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Updated: Aug 9, 2025

Utilizing Murine Inducible Telomerase Alleles in the Studies of Tissue Degeneration/Regeneration and Cancer
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Utilizing Murine Inducible Telomerase Alleles in the Studies of Tissue Degeneration/Regeneration and Cancer

Published on: April 13, 2015

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Histone demethylase KDM2A is a selective vulnerability of cancers relying on alternative telomere maintenance

Fei Li, Yizhe Wang, Inah Hwang

    Biorxiv : the Preprint Server for Biology
    |February 17, 2023
    PubMed

    Insights

    Scientists identified histone lysine demethylase KDM2A as a key vulnerability in cancers using alternative lengthening of telomeres (ALT). Targeting KDM2A offers a promising new therapeutic strategy for these specific tumors.

    Area of Science:

    • Oncology
    • Molecular Biology
    • Genetics

    Background:

    • Telomere length maintenance is crucial for cellular immortalization and cancer development.
    • Alternative lengthening of telomeres (ALT) is a recombination-based mechanism enabling replicative immortality in 5-10% of human cancers.
    • Currently, no targeted therapies exist for ALT-dependent cancers.

    Approach:

    • Utilized CRISPR/Cas9 genetic screens in an ALT-immortalized cellular model.
    • Identified histone lysine demethylase KDM2A as a selective molecular vulnerability.
    • Investigated the mechanistic role of KDM2A in ALT telomere maintenance.

    Key Points:

    • KDM2A is essential for the dissolution of ALT-specific telomere clusters post-homology-directed telomere DNA synthesis.
    • KDM2A facilitates SENP6-mediated SUMO deconjugation at telomeres, promoting de-clustering of ALT multitelomeres.
    • Inactivation of KDM2A or SENP6 disrupts telomere de-SUMOylation, leading to chromosome missegregation and cell death.

    Conclusions:

    • KDM2A is a critical factor in ALT telomere maintenance and cluster dissolution.
    • KDM2A represents a selective molecular vulnerability for ALT-dependent cancers.
    • KDM2A is a promising drug target for treating ALT-driven malignancies.

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