title: Cell cycle-regulated membrane binding of NuMA contributes to efficient anaphase chromosome separation.
abstract: Accurate and efficient separation of sister chromatids during anaphase is critical for faithful cell division. It has been proposed that cortical dynein-generated pulling forces on astral microtubules contribute to anaphase spindle elongation and chromosome separation. In mammalian cells, however, definitive evidence for the involvement of cortical dynein in chromosome separation is missing. It is believed that dynein is recruited and anchored at the cell cortex during mitosis by the α subunit of heterotrimeric G protein (Gα)/mammalian homologue of Drosophila Partner of Inscuteable/nuclear mitotic apparatus (NuMA) ternary complex. Here we uncover a Gα/LGN-independent lipid- and membrane-binding domain at the C-terminus of NuMA. We show that the membrane binding of NuMA is cell cycle regulated-it is inhibited during prophase and metaphase by cyclin-dependent kinase 1 (CDK1)-mediated phosphorylation and only occurs after anaphase onset when CDK1 activity is down-regulated. Further studies indicate that cell cycle-regulated membrane association of NuMA underlies anaphase-specific enhancement of cortical NuMA and dynein. By replacing endogenous NuMA with membrane-binding-deficient NuMA, we can specifically reduce the cortical accumulation of NuMA and dynein during anaphase and demonstrate that cortical NuMA and dynein contribute to efficient chromosome separation in mammalian cells.
authors.affiliation: Institute of Molecular Medicine and Genetics, Georgia Regents University, Augusta, GA 30912 Department of Neurology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912 Lakeside High School, Evans, GA 30809.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zheng
authors.forename: Qingwen
authors.initials: Q
authors.lastname: Wan
authors.forename: Gerry
authors.initials: G
authors.lastname: Meixiong
authors.forename: Quansheng
authors.initials: Q
authors.lastname: Du
mesh_terms: D000705:Anaphase / Q000502:physiology*; D000818:Animals; D001665:Binding Sites; D016203:CDC2 Protein Kinase / Q000378:metabolism; D019556:COS Cells; D002455:Cell Division; D002462:Cell Membrane / Q000378:metabolism; D020090:Chromosome Segregation; D002875:Chromosomes / Q000378:metabolism; D004285:Dogs; D004398:Dyneins / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D008677:Metaphase; D034521:Nuclear Matrix-Associated Proteins / Q000737:chemistry / Q000378:metabolism*; D010766:Phosphorylation; D017434:Protein Structure, Tertiary
chemical_list: D034521:Nuclear Matrix-Associated Proteins; D016203:CDC2 Protein Kinase; D004398:Dyneins