title: A high-sensitivity phospho-switch triggered by Cdk1 governs chromosome morphogenesis during cell division.
abstract: The initiation of chromosome morphogenesis marks the beginning of mitosis in all eukaryotic cells. Although many effectors of chromatin compaction have been reported, the nature and design of the essential trigger for global chromosome assembly remain unknown. Here we reveal the identity of the core mechanism responsible for chromosome morphogenesis in early mitosis. We show that the unique sensitivity of the chromosome condensation machinery for the kinase activity of Cdk1 acts as a major driving force for the compaction of chromatin at mitotic entry. This sensitivity is imparted by multisite phosphorylation of a conserved chromatin-binding sensor, the Smc4 protein. The multisite phosphorylation of this sensor integrates the activation state of Cdk1 with the dynamic binding of the condensation machinery to chromatin. Abrogation of this event leads to chromosome segregation defects and lethality, while moderate reduction reveals the existence of a novel chromatin transition state specific to mitosis, the intertwist configuration. Collectively, our results identify the mechanistic basis governing chromosome morphogenesis in early mitosis and how distinct chromatin compaction states can be established via specific thresholds of Cdk1 kinase activity.
authors.affiliation: Institute for Research in Immunology and Cancer (IRIC), Département de Pathologie et Biologie Cellulaire, Université de Montréal, Montréal, Quebec H3C 3J7, Canada;
authors.forename: Xavier
authors.initials: X
authors.lastname: Robellet
authors.affiliation: Institute for Research in Immunology and Cancer (IRIC), Département de Pathologie et Biologie Cellulaire, Université de Montréal, Montréal, Quebec H3C 3J7, Canada;
authors.forename: Yogitha
authors.initials: Y
authors.lastname: Thattikota
authors.affiliation: Institute for Research in Immunology and Cancer (IRIC), Département de Pathologie et Biologie Cellulaire, Université de Montréal, Montréal, Quebec H3C 3J7, Canada;
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.affiliation: Advanced BioImaging Facility (ABIF), Department of Physiology, McGill University, Montréal, Quebec H3G 0B1, Canada.
authors.forename: Tse-Luen
authors.initials: TL
authors.lastname: Wee
authors.affiliation: Institute for Research in Immunology and Cancer (IRIC), Département de Pathologie et Biologie Cellulaire, Université de Montréal, Montréal, Quebec H3C 3J7, Canada;
authors.forename: Mirela
authors.initials: M
authors.lastname: Pascariu
authors.affiliation: Institute for Research in Immunology and Cancer (IRIC), Département de Pathologie et Biologie Cellulaire, Université de Montréal, Montréal, Quebec H3C 3J7, Canada;
authors.forename: Sahana
authors.initials: S
authors.lastname: Shankar
authors.affiliation: Institute for Research in Immunology and Cancer (IRIC).
authors.forename: Éric
authors.initials: É
authors.lastname: Bonneil
authors.affiliation: Advanced BioImaging Facility (ABIF), Department of Physiology, McGill University, Montréal, Quebec H3G 0B1, Canada.
authors.forename: Claire M
authors.initials: CM
authors.lastname: Brown
authors.affiliation: Institute for Research in Immunology and Cancer (IRIC), Département de Pathologie et Biologie Cellulaire, Université de Montréal, Montréal, Quebec H3C 3J7, Canada;
authors.forename: Damien
authors.initials: D
authors.lastname: D'Amours
mesh_terms: D000251:Adenosine Triphosphatases / Q000737:chemistry / Q000378:metabolism; D002455:Cell Division / Q000235:genetics*; D042002:Chromatin Assembly and Disassembly / Q000235:genetics; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D015825:Chromosomes, Fungal / Q000235:genetics*; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D005812:Genes, Switch / Q000502:physiology; D008938:Mitosis; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D012441:Saccharomyces cerevisiae / Q000166:cytology* / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D046912:Multiprotein Complexes; C409162:SMC4 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; C108312:condensin complexes; D018844:Cyclin-Dependent Kinases; D000251:Adenosine Triphosphatases
keywords: Cdk1; Smc4; chromosome; morphogenesis; multisite phosphorylation