端粒长度的维持对于细胞不老化和肿瘤发生至关重要。人类癌症中的5%-10%利用一种名为“端粒替代性长度调节”（ALT）的重组机制来维持其复制的不朽性，然而目前尚无针对性的治疗方法。通过ALT不死化等位靶向性基因筛查，我们在同系细胞模型中鉴定到组蛋白赖氨酸去甲基化酶KDM2A是一种分子易感性。机制上，我们证明KDM2A是必需的，以便溶解ALT特有的端粒簇随着重组导向的端粒DNA合成而随之消失。我们展示了KDM2A促进了ALT多端粒通过促进异构蛋白酶SENP6介导的SUMO脱共轭作用在端粒处脱离簇。KDM2A或SENP6的失活会妨碍后重组端粒的去SUMO化作用，从而导致ALT端粒簇的溶解不良，从而导致严重的染色体错配和有丝分裂细胞死亡。这些发现共同确定了KDM2A作为选择性的分子易感性和ALT依赖性癌症的一个有前途的药物靶点。©2023年作者。

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 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.© 2023. The Author(s).