Title | Histone demethylase KDM2A is a selective vulnerability of cancers relying on alternative telomere maintenance. |
Publication Type | Journal Article |
Year of Publication | 2023 |
Authors | Li 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 |
Journal | bioRxiv |
Date Published | 2023 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. |
DOI | 10.1101/2023.02.10.528023 |
Alternate Journal | bioRxiv |
PubMed ID | 36798426 |
PubMed Central ID | PMC9934630 |
Related Faculty:
Hongwu Zheng, Ph.D. Ji-Hye Paik, Ph.D.