Cell-cycle phospho-regulation of the kinetochore
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REVIEW
Cell‑cycle phospho‑regulation of the kinetochore Cinzia Klemm1 · Peter H. Thorpe1 · Guðjón Ólafsson1,2 Received: 4 September 2020 / Revised: 27 October 2020 / Accepted: 29 October 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract The kinetochore is a mega-dalton protein assembly that forms within centromeric regions of chromosomes and directs their segregation during cell division. Here we review cell cycle-mediated phosphorylation events at the kinetochore, with a focus on the budding yeast Saccharomyces cerevisiae and the insight gained from forced associations of kinases and phosphatases. The point centromeres found in the budding yeast S. cerevisiae are one of the simplest such structures found in eukaryotes. The S. cerevisiae kinetochore comprises a single nucleosome, containing a centromere-specific H3 variant Cse4CENP-A, bound to a set of kinetochore proteins that connect to a single microtubule. Despite the simplicity of the budding yeast kinetochore, the proteins are mostly homologous with their mammalian counterparts. In some cases, human proteins can complement their yeast orthologs. Like its mammalian equivalent, the regulation of the budding yeast kinetochore is complex: integrating signals from the cell cycle, checkpoints, error correction, and stress pathways. The regulatory signals from these diverse pathways are integrated at the kinetochore by post-translational modifications, notably phosphorylation and dephosphorylation, to control chromosome segregation. Here we highlight the complex interplay between the activity of the different cell-cycle kinases and phosphatases at the kinetochore, emphasizing how much more we have to understand this essential structure. Keywords Kinetochore regulation · Phosphorylation · Polo-like kinase · Cdc5 · DDK · Cdc14 · CDK · CK2 · PP1 · PP2A
Introduction Kinetochore phospho-regulation is essential for chromosome segregation and cell-cycle progression. Extensive knowledge has been gained about key kinetochore phosphorylation events, including the activation of the Spindle Assembly Checkpoint (SAC) by Mps1 kinase and the error correction pathway driven by Ipl1Aurora B kinase, part of the chromosomal passenger complex (CPC) (reviewed in: Musacchio and Salmon 2007; Carmena et al. 2012; Funabiki and Wynne 2013; Van Der Horst and Lens 2014; Joglekar 2016; Corbett 2017; Vallardi et al. 2017; Lampson and Grishchuk
Communicated by M. Kupiec. * Peter H. Thorpe [email protected] * Guðjón Ólafsson [email protected] 1
School of Biological and Chemical Sciences, Queen Mary, University of London, London E1 4NS, UK
Present Address: Institute for Systems Genetics, NYU Langone Health, New York, NY 10016, USA
2
2017). The major cell-cycle kinases, such as cyclin-dependent kinase (CDK), Dbf4-dependent kinase (DDK), casein kinase 2 (CK2), and Polo-like kinase ( Cdc5Plk1), also phosphorylate kinetochore proteins. These phosphorylations are countered by phosphatases such as PP1, PP2A and Cdc14. Most kinetochore subcomplexe
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