title: MLL5 maintains spindle bipolarity by preventing aberrant cytosolic aggregation of PLK1.
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.
authors.affiliation: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597.
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597 bchdlw@nus.edu.sg.
authors.forename: Lih-Wen
authors.initials: LW
authors.lastname: Deng
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D016764:Cell Polarity; D003600:Cytosol / Q000201:enzymology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D022101:Microtubule-Organizing Center / Q000201:enzymology; D008938:Mitosis; D009154:Mutation; D010766:Phosphorylation; D066329:Protein Aggregates; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D008941:Spindle Apparatus / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D066329:Protein Aggregates; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1; C460660:KMT2E protein, human