# The role of SMARCAL1 in glioma telomere maintenance.

> **NIH NIH K22** · DUKE UNIVERSITY · 2024 · $150,784

## Abstract

PROJECT SUMMARY
Gliomas are the most common primary malignant brain tumors in adults and account for over 14,000 deaths
annually in the United States. Glioblastoma (GBM, grade IV glioma) is the most common and deadly glioma
subtype and is associated with a median overall survival of only ~15 months with aggressive therapy. Telomere
maintenance mechanisms are a hallmark of cancer and are required to enable replicative immortality of
malignant cells, including gliomas. To maintain telomeres, the majority of gliomas use the enzyme telomerase,
which uses an RNA template and reverse transcription to extend telomeric repeats at the ends of chromosomes.
In contrast, a subset of gliomas employs telomerase-independent mechanisms, termed Alternative Lengthening
of Telomeres (ALT). ALT uses homologous recombination to maintain telomere length and is characterized by
increased replicative stress in telomere regions and remodeling of telomeric chromatin architecture to an
epigenetic state that is permissive to homologous recombination. ~10% of GBM cases and virtually all
progressive grade II/III IDH-mutant astrocytomas harbor genetic alterations involved in the induction of ALT. In
addition to ATRX mutations, we recently identified recurrent loss-of-function mutations in the SMARCAL1
(SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A-like1) gene as novel
genetic mutations associated with the ALT phenotype in IDH-wildtype – TERT promoter wild-type GBM.
SMARCAL1 encodes an annealing helicase that localizes to sites of DNA damage and replication stress and
resolves stalled replication fork structures to facilitate fork progression within difficult-to-replicate DNA
sequences, such as telomeres. Recent studies indicate that SMARCAL1 localizes to telomeric DNA in ALT-
positive cancer cells with native ATRX-inactivating mutations and that SMARCAL1 helicase activity suppresses
markers of replication stress and DNA damage at telomeres. Based on these observations, we hypothesize that
SMARCAL1 activity is essential for resolving replication stress at telomeric regions and SMARCAL1 loss-of-
function leads to an increase in unresolved replication fork collapse and DNA damage at telomeres in a manner
that is permissive to homologous recombination and ALT. In Aim 1 we will use genetically engineered cell lines
and cancer cell lines with native SMARCAL1 mutations to identify specific ALT pathway components required
for telomere synthesis and cellular immortalization in the context of SMARCAL1 loss-of-function mutations. In
Aim 2, we will use patient-derived glioma cell lines and xenografts to determine the extent to which SMARCAL1
helicase activity resolves replication stress at telomeres in ATRX-mutant GBM cell lines using ALT. Collectively,
the proposed studies are expected to significantly advance our understanding of the role of SMARCAL1 in GBM
telomere maintenance and are designed to establish proof of concept for therapeutic targe...

## Key facts

- **NIH application ID:** 10767322
- **Project number:** 5K22CA258965-03
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Matthew Waitkus
- **Activity code:** K22 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $150,784
- **Award type:** 5
- **Project period:** 2022-02-20 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10767322

## Citation

> US National Institutes of Health, RePORTER application 10767322, The role of SMARCAL1 in glioma telomere maintenance. (5K22CA258965-03). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10767322. Licensed CC0.

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