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Actin reduction by MsrB2 is a key component of the cytokinetic abscission checkpoint and prevents tetraploidy

Abstract : Abscission is the terminal step of cytokinesis leading to the physical separation of the daughter cells. In response to the abnormal presence of lagging chromatin between dividing cells, an evolutionarily-conserved abscission/NoCut checkpoint delays abscission and prevents formation of binucleated cells by stabilizing the cytokinetic intercellular bridge. How this bridge is stably maintained for hours while the checkpoint is activated is poorly understood and has been proposed to rely on F-actin in the bridge region. This thesis work revealed that actin polymerization is essential for stabilizing the cytokinetic bridge in human cells, exclusively when lagging chromatin is present. Mechanistically, we found that a cytosolic pool of human Methionine sulfoxide reductase B2 (MsrB2) is strongly recruited at the midbody specifically in the presence of lagging chromatin, where it promotes actin polymerization. In MsrB2-depleted cells, F-actin levels are decreased and dividing cells with lagging chromatin become binucleated as a consequence of unstable bridges. We further demonstrated that MsrB2 selectively reduces oxidized actin monomers and thereby counteracts MICAL1, an enzyme known to depolymerize actin filaments by direct oxidation. This work thus reveals that actin reduction by MsrB2 is a key component of the abscission checkpoint that favors F-actin polymerization and limits tetraploidy, a starting point for tumorigenesis. This work demonstrates the first implication of a protein reduction reaction in cell division.
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Jian Bai. Actin reduction by MsrB2 is a key component of the cytokinetic abscission checkpoint and prevents tetraploidy. Cellular Biology. Sorbonne Université, 2019. English. ⟨NNT : 2019SORUS041⟩. ⟨tel-02935861⟩

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