title: Human condensin function is essential for centromeric chromatin assembly and proper sister kinetochore orientation.
abstract: Condensins I and II in vertebrates are essential ATP-dependent complexes necessary for chromosome condensation in mitosis. Condensins depletion is known to perturb structure and function of centromeres, however the mechanism of this functional link remains elusive. Depletion of condensin activity is now shown to result in a significant loss of loading of CENP-A, the histone H3 variant found at active centromeres and the proposed epigenetic mark of centromere identity. Absence of condensins and/or CENP-A insufficiency produced a specific kinetochore defect, such that a functional mitotic checkpoint cannot prevent chromosome missegregation resulting from improper attachment of sister kinetochores to spindle microtubules. Spindle microtubule-dependent deformation of both inner kinetochores and the HEC1/Ndc80 microtubule-capturing module, then results in kinetochore separation from the Aurora B pool and ensuing reduced kinase activity at centromeres. Moreover, recovery from mitosis-inhibition by monastrol revealed a high incidence of merotelic attachment that was nearly identical with condensin depletion, Aurora B inactivation, or both, indicating that the Aurora B dysfunction is the key defect leading to chromosome missegregation in condensin-depleted cells. Thus, beyond a requirement for global chromosome condensation, condensins play a pivotal role in centromere assembly, proper spatial positioning of microtubule-capturing modules and positioning complexes of the inner centromere versus kinetochore plates.
authors.affiliation: Unit on Chromosome Structure and Function, National Institute of Child Health and Human Development (NICHD), Laboratory of Gene Regulation and Development (LGRD), Bethesda, Maryland, United States of America.
authors.forename: Alexander
authors.initials: A
authors.lastname: Samoshkin
authors.forename: Alexei
authors.initials: A
authors.lastname: Arnaoutov
authors.forename: Lars E T
authors.initials: LE
authors.lastname: Jansen
authors.forename: Ilia
authors.initials: I
authors.lastname: Ouspenski
authors.forename: Louis
authors.initials: L
authors.lastname: Dye
authors.forename: Tatiana
authors.initials: T
authors.lastname: Karpova
authors.forename: James
authors.initials: J
authors.lastname: McNally
authors.forename: Mary
authors.initials: M
authors.lastname: Dasso
authors.forename: Don W
authors.initials: DW
authors.lastname: Cleveland
authors.forename: Alexander
authors.initials: A
authors.lastname: Strunnikov
mesh_terms: D000251:Adenosine Triphosphatases / Q000502:physiology*; D000595:Amino Acid Sequence; D064107:Aurora Kinase B; D064127:Aurora Kinases; D001324:Autoantigens / Q000378:metabolism; D001483:Base Sequence; D002503:Centromere; D000076247:Centromere Protein A; D002843:Chromatin / Q000378:metabolism*; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000502:physiology*; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D008938:Mitosis; D046912:Multiprotein Complexes / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D001324:Autoantigens; C000619700:CENPA protein, human; D000076247:Centromere Protein A; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D017931:DNA Primers; D004268:DNA-Binding Proteins; D006657:Histones; D046912:Multiprotein Complexes; C108312:condensin complexes; C576921:AURKB protein, human; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D000251:Adenosine Triphosphatases