# Co-Regulation of Alternative Lengthening of Telomeres and Chromatin Dynamics in ATRX-DAXX deficient cancer cells

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $456,960

## Abstract

Abstract
Cancer cells must activate a telomere elongation mechanism and acquire genomic alterations. Many of the most
lethal cancers rely on the Alternative Lengthening of Telomeres (ALT) pathway. ALT is a specialized
homology directed repair (HDR) mechanism dedicated to repair and elongate telomeres, thereby ensuring the
proliferative immortality of these cancer cells. Recurrent inactivating missense mutations in genes encoding the
ATRX-DAXX chromatin remodeling/histone H3.3 deposition complex exhibit a strong concordance with
tumors in which ALT is activated, with both arising late in metastatic disease. These loss of function mutations
disrupt ATRX-DAXX mediated assembly of chromatin, provoking replicative stress and double-strand breaks
(DSBs) within telomeres that is believed to stimulate ALT-associated HDR. Whereas the HDR mechanisms that
underpin ALT have been extensively studied, the mechanisms governing how cells compensate for loss of
ATRX-DAXX to maintain chromatin while also acquiring metastatic traits remain ill-defined. This proposal
builds on our recent report that upon inactivation of ATRX-DAXX, a related chromatin assembly factor known
as HIRA becomes indispensable for de novo histone H3.3 deposition and telomere extension in ALT cancer
cells. Furthermore, we discovered that the depletion of HIRA provoked acute systemic death of ATRX-DAXX
deficient cells. Strikingly, this cytotoxicity was reversed by reconstitution of ALT cells with wild type ATRX
protein. These data provided compelling evidence for a compensatory function adopted by HIRA due to
ATRX-DAXX deficiency that could be harnessed to eliminate ALT cancer cells.

## Key facts

- **NIH application ID:** 10440845
- **Project number:** 1R01CA262316-01A1
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Roderick O'Sullivan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $456,960
- **Award type:** 1
- **Project period:** 2022-06-23 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10440845

## Citation

> US National Institutes of Health, RePORTER application 10440845, Co-Regulation of Alternative Lengthening of Telomeres and Chromatin Dynamics in ATRX-DAXX deficient cancer cells (1R01CA262316-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10440845. Licensed CC0.

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