Wei Zhao | A/P Deng Lih Wen

MLL5 maintains spindle bipolarity by preventing aberrant cytosolic aggregation of PLK1

Authors: Wei Zhao, Jie Liu, Xiaoming Zhang and Lih-Wen Deng
Affiliation: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore
Publication Journal: Journal of Cell Biology 28 March 2016 vol. 212 no. 7.
Abstract: Faithful chromosome segregation with bipolar spindle formation is critical for the maintenance of genomic stability. Perturbation of this process often leads to severe mitotic failure, contributing to tumorigenesis. MLL5 has been demonstrated to play vital roles in cell cycle progression and the maintenance of genomic stability. Here, we identify a novel interaction between MLL5 and PLK1 in the cytosol that is crucial for sustaining spindle bipolarity during mitosis. Knockdown of MLL5 caused aberrant PLK1 aggregation that led to acentrosomal microtubule-organizing center (aMTOC) formation and subsequent spindle multipolarity. Further molecular studies revealed that the polo-box domain (PBD) of PLK1 interacted with a binding motif on MLL5 (Thr887-Ser888-Thr889), and this interaction was essential for spindle bipolarity. Overexpression of wild-type MLL5 was able to rescue PLK1 mislocalization and aMTOC formation in MLL5-KD cells, whereas MLL5 mutants incapable of interacting with the PBD failed to do so. We thus propose that MLL5 preserves spindle bipolarity through maintaining cytosolic PLK1 in a nonaggregated form.

Figure Legend: Proposed working model for MLL5 maintaining spindle bipolarity. Pc, pericentrin; M5, MLL5; γ-TuRC, γ-tubulin ring complex; PLK1*, PLK1 aggregates; PS, PHD/SET domain; CT, C-terminal domain; p, phosphorylated; KD, kinase domain; and TS888T, Thr887-Ser888-Thr889 motif on MLL5.