title: The human CENP-A centromeric nucleosome-associated complex.
abstract: The basic element for chromosome inheritance, the centromere, is epigenetically determined in mammals. The prime candidate for specifying centromere identity is the array of nucleosomes assembled with CENP-A, the centromere-specific histone H3 variant. Here, we show that CENP-A nucleosomes directly recruit a proximal CENP-A nucleosome associated complex (NAC) comprised of three new human centromere proteins (CENP-M, CENP-N and CENP-T), along with CENP-U(50), CENP-C and CENP-H. Assembly of the CENP-A NAC at centromeres is dependent on CENP-M, CENP-N and CENP-T. Facilitates chromatin transcription (FACT) and nucleophosmin-1 (previously implicated in transcriptional chromatin remodelling and as a multifunctional nuclear chaperone, respectively) are absent from histone H3-containing nucleosomes, but are stably recruited to CENP-A nucleosomes independent of CENP-A NAC. Seven new CENP-A-nucleosome distal (CAD) centromere components (CENP-K, CENP-L, CENP-O, CENP-P, CENP-Q, CENP-R and CENP-S) are identified as assembling on the CENP-A NAC. The CENP-A NAC is essential, as disruption of the complex causes errors of chromosome alignment and segregation that preclude cell survival despite continued centromere-derived mitotic checkpoint signalling.
authors.affiliation: Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093-0670, USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Foltz
authors.forename: Lars E T
authors.initials: LE
authors.lastname: Jansen
authors.forename: Ben E
authors.initials: BE
authors.lastname: Black
authors.forename: Aaron O
authors.initials: AO
authors.lastname: Bailey
authors.forename: John R
authors.initials: JR
authors.lastname: Yates
authors.forename: Don W
authors.initials: DW
authors.lastname: Cleveland
mesh_terms: D000595:Amino Acid Sequence; D001324:Autoantigens / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D002503:Centromere / Q000378:metabolism*; D000076247:Centromere Protein A; D056504:Chromatin Assembly Factor-1; D042002:Chromatin Assembly and Disassembly / Q000235:genetics; D002868:Chromosomal Proteins, Non-Histone / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D002877:Chromosomes, Human / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D006367:HeLa Cells; D006657:Histones / Q000737:chemistry; D006801:Humans; D008938:Mitosis / Q000235:genetics; D008969:Molecular Sequence Data; D009707:Nucleosomes / Q000378:metabolism*; D011485:Protein Binding; D015398:Signal Transduction
chemical_list: D001324:Autoantigens; C000619700:CENPA protein, human; C571071:CENPN protein, human; D000076247:Centromere Protein A; D056504:Chromatin Assembly Factor-1; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D006657:Histones; D009707:Nucleosomes