Cell cycle regulation

Redox shielding

J. Cell Biol. 210, 23–33 (2015)

Credit: DONGMIN KANG

The regulation of the anaphase-promoting complex/cyclosome (APC/C) between kinases and phosphatases dictates the stability of cell cycle mediators. In particular, the cyclin-dependent kinases (Cdks) phosphorylate an APC/C activating-protein Cdh1, while the protein tyrosine phosphatase Cdc14B opposes this modification. These cell cycle regulators are localized at the centrosome, which is the main microtubule-organizing center of animal cells required for mitotic progression. Recent studies have introduced redox regulation into this interplay as the Cdk-cyclin B complex has been observed to phosphorylate and inhibit the hydrogen peroxide (H2O2)-degrading enzyme peroxiredoxin I (PrxI). In addition, changes in H2O2 levels are known to modulate cell cycle progression. To determine the temporal regulation between PrxI and H2O2, Lim et al. investigated how PrxI is regulated during the cell cycle. Interestingly, they found that PrxI is phosphorylated at early mitotic centrosomes but becomes dephosphorylated after anaphase onset, hinting that H2O2 accumulates at early mitotic centrosomes and the centrosome-associated H2O2 promotes mitotic entry. Consistent with this idea, reduction of centrosomal H2O2 levels through the expression of centrosome-targeting catalase, a H2O2-metabolizing enzyme, delayed mitotic entry. Biotinylation labeling studies revealed that Cdc14B is highly sensitive to H2O2-dependent oxidation. From these observations, the authors suspected that Cdc14B might be targeted for inhibition through oxidation. Cdc14B oxidation presumably reduced its phosphatase activity, thus resulting in the maintenance of Cdh1 serine phosphorylation that prevents interactions with the APC/C complex. Lowering H2O2 levels through centrosomal catalase expression also decreased Cdh1 serine phosphorylation. Hence, H2O2-mediated Cdc14 inactivation, and therefore Cdh1 phosphorylation during early mitosis, are likely to be critical to ensuring normal M-phase progression by preventing precocious APC/C activation.

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Miura, G. Redox shielding. Nat Chem Biol 11, 632 (2015). https://doi.org/10.1038/nchembio.1901

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