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Histone demethylase KDM2A is a selective vulnerability of cancers relying on alternative telomere maintenance
Fei Li # 1 2, Yizhe Wang # 3, Inah Hwang # 3 4, Ja-Young Jang 3, Libo Xu 2 5, Zhong Deng 6, Eun Young Yu 7, Yiming Cai 8, Caizhi Wu 2, Zhenbo Han 8, Yu-Han Huang 2, Xiangao Huang 3, Ling Zhang 2 5, Jun Yao 8, Neal F Lue 7, Paul M Lieberman 6, Haoqiang Ying 8, Jihye Paik 9, Hongwu Zheng 10
...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 recombination-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.