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

TitleHistone demethylase KDM2A is a selective vulnerability of cancers relying on alternative telomere maintenance.
Publication TypeJournal Article
Year of Publication2023
AuthorsLi F, Wang Y, Hwang I, Jang J-Y, Xu L, Deng Z, Yu EYoung, Cai Y, Wu C, Han Z, Huang Y-H, Huang X, Zhang L, Yao J, Lue NF, Lieberman PM, Ying H, Paik J, Zheng H
JournalbioRxiv
Date Published2023 Feb 11
Abstract

Telomere length maintenance is essential for cellular immortalization and tumorigenesis. 5% - 10% of human cancers rely on a recombination-based mechanism termed alternative lengthening of telomeres (ALT) to sustain their replicative immortality, yet there are currently no targeted therapies. Through CRISPR/Cas9-based genetic screens in an ALT-immortalized isogenic cellular model, here we identify histone lysine demethylase KDM2A as a molecular vulnerability selectively for cells contingent on ALT-dependent telomere maintenance. Mechanistically, we demonstrate that KDM2A is required for dissolution of the ALT-specific telomere clusters following homology-directed telomere DNA synthesis. We show that KDM2A promotes de-clustering of ALT multitelomeres through facilitating isopeptidase SENP6-mediated SUMO deconjugation at telomeres. Inactivation of KDM2A or SENP6 impairs post-recombination telomere de-SUMOylation and thus dissolution of ALT telomere clusters, leading to gross chromosome missegregation and mitotic cell death. These findings together establish KDM2A as a selective molecular vulnerability and a promising drug target for ALT-dependent cancers.

DOI10.1101/2023.02.10.528023
Alternate JournalbioRxiv
PubMed ID36798426
PubMed Central IDPMC9934630
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Hongwu Zheng, Ph.D. Ji-Hye Paik, Ph.D.

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