Dimond Andrew, Gim Do Hyeon, Ing-Simmons Elizabeth, Whilding Chad, Kramer Holger B, Djeghloul Dounia, Montoya Alex, Patel Bhavik, Cheriyamkunnel Sherry, Brown Karen E, Shliaha Pavel V, Vaquerizas Juan M, Merkenschlager Matthias, Fisher Amanda G
Epigenetic Memory Group, MRC LMS, Imperial College London, Hammersmith Hospital Campus, London, UK.
Department of Biochemistry, University of Oxford, Oxford, UK.
Nat Commun. 2025 Sep 23;16(1):8348. doi: 10.1038/s41467-025-63740-4.
PBK/TOPK is a mitotic kinase implicated in haematological and non-haematological cancers. Here we show that the key haemopoietic regulators Ikaros and Aiolos require PBK-mediated phosphorylation to dissociate from chromosomes in mitosis. Eviction of Ikaros is rapidly reversed by addition of the PBK-inhibitor OTS514, revealing dynamic regulation by kinase and phosphatase activities. To identify more PBK targets, we analysed loss of mitotic phosphorylation events in Pbk preB cells and performed proteomic comparisons on isolated mitotic chromosomes. Among a large pool of C2H2-zinc finger targets, PBK is essential for evicting the CCCTC-binding protein CTCF and zinc finger proteins encoded by Ikzf1, Ikzf3, Znf131 and Zbtb11. PBK-deficient cells were able to divide but showed altered chromatin accessibility and nucleosome positioning consistent with CTCF retention. Our studies reveal that PBK controls the dissociation of selected factors from condensing mitotic chromosomes and contributes to their compaction.
PBK/TOPK是一种与血液系统和非血液系统癌症相关的有丝分裂激酶。我们在此表明，关键的造血调节因子Ikaros和Aiolos需要PBK介导的磷酸化才能在有丝分裂过程中从染色体上解离。通过添加PBK抑制剂OTS514，Ikaros的解离会迅速逆转，这揭示了激酶和磷酸酶活性的动态调节。为了鉴定更多的PBK靶点，我们分析了Pbk preB细胞中有丝分裂磷酸化事件的缺失，并对分离的有丝分裂染色体进行了蛋白质组学比较。在大量C2H2锌指靶点中，PBK对于清除CCCTC结合蛋白CTCF以及由Ikzf1、Ikzf3、Znf131和Zbtb11编码的锌指蛋白至关重要。缺乏PBK的细胞能够分裂，但显示出染色质可及性和核小体定位改变，这与CTCF的保留一致。我们的研究表明，PBK控制着特定因子从浓缩的有丝分裂染色体上的解离，并有助于它们的压缩。
