Cancer lettersOct 15, 2026

Using CRISPR to identify key factors, stress protection, and treatment weaknesses in alternative telomere lengthening

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Oct 16, 2026

Abstract

Approximately 5-10% of human tumors utilize alternative lengthening of telomeres (ALT) for growth.

ALT is a telomerase-independent mechanism that maintains telomeres in certain tumors.
CRISPR-based functional genomics can identify genetic dependencies linked to the ALT state.
Recurrent genetic dependencies in ALT-positive cells involve pathways related to replication stress, DNA repair, and telomere maintenance.
Key factors identified include FANCM, SMARCAL1, and SUB1, which may help prevent telomeric dysfunction.
ALT-positive cells may depend on common stress-buffering mechanisms rather than unique factors.

Simplified

Alternative lengthening of telomeres (ALT) is a telomerase-independent telomere maintenance mechanism that supports the growth of approximately 5-10% of human tumors and represents an attractive but insufficiently explored therapeutic target. CRISPR-based functional genomics has emerged as a powerful approach to systematically interrogate ALT biology and identify genetic dependencies associated with the ALT state. In this Review, we discuss the CRISPR-based strategies applied to ALT, including hypothesis-driven targeted loss-of-function screens, phenotype-driven optical screens, in silico mining of large-scale dependency datasets, and genome-wide screens in ALT-adjacent states. Across these approaches, recurrent dependencies converge on pathways mediating replication stress buffering, DNA repair, and telomere maintenance, including FANCM, SMARCAL1, and SUB1. Collectively, these findings support a model in which ALT-positive cells rely not on a unique ALT-specific factor, but rather on stress-buffering mechanisms that prevent chronic telomeric dysfunction from triggering replication catastrophe and cell death, highlighting these pathways as promising candidates for further therapeutic investigation.

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Using CRISPR to identify key factors, stress protection, and treatment weaknesses in alternative telomere lengthening

Abstract

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