title: The lethal response to Cdk1 inhibition depends on sister chromatid alignment errors generated by KIF4 and isoform 1 of PRC1.
abstract: Cyclin-dependent kinase 1 (Cdk1) is absolutely essential for cell division. Complete ablation of Cdk1 precludes the entry of G2 phase cells into mitosis, and is early embryonic lethal in mice. Dampening Cdk1 activation, by reducing gene expression or upon treatment with cell-permeable Cdk1 inhibitors, is also detrimental for proliferating cells, but has been associated with defects in mitotic progression, and the formation of aneuploid daughter cells. Here, we used a large-scale RNAi screen to identify the human genes that critically determine the cellular toxicity of Cdk1 inhibition. We show that Cdk1 inhibition leads to fatal sister chromatid alignment errors and mitotic arrest in the spindle checkpoint. These problems start early in mitosis and are alleviated by depletion of isoform 1 of PRC1 (PRC1-1), by gene ablation of its binding partner KIF4, or by abrogation of KIF4 motor activity. Our results show that, normally, Cdk1 activity must rise above the level required for mitotic entry. This prevents KIF4-dependent PRC1-1 translocation to astral microtubule tips and safeguards proper chromosome congression. We conclude that cell death in response to Cdk1 inhibitors directly relates to chromosome alignment defects generated by insufficient repression of PRC1-1 and KIF4 during prometaphase.
authors.affiliation: Division of Cell Biology I (B5) and Division of Molecular Carcinogenesis (B7), The Netherlands Cancer Insitute (NKI-AvL), Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Erik
authors.initials: E
authors.lastname: Voets
authors.affiliation: Division of Cell Biology I (B5) and Division of Molecular Carcinogenesis (B7), The Netherlands Cancer Insitute (NKI-AvL), Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Judith
authors.initials: J
authors.lastname: Marsman
authors.affiliation: Proteomics Center, Erasmus University Medical Center, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Demmers
authors.affiliation: Division of Cell Biology I (B5) and Division of Molecular Carcinogenesis (B7), The Netherlands Cancer Insitute (NKI-AvL), Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Roderick
authors.initials: R
authors.lastname: Beijersbergen
authors.affiliation: Division of Cell Biology I (B5) and Division of Molecular Carcinogenesis (B7), The Netherlands Cancer Insitute (NKI-AvL), Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.|Section of Oncogenetics, Department of Clinical Genetics and CCA/V-ICI Research Program Oncogenesis, VUmc Medical Faculty, van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands.
authors.forename: Rob
authors.initials: R
authors.lastname: Wolthuis
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002842:Chromatids / Q000235:genetics* / Q000378:metabolism*; D002877:Chromosomes, Human / Q000378:metabolism; D019926:Cyclin B / Q000378:metabolism; D048749:Cytokinesis / Q000235:genetics; D006801:Humans; D016547:Kinesins / Q000235:genetics / Q000378:metabolism*; D008938:Mitosis; D011485:Protein Binding; D020033:Protein Isoforms; D011804:Quinolines / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D008941:Spindle Apparatus / Q000187:drug effects / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology
chemical_list: D018797:Cell Cycle Proteins; D019926:Cyclin B; C116662:PRC1 protein, human; D020033:Protein Isoforms; D011804:Quinolines; D034741:RNA, Small Interfering; C512984:RO 3306; D013844:Thiazoles; D016203:CDC2 Protein Kinase; C484228:KIF4A protein, human; D016547:Kinesins