roderick Josullivanr@upmc.edu
Committee MemberGreider, Carol Wcgreider@ucsc.edu
Date: 16 September 2024
Date Type: Publication
Defense Date: 10 October 2023
Approval Date: 16 September 2024
Submission Date: 27 November 2023
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 125
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Molecular Pharmacology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: POT1, telomere, NGS, idopathic pulmonary fibrosis, DNA damager response, telomerase, telomere sequence
Date Deposited: 16 Sep 2024 18:49
Last Modified: 16 Sep 2024 18:49
URI: http://d-scholarship.pitt.edu/id/eprint/45488

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