title: Cdk activity couples epigenetic centromere inheritance to cell cycle progression.
abstract: Centromeres form the site of chromosome attachment to microtubules during mitosis. Identity of these loci is maintained epigenetically by nucleosomes containing the histone H3 variant CENP-A. Propagation of CENP-A chromatin is uncoupled from DNA replication initiating only during mitotic exit. We now demonstrate that inhibition of Cdk1 and Cdk2 activities is sufficient to trigger CENP-A assembly throughout the cell cycle in a manner dependent on the canonical CENP-A assembly machinery. We further show that the key CENP-A assembly factor Mis18BP1(HsKNL2) is phosphorylated in a cell cycle-dependent manner that controls its centromere localization during mitotic exit. These results strongly support a model in which the CENP-A assembly machinery is poised for activation throughout the cell cycle but kept in an inactive noncentromeric state by Cdk activity during S, G2, and M phases. Alleviation of this inhibition in G1 phase ensures tight coupling between DNA replication, cell division, and subsequent centromere maturation.
authors.affiliation: Instituto Gulbenkian de Ciência, 2780-156 Oeiras, Portugal.
authors.forename: Mariana C C
authors.initials: MC
authors.lastname: Silva
authors.forename: Dani L
authors.initials: DL
authors.lastname: Bodor
authors.forename: Madison E
authors.initials: ME
authors.lastname: Stellfox
authors.forename: Nuno M C
authors.initials: NM
authors.lastname: Martins
authors.forename: Helfrid
authors.initials: H
authors.lastname: Hochegger
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Foltz
authors.forename: Lars E T
authors.initials: LE
authors.lastname: Jansen
mesh_terms: D001324:Autoantigens / Q000378:metabolism*; D015153:Blotting, Western; D016203:CDC2 Protein Kinase / Q000378:metabolism*; D002453:Cell Cycle; D002455:Cell Division; D002503:Centromere / Q000502:physiology*; D000076247:Centromere Protein A; D002843:Chromatin / Q000235:genetics; D002868:Chromosomal Proteins, Non-Histone / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism*; D057890:Epigenomics; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D016193:G1 Phase / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D008938:Mitosis / Q000502:physiology; D010766:Phosphorylation
chemical_list: D001324:Autoantigens; C000619700:CENPA protein, human; D000076247:Centromere Protein A; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; C517147:MIS18BP1 protein, human; D016203:CDC2 Protein Kinase; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2