SMARCAL1 is a candidate therapeutic target for ALT-positive tumors.

Authors

Angelo Taglialatela, Jina Lee, Benura Azeroglu, Xiao Chen, Maria Rosaria Dello Stritto, Antoine Gouge, Tomas Lama-Diaz, Alina Vaitsiankova, Giuseppe Leuzzi, Filemon Dela Cruz, Zahra F Khan, Andrew L Kung, Petr Cejka, Eros Lazzerini Denchi, Jaewon Min, Alberto Ciccia

Published in

Genes & development. Jul 14, 2026. Epub Jul 14, 2026.

Abstract

A significant subset of tumors, including >50% of osteosarcomas-an aggressive bone malignancy affecting children, adolescents, and young adults-relies on alternative lengthening of telomeres (ALT), a telomerase-independent, DNA repair-based mechanism for telomere elongation. The overall 5 year survival rate for osteosarcoma patients is ∼65%, underscoring the need to develop novel targeted therapies. Through the Cancer Dependency Map, we identified SMARCAL1, a DNA translocase previously shown to remodel stalled replication forks, as a top selective dependency factor in telomerase-negative tumors. Using a panel of ALT-positive and ALT-negative cancer cell lines, as well as osteosarcoma patient-derived xenograft cells, we confirmed that ALT-positive cells are uniquely sensitive to the loss of SMARCAL1, whose depletion exacerbates ALT-dependent phenotypes and telomeric DNA damage. Notably, we demonstrated that suppressing ALT abrogates their dependency on SMARCAL1. Mechanistically, we showed that SMARCAL1 loss leads to telomeric ssDNA accumulation in ALT-positive cells, dependent in part on DNA repriming mediated by the DNA primase/polymerase PRIMPOL. Moreover, SMARCAL1's ssDNA annealing activity counteracts DNA unwinding by the BLM helicase, limiting telomeric ssDNA accumulation and DNA damage in ALT-positive cells. Importantly, SMARCAL1 depletion induces senescence in ALT-positive cancer cells, rendering them susceptible to treatment with senolytic agents. Together, these findings establish SMARCAL1 as a key regulator of ALT metabolism and highlight SMARCAL1 as a promising therapeutic target for ALT-positive tumors.

PMID:
42448564
Bibliographic data and abstract were imported from PubMed on 15 Jul 2026.

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