@article{284c53ef999a4079a98a1c7b6812faa3,
title = "CDK1 and CDK2 regulate NICD1 turnover and the periodicity of the segmentation clock",
abstract = "All vertebrates share a segmented body axis. Segments form from the rostral end of the presomitic mesoderm (PSM) with a periodicity that is regulated by the segmentation clock. The segmentation clock is a molecular oscillator that exhibits dynamic clock gene expression across the PSM with a periodicity that matches somite formation. Notch signalling is crucial to this process. Altering Notch intracellular domain (NICD) stability affects both the clock period and somite size. However, the mechanism by which NICD stability is regulated in this context is unclear. We identified a highly conserved site crucial for NICD recognition by the SCF E3 ligase, which targets NICD for degradation. We demonstrate both CDK1 and CDK2 can phosphorylate NICD in the domain where this crucial residue lies and that NICD levels vary in a cell cycle-dependent manner. Inhibiting CDK1 or CDK2 activity increases NICD levels both in vitro and in vivo, leading to a delay of clock gene oscillations and an increase in somite size.",
keywords = "FBXW7, Notch, cell cycle, phosphorylation, somitogenesis",
author = "Carrieri, {Francesca Anna} and Murray, {Philip J.} and Dimitrinka Ditsova and Ferris, {Margaret Ashley} and Paul Davies and Dale, {Jacqueline Kim}",
note = "Funding Information: We would like to thank Ioanna Mastromina and Michaela Omelkova for reading of the manuscript and constructive feedbacks. Special thanks also go to Genta Ito for assistance with Phos-tag gel assay. We thank the groups of D. Alessi and S. Rocha for reagents and Laura D{\textquoteright}Ignazio for experimental assistance. The authors would like to thank Rachel Toth, Mel Wightman and Tom Macartney (MRC-PPU Reagents and Services) for cloning and Dr David Campbell, Bob Gourlay and Joby Vhargese (MRC-PPU) for mass spectrometry analysis. We also thank Professor Daan van Aalten and Professor Victoria Cowling and for their inputs. This work was supported by a Wellcome Trust PhD studentship to F.A.C.; an MRC PhD studentship to D.D.; an MRC grant [MC_UU_12016] to P.D.; a Wellcome Trust Strategic award [097945/Z/11/Z] to J.K.D. Funding Information: We would like to thank Ioanna Mastromina and Michaela Omelkova for reading of the manuscript and constructive feedbacks. Special thanks also go to Genta Ito for assistance with Phos-tag gel assay. We thank the groups of D. Alessi and S. Rocha for reagents and Laura D'Ignazio for experimental assistance. The authors would like to thank Rachel Toth, Mel Wightman and Tom Macartney (MRC-PPU Reagents and Services) for cloning and Dr David Campbell, Bob Gourlay and Joby Vhargese (MRC-PPU) for mass spectrometry analysis. We also thank Professor Daan van Aalten and Professor Victoria Cowling and for their inputs. This work was supported by a Wellcome Trust PhD studentship to F.A.C.; an MRC PhD studentship to D.D.; an MRC grant [MC_UU_12016] to P.D.; a Wellcome Trust Strategic award [097945/Z/11/Z] to J.K.D. Publisher Copyright: {\textcopyright} 2019 The Authors. Published under the terms of the CC BY 4.0 license",
year = "2019",
month = jul,
doi = "10.15252/embr.201846436",
language = "English",
volume = "20",
journal = "EMBO Reports",
issn = "1469-221X",
number = "7",
}