# Contributions of IDH1 mutation to alternative lengthening of telomeres in lower-grade glioma

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $346,719

## Abstract

The long term objective of this proposal is to improve the therapy of lower-grade astrocytoma
(LGA) by glioma by defining how expression of the mutant IDH1 protein contributes to
alternative lengthening of telomeres (ALT). LGA account for 20% of all malignant glioma, and
nearly all progress over time to fatal high-grade glioma. Most LGA express a mutant form of
isocitrate dehydrogenase (IDH1mut) that generates the oncometabolite 2-hydroxyglutarate, alters
gene expression, and drives tumorigenesis. An unexplored aspect of how IDH1mut drives
gliomagenesis is its potential link to telomere regulation. Telomeres are DNA repeats at the
ends of chromosomes that, in the absence of TERT, shorten with each cell cycle, eventually
leading to dissociation of a telomere-protective sheltrin cap, chromosomal fusion, and cell
death. Telomeric dysfunction is resolved in most glioma cells by TERT reactivation. Virtually all
LGA, however, use an alternative, homologous recombination (HR)-based mechanism to
elongate telomeres and survive in the absence of TERT. We recently showed that expression of
IDH1mut in an ATRX-deficient background was sufficient to drive the ALT phenotype in p53/pRb-
deficient human astrocytes. These ALT cells, as well as IDH1mut LGA, consistently
downregulated RAP1 and XRCC1, and re-expression of XRCC1 and/or RAP1 suppressed the
ALT phenotype. RAP1 is part of the sheltrin complex, and its loss can cause telomere
uncapping. XRCC1 in turn is a critical component of the alternative non-homologous end
joining (aNHEJ) pathway that generates lethal chromosome end-to-end fusions following
telomere uncapping. Based on these observations we hypothesize that IDH1mut-driven down-
regulation of RAP1 and XRCC1 leads to telomere dysfunction and inhibition of the aNHEJ
pathway, enabling IDH1mut /ATRX-deficient cells to use HR and ALT to resolve telomeric
dysfunction and escape cell death. This hypothesis will be tested by determining 1) if
downregulation of RAP1 causes telomeric dysfunction, and if this contributes to IDH1mut- driven
ALT, 2) if downregulation of XRCC1 changes the pathway by which uncapped telomeres are
repaired, and if this contributes to IDH1mut- driven ALT, and 3) if IDH1mut-driven changes in DNA
repair provide collateral therapeutic vulnerability.

## Key facts

- **NIH application ID:** 9932516
- **Project number:** 5R01NS105087-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Russell O. Pieper
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $346,719
- **Award type:** 5
- **Project period:** 2017-09-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9932516

## Citation

> US National Institutes of Health, RePORTER application 9932516, Contributions of IDH1 mutation to alternative lengthening of telomeres in lower-grade glioma (5R01NS105087-04). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/9932516. Licensed CC0.

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