Cancer-associated SMARCAL1 loss-of-function mutations promote alternative lengthening of telomeres and tumorigenesis in telomerase-negative glioblastoma cells.

Autor:	Liu H; The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina, USA.; Department of Pathology, Duke University Medical Center, Durham, North Carolina, USA., Xu C; The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina, USA.; Department of Pathology, Duke University Medical Center, Durham, North Carolina, USA., Diplas BH; The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina, USA.; Department of Pathology, Duke University Medical Center, Durham, North Carolina, USA., Brown A; The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina, USA.; Department of Neurosurgery, Duke University Medical Center, Durham, North Carolina, USA., Strickland LM; The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina, USA.; Department of Neurosurgery, Duke University Medical Center, Durham, North Carolina, USA., Yao H; The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina, USA.; Department of Pathology, Duke University Medical Center, Durham, North Carolina, USA., Ling J; The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina, USA.; Department of Pathology, Duke University Medical Center, Durham, North Carolina, USA., McLendon RE; The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina, USA.; Department of Pathology, Duke University Medical Center, Durham, North Carolina, USA., Keir ST; The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina, USA.; Department of Neurosurgery, Duke University Medical Center, Durham, North Carolina, USA., Ashley DM; The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina, USA.; Department of Neurosurgery, Duke University Medical Center, Durham, North Carolina, USA., He Y; The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina, USA.; Department of Pathology, Duke University Medical Center, Durham, North Carolina, USA., Waitkus MS; The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina, USA.; Department of Neurosurgery, Duke University Medical Center, Durham, North Carolina, USA.
Jazyk:	angličtina
Zdroj:	Neuro-oncology [Neuro Oncol] 2023 Sep 05; Vol. 25 (9), pp. 1563-1575.
DOI:	10.1093/neuonc/noad022
Abstrakt:	Background: Telomere maintenance mechanisms are required to enable the replicative immortality of malignant cells. While most cancers activate the enzyme telomerase, a subset of cancers uses telomerase-independent mechanisms termed alternative lengthening of telomeres (ALT). ALT occurs via homology-directed-repair mechanisms and is frequently associated with ATRX mutations. We previously showed that a subset of adult glioblastoma (GBM) patients with ATRX-expressing ALT-positive tumors harbored loss-of-function mutations in the SMARCAL1 gene, which encodes an annealing helicase involved in replication fork remodeling and the resolution of replication stress. However, the causative relationship between SMARCAL1 deficiency, tumorigenesis, and de novo telomere synthesis is not understood. Methods: We used a patient-derived ALT-positive GBM cell line with native SMARCAL1 deficiency to investigate the role of SMARCAL1 in ALT-mediated de novo telomere synthesis, replication stress, and gliomagenesis in vivo. Results: Inducible rescue of SMARCAL1 expression suppresses ALT indicators and inhibits de novo telomere synthesis in GBM and osteosarcoma cells, suggesting that SMARCAL1 deficiency plays a functional role in ALT induction in cancers that natively lack SMARCAL1 function. SMARCAL1-deficient ALT-positive cells can be serially propagated in vivo in the absence of detectable telomerase activity, demonstrating that the SMARCAL1-deficient ALT phenotype maintains telomeres in a manner that promotes tumorigenesis. Conclusions: SMARCAL1 deficiency is permissive to ALT and promotes gliomagenesis. Inducible rescue of SMARCAL1 in ALT-positive cell lines permits the dynamic modulation of ALT activity, which will be valuable for future studies aimed at understanding the mechanisms of ALT and identifying novel anticancer therapeutics that target the ALT phenotype. (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
Databáze:	MEDLINE
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