title: Phosphorylation and DNA binding of HJURP determine its centromeric recruitment and function in CenH3(CENP-A) loading.
abstract: Centromeres, epigenetically defined by the presence of the histone H3 variant CenH3, are essential for ensuring proper chromosome segregation. In mammals, centromeric CenH3(CENP-A) deposition requires its dedicated chaperone HJURP and occurs during telophase/early G1. We find that the cell-cycle-dependent recruitment of HJURP to centromeres depends on its timely phosphorylation controlled via cyclin-dependent kinases. A nonphosphorylatable HJURP mutant localizes prematurely to centromeres in S and G2 phase. This unregulated targeting causes a premature loading of CenH3(CENP-A) at centromeres, and cell-cycle delays ensue. Once recruited to centromeres, HJURP functions to promote CenH3(CENP-A) deposition by a mechanism involving a unique DNA-binding domain. With our findings, we propose a model wherein (1) the phosphorylation state of HJURP controls its centromeric recruitment in a cell-cycle-dependent manner, and (2) HJURP binding to DNA is a mechanistic determinant in CenH3(CENP-A) loading.
authors.affiliation: Institut Curie, Centre de Recherche, Paris 75248, France; CNRS, UMR3664, Paris 75248, France; Equipe Labellisée Ligue contre le Cancer, UMR3664, Paris 75248, France; UPMC, UMR3664, Paris 75248, France; Sorbonne University, Paris 75005, France.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Müller
authors.affiliation: Institut Curie, Centre de Recherche, Paris 75248, France; CNRS, UMR3664, Paris 75248, France; Equipe Labellisée Ligue contre le Cancer, UMR3664, Paris 75248, France; UPMC, UMR3664, Paris 75248, France; Sorbonne University, Paris 75005, France.
authors.forename: Rocio
authors.initials: R
authors.lastname: Montes de Oca
authors.affiliation: Institut Curie, Centre de Recherche, Paris 75248, France; CNRS, UMR3664, Paris 75248, France; Equipe Labellisée Ligue contre le Cancer, UMR3664, Paris 75248, France; UPMC, UMR3664, Paris 75248, France; Sorbonne University, Paris 75005, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Lacoste
authors.affiliation: Institut Curie, Centre de Recherche, Paris 75248, France; Laboratory of Proteomic Mass Spectrometry, 75248 Paris Cedex 05, France.
authors.forename: Florent
authors.initials: F
authors.lastname: Dingli
authors.affiliation: Institut Curie, Centre de Recherche, Paris 75248, France; Laboratory of Proteomic Mass Spectrometry, 75248 Paris Cedex 05, France.
authors.forename: Damarys
authors.initials: D
authors.lastname: Loew
authors.affiliation: Institut Curie, Centre de Recherche, Paris 75248, France; CNRS, UMR3664, Paris 75248, France; Equipe Labellisée Ligue contre le Cancer, UMR3664, Paris 75248, France; UPMC, UMR3664, Paris 75248, France; Sorbonne University, Paris 75005, France. Electronic address: genevieve.almouzni@curie.fr.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Almouzni
mesh_terms: D000595:Amino Acid Sequence; D001324:Autoantigens / Q000378:metabolism*; D001665:Binding Sites; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002503:Centromere / Q000378:metabolism*; D000076247:Centromere Protein A; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism*; D004247:DNA / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011485:Protein Binding
chemical_list: D001324:Autoantigens; C000619700:CENPA protein, human; D000076247:Centromere Protein A; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; C524371:HJURP protein, human; D004247:DNA