Phosphorylation of the CPC by Cdk1 promotes chromosome bi-orientation

Abstract

Successful partition of replicated genomes at cell division requires chromosome attachment to opposite poles of mitotic spindle (bi-orientation). Any defects in this regulation bring about chromosomal instability, which may accelerate tumour progression in humans. To achieve chromosome bi-orientation at prometaphase, the chromosomal passenger complex (CPC), composed of catalytic kinase Aurora B and regulatory components (INCENP, Survivin and Borealin), must be localized to centromeres to phosphorylate kinetochore substrates. Although the CPC dynamically changes the subcellular localization, the regulation of centromere targeting is largely unknown. Here we isolated a fission yeast cyclin B mutant defective specifically in chromosome bi-orientation. Accordingly, we identified Cdk1 (also known as Cdc2)-cyclin-B-dependent phosphorylation of Survivin. Preventing Survivin phosphorylation impairs centromere CPC targeting as well as chromosome bi-orientation, whereas phosphomimetic Survivin suppresses the bi-orientation defect in the cyclin B mutant. Survivin phosphorylation promotes direct binding with shugoshin, which we now define as a conserved centromeric adaptor of the CPC. In human cells, the phosphorylation of Borealin has a comparable role. Thus, our study resolves the conserved mechanisms of CPC targeting to centromeres, highlighting a key role of Cdk1-cyclin B in chromosome bi-orientation.

Mps1 promotes rapid centromere accumulation of Aurora B

“…As Cdk1 activity is important for proper centromere localization of the CPC [19], we wanted to test if the defects in Aurora B recruitment upon Mps1 inhibition were related to reduced Cyclin B levels owing to checkpoint inactivation. First, we depleted the checkpoint protein BubR1 and found it had no effect on Aurora B localization ( Fig 1A; supplementary Fig S1B,C online).…”

Connections between cadherin-catenin proteins, spindle misorientation, and cancer

“…151,152 Interestingly, loss of Yap1 has been associated to centrosomal and mitotic spindle defects, by a mechanism that involves cyclin-dependent kinase CDK1 mediated phosphorylation, 153 which is also important to regulate mitotic spindle bi-orientation. 154 Moreover, members of the Hippo pathway are important to orient the plane of cell division in certain tissues such as in the developing kidney. 155,156 In addition, upstream regulators of the Hippo/Yap pathway such as the tumor suppressor LKB1, 157,158 AMPK 159 and TAO1 kinase 160,161 are involved in spindle orientation.…”

Survivine, interprète du code histone mitotique

“…En fait, le groupe de Y. Watanabe a montré que la phosphorylation de l'histone H3-Thr3 agissait de concert avec une autre modification portée par l'histone H2A [8,9]. En effet, au cours de la mitose, la kinase Bub1 est pré-sente sur les centromères internes et phosphoryle la Ser 210 de l'histone H2A recrutant ainsi les protéines shugoshine [7].…”

“…Watanabe et al suggèrent que la phosphorylation de l'histone H2A permet le recrutement des protéines Sgo qui attirent à leur tour la protéine boréaline phosphorylée par cdk1(cdc2)-cycline B. In fine, cela permet le recrutement du complexe passager (Figure 1) [6][7][8]. …”