Premature activation of Cdk1 leads to mitotic events in S phase and embryonic lethality

• Published in: Oncogene Vol. 38; no. 7; pp. 998 - 1018
• Main Authors: Szmyd, Radoslaw, Niska-Blakie, Joanna, Diril, M. Kasim, Renck Nunes, Patrícia, Tzelepis, Konstantinos, Lacroix, Aurélie, van Hul, Noémi, Deng, Lih-Wen, Matos, Joao, Dreesen, Oliver, Bisteau, Xavier, Kaldis, Philipp
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2019; Nature Publishing Group
• Subjects: 13/1; 13/106; 13/31; 13/89; 42/41; 631/67/70; 631/80/641/1655; 64/60; 96/95; Amino Acid Substitution; Animals; Antineoplastic agents; Apoptosis; Cancer; Cancer treatment; Carcinogenesis; CDC2 Protein Kinase - genetics; CDC2 Protein Kinase - metabolism; Cell Biology; Cell cycle; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell proliferation; Cellular signal transduction; Clinical trials; Cyclin-dependent kinase 2; Cyclin-dependent kinases; Deoxyribonucleic acid; DNA; DNA biosynthesis; DNA damage; DNA replication; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Embryo fibroblasts; Embryo Loss - enzymology; Embryo Loss - genetics; Embryo Loss - pathology; Embryo, Mammalian - enzymology; Embryo, Mammalian - pathology; Embryos; Endonuclease; Enzyme Activation; Genetic aspects; Genomes; Genomics; Health aspects; Human Genetics; Intelligence gathering; Internal Medicine; Kinases; Lethality; Liver; Medicine; Medicine & Public Health; Mice; Mice, Transgenic; Mitosis; Mutation, Missense; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Nucleases; Oncology; p53 Protein; Phosphorylation; Phosphotransferases; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - metabolism; S Phase; Transcription Factors - genetics; Transcription Factors - metabolism; Tumor proteins; Tumors
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-018-0464-0

Cell cycle regulation, especially faithful DNA replication and mitosis, are crucial to maintain genome stability. Cyclin-dependent kinase (CDK)/cyclin complexes drive most processes in cellular proliferation. In response to DNA damage, cell cycle surveillance mechanisms enable normal cells to arrest and undergo repair processes. Perturbations in genomic stability can lead to tumor development and suggest that cell cycle regulators could be effective targets in anticancer therapy. However, many clinical trials ended in failure due to off-target effects of the inhibitors used. Here, we investigate in vivo the importance of WEE1- and MYT1-dependent inhibitory phosphorylation of mammalian CDK1. We generated Cdk1 AF knockin mice, in which two inhibitory phosphorylation sites are replaced by the non-phosphorylatable amino acids T14A/Y15F. We uncovered that monoallelic expression of CDK1 AF is early embryonic lethal in mice and induces S phase arrest accompanied by γH2AX and DNA damage checkpoint activation in mouse embryonic fibroblasts (MEFs). The chromosomal fragmentation in Cdk1 AF MEFs does not rely on CDK2 and is partly caused by premature activation of MUS81-SLX4 structure-specific endonuclease complexes, as well as untimely onset of chromosome condensation followed by nuclear lamina disassembly. We provide evidence that tumor development in liver expressing CDK1 AF is inhibited. Interestingly, the regulatory mechanisms that impede cell proliferation in CDK1 AF expressing cells differ partially from the actions of the WEE1 inhibitor, MK-1775, with p53 expression determining the sensitivity of cells to the drug response. Thus, our work highlights the importance of improved therapeutic strategies for patients with various cancer types and may explain why some patients respond better to WEE1 inhibitors.