Abstract
The Greatwall/Ensa/PP2A-B55 pathway is essential for controlling mitotic substrate phosphorylation and mitotic entry. Here, we investigate the effect of the knockdown of the Gwl substrate, Ensa, in human cells. Unexpectedly, Ensa knockdown promotes a dramatic extension of S phase associated with a lowered density of replication forks. Notably, Ensa depletion results in a decrease of Treslin levels, a pivotal protein for the firing of replication origins. Accordingly, the extended S phase in Ensa-depleted cells is completely rescued by the overexpression of Treslin. Our data herein reveal a new mechanism by which normal cells regulate S-phase duration by controlling the ubiquitin-proteasome degradation of Treslin in a Gwl/Ensa-dependent pathway.
Highlights
The Greatwall/Ensa/PP2A-B55 pathway is essential for controlling mitotic substrate phosphorylation and mitotic entry
We used two small interfering RNA (siRNA) directed against two different sequences of the messenger RNA of this gene
The Gwl/Arpp19-Ensa/PP2A-B55 axis was originally identified in Xenopus egg extracts[26,27,28] and subsequently reported in other models such as Drosophila[29] and human cells[17, 18]
Summary
The Greatwall/Ensa/PP2A-B55 pathway is essential for controlling mitotic substrate phosphorylation and mitotic entry. Others demonstrated that the activation of the Greatwall (Gwl) kinase at the G2/M transition via the phosphorylation of its substrates Arpp[19] and Ensa, promotes the inactivation of PP2AB55, the phosphatase responsible of the dephosphorylation of cyclin B-Cdk[1] substrates[17,18,19,20]. This inactivation results in the stable phosphorylation of these substrates and correct entry and progression through mitosis. Our data demonstrate that Gwl/Ensa/PP2A-B55 axis regulates S phase by controlling the Cullin-dependent degradation of the pivotal replication factor Treslin
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