# Deciphering the role of heterochromatin in telomere function and maintenance mechanisms

> **NIH NIH R35** · UNIVERSITY OF COLORADO · 2023 · $10,459

## Abstract

PROJECT SUMMARY
Telomeres are nucleoprotein structures that protect the ends of linear chromosomes and thereby
maintain genome stability. Telomeres solve both the end-protection and the end-replication problems: 1)
They inhibit DNA damage at chromosome ends, which would otherwise resemble broken DNA, 2) Since
chromosome ends shorten during replication, telomeres act as buffer sequences to prevent loss of coding
regions, 3) Once telomeres become too short, they can no longer inhibit DNA damage, leading to
permanent cell cycle arrest (senescence). This “mitotic clock” is a critical tumor-suppressive barrier that
forces aging cells to stop dividing. To become cancerous, cells must acquire unlimited division potential
by activating a telomere maintenance mechanism, either reactivation of telomerase, the enzyme that
elongates telomeres during development, or through the alternative lengthening of telomeres (ALT)
mechanism, which is based on recombination.
ALT+ cancers cells are characterized by clustering of telomeres into ALT-associated PML bodies (APBs)
that serve as platforms for telomere recombination. ALT+ telomeres also display singular chromatin, with
a lower nucleosome density and loss of the ATRX/DAXX pathway that normally deposits H3.3 at
telomeres. We found, however, that H3K9 trimethylation at telomeres promotes formation of APBs, as
well as subsequent ALT activity. We propose here to determine which chromatin regulators as well
as DNA damage and repair genes modulate APB formation in ALT+ cells.

## Key facts

- **NIH application ID:** 10809508
- **Project number:** 3R35GM143108-03S1
- **Recipient organization:** UNIVERSITY OF COLORADO
- **Principal Investigator:** Nausica C. Arnoult
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $10,459
- **Award type:** 3
- **Project period:** 2021-08-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10809508

## Citation

> US National Institutes of Health, RePORTER application 10809508, Deciphering the role of heterochromatin in telomere function and maintenance mechanisms (3R35GM143108-03S1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10809508. Licensed CC0.

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