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Implications of alternative routes to APC/C inhibition by the mitotic checkpoint complex

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  • Fridolin Gross
  • Paolo Bonaiuti
  • Silke Hauf
  • Andrea Ciliberto

Abstract

The mitotic checkpoint (also called spindle assembly checkpoint) is a signaling pathway that ensures faithful chromosome segregation. Mitotic checkpoint proteins inhibit the anaphase-promoting complex (APC/C) and its activator Cdc20 to prevent precocious anaphase. Checkpoint signaling leads to a complex of APC/C, Cdc20, and checkpoint proteins, in which the APC/C is inactive. In principle, this final product of the mitotic checkpoint can be obtained via different pathways, whose relevance still needs to be fully ascertained experimentally. Here, we use mathematical models to compare the implications on checkpoint response of the possible pathways leading to APC/C inhibition. We identify a previously unrecognized funneling effect for Cdc20, which favors Cdc20 incorporation into the inhibitory complex and therefore promotes checkpoint activity. Furthermore, we find that the presence or absence of one specific assembly reaction determines whether the checkpoint remains functional at elevated levels of Cdc20, which can occur in cancer cells. Our results reveal the inhibitory logics behind checkpoint activity, predict checkpoint efficiency in perturbed situations, and could inform molecular strategies to treat malignancies that exhibit Cdc20 overexpression.Author summary: Cell division is a fundamental event in the life of cells. It requires that a mother cell gives rise to two daughters which carry the same genetic material of their mother. Thus, during each cell cycle the genetic material needs to be replicated, compacted into chromosomes and redistributed to the two daughter cells. Any mistake in chromosome segregation would attribute the wrong number of chromosomes to the progeny. Hence, the process of chromosome segregation is closely watched by a surveillance mechanism known as the mitotic checkpoint. The molecular players of the checkpoint pathway are well known: we know both the input (ie, the species to be inhibited and their inhibitors), and the output (ie, the inhibited species). However, we do not exactly know the path that leads from the former to the latter. In this manuscript, we use a mathematical approach to explore the properties of plausible mitotic checkpoint networks. We find that seemingly similar circuits show very different behaviors for high levels of the protein targeted by the mitotic checkpoint, Cdc20. Interestingly, this protein is often overexpressed in cancer cells. For physiological levels of Cdc20, instead, all the models we have analyzed are capable to mount an efficient response. We find that this is due to a series of consecutive protein-protein binding reactions that funnel Cdc20 towards its inhibited state. We call this the funneling effect. Our analysis helps understanding the inhibitory logics underlying the checkpoint, and proposes new concepts that could be applied to other inhibitory pathways.

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  • Fridolin Gross & Paolo Bonaiuti & Silke Hauf & Andrea Ciliberto, 2018. "Implications of alternative routes to APC/C inhibition by the mitotic checkpoint complex," PLOS Computational Biology, Public Library of Science, vol. 14(9), pages 1-19, September.
  • Handle: RePEc:plo:pcbi00:1006449
    DOI: 10.1371/journal.pcbi.1006449
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    1. Marco Simonetta & Romilde Manzoni & Roberto Mosca & Marina Mapelli & Lucia Massimiliano & Martin Vink & Bela Novak & Andrea Musacchio & Andrea Ciliberto, 2009. "The Influence of Catalysis on Mad2 Activation Dynamics," PLOS Biology, Public Library of Science, vol. 7(1), pages 1-14, January.
    2. Claudio Alfieri & Leifu Chang & Ziguo Zhang & Jing Yang & Sarah Maslen & Mark Skehel & David Barford, 2016. "Molecular basis of APC/C regulation by the spindle assembly checkpoint," Nature, Nature, vol. 536(7617), pages 431-436, August.
    3. Jing Chen & Jian Liu, 2014. "Spatial-temporal model for silencing of the mitotic spindle assembly checkpoint," Nature Communications, Nature, vol. 5(1), pages 1-13, December.
    4. William C. H. Chao & Kiran Kulkarni & Ziguo Zhang & Eric H. Kong & David Barford, 2012. "Structure of the mitotic checkpoint complex," Nature, Nature, vol. 484(7393), pages 208-213, April.
    5. Leifu Chang & Ziguo Zhang & Jing Yang & Stephen H. McLaughlin & David Barford, 2014. "Molecular architecture and mechanism of the anaphase-promoting complex," Nature, Nature, vol. 513(7518), pages 388-393, September.
    6. Alex C. Faesen & Maria Thanasoula & Stefano Maffini & Claudia Breit & Franziska Müller & Suzan van Gerwen & Tanja Bange & Andrea Musacchio, 2017. "Basis of catalytic assembly of the mitotic checkpoint complex," Nature, Nature, vol. 542(7642), pages 498-502, February.
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