MLL5 maintains spindle bipolarity by preventing aberrant cytosolic aggregation of PLK1

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 mai...

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Published inThe Journal of cell biology Vol. 212; no. 7; pp. 829 - 843
Main Authors Zhao, Wei, Liu, Jie, Zhang, Xiaoming, Deng, Lih-Wen
Format Journal Article
LanguageEnglish
Published United States Rockefeller University Press 28.03.2016
The Rockefeller University Press
Subjects
Cell cycle
Cell Cycle Proteins - genetics
Cell Cycle Proteins - metabolism
Cell division
Cell Line, Tumor
Cell Polarity
Chromosomes
Cytosol - enzymology
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
Enzymes
Genomics
HEK293 Cells
Humans
Microtubule-Organizing Center - enzymology
Mitosis
Mutation
Phosphorylation
Polo-Like Kinase 1
Protein Aggregates
Protein Binding
Protein Interaction Domains and Motifs
Protein Serine-Threonine Kinases - genetics
Protein Serine-Threonine Kinases - metabolism
Proto-Oncogene Proteins - genetics
Proto-Oncogene Proteins - metabolism
RNA Interference
Signal Transduction
Spindle Apparatus - metabolism
Time Factors
Transfection
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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.
AbstractList 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.
Zhao et al. show that MLL5 and PLK interact in the cytosol and propose a model wherein MLL5 maintains spindle bipolarity by preventing cytosolic PLK1 aggregation during mitosis. 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.
Author Zhao, Wei
Liu, Jie
Zhang, Xiaoming
Deng, Lih-Wen
AuthorAffiliation Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597
AuthorAffiliation_xml – name: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597
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  surname: Zhao
  fullname: Zhao, Wei
  organization: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597
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  givenname: Jie
  surname: Liu
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  organization: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597
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  givenname: Xiaoming
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  surname: Deng
  fullname: Deng, Lih-Wen
  email: bchdlw@nus.edu.sg
  organization: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597 bchdlw@nus.edu.sg
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Snippet Faithful chromosome segregation with bipolar spindle formation is critical for the maintenance of genomic stability. Perturbation of this process often leads...
Zhao et al. show that MLL5 and PLK interact in the cytosol and propose a model wherein MLL5 maintains spindle bipolarity by preventing cytosolic PLK1...
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SubjectTerms Cell cycle
Cell Cycle Proteins - genetics
Cell Cycle Proteins - metabolism
Cell division
Cell Line, Tumor
Cell Polarity
Chromosomes
Cytosol - enzymology
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
Enzymes
Genomics
HEK293 Cells
Humans
Microtubule-Organizing Center - enzymology
Mitosis
Mutation
Phosphorylation
Polo-Like Kinase 1
Protein Aggregates
Protein Binding
Protein Interaction Domains and Motifs
Protein Serine-Threonine Kinases - genetics
Protein Serine-Threonine Kinases - metabolism
Proto-Oncogene Proteins - genetics
Proto-Oncogene Proteins - metabolism
RNA Interference
Signal Transduction
Spindle Apparatus - metabolism
Time Factors
Transfection
Title MLL5 maintains spindle bipolarity by preventing aberrant cytosolic aggregation of PLK1
URI https://www.ncbi.nlm.nih.gov/pubmed/27002166
https://www.proquest.com/docview/1777505574
https://search.proquest.com/docview/1777076898
https://pubmed.ncbi.nlm.nih.gov/PMC4810297
Volume 212
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