# Discerning the mechanism of telomere dysfunction caused by a mutant telomerase template

> **NIH NIH F31** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $46,036

## Abstract

Project Summary/Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease that is strongly linked to deficits in
telomere maintenance. Telomeres are protective non-coding DNA end caps at the ends of eukaryotic
chromosomes. The telomere sequence, TTAGGG, is conserved in all vertebrates and is bound by a protective
protein complex termed shelterin in a sequence-dependent manner. Displacement of the shelterin complex
leads to a DNA damage response, resulting in chromosomal fusions and cell cycle arrest. With each round of
cell division, telomere ends shorten due to a combination of the end replication problem and genomic stress.
To counterbalance this shortening, cells utilize the enzyme telomerase. Telomerase is composed of a protein
component telomerase reverse transcriptase (TERT) and an RNA template, the telomerase RNA component
(TR). Mutations in IPF are often linked to genes required for telomere maintenance, such as mutations in
TERT, TERC (TR), RTEL1, DKC1, and related genes. TR is 451 base pairs and contains an 11 base pair
template responsible for binding the telomeric overhang and acting as a template for the reverse transcription
of six new bases. We have identified a patient with IPF that is heterozygous for a mutation in the TR template
region which is predicted to code for a variant telomere sequence. Remarkably, whole genome sequencing
from the patient demonstrated that the telomeres display a significant portion of variant telomere sequences.
Strict conservation of the telomere sequence throughout 400 million years of evolution suggests that variation
in the telomere sequence would not be tolerated due to blocking shelterin binding. The nature of this
unexpected find will be examined in this proposal. We hypothesize that this variant telomerase template, and
subsequent variant telomere addition, may cause cellular dysfunction through two independent mechanisms;
through telomere shortening and/or a loss of shelterin binding. These mechanisms will be explored in the
following aims. Aim 1 will examine how the addition of a variant telomere sequence affects the enzymatic
activity of telomerase and resulting telomere length in cells. Aim 2 will examine the effect that the variant
sequence has on genomic stability, including shelterin binding and the DNA damage response in cells.
Completion of this proposal will give us new insights into how telomeric sequence degeneration can affect
genomic stability and telomere maintenance.

## Key facts

- **NIH application ID:** 10231326
- **Project number:** 1F31HL158063-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Angela Marie Hinchie
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $46,036
- **Award type:** 1
- **Project period:** 2021-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10231326

## Citation

> US National Institutes of Health, RePORTER application 10231326, Discerning the mechanism of telomere dysfunction caused by a mutant telomerase template (1F31HL158063-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10231326. Licensed CC0.

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