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• W2013711216 abstract "Centromeres direct chromosome inheritance, but in multicellular organisms their positions on chromosomes are primarily specified epigenetically rather than by a DNA sequence. The major candidate for the epigenetic mark is chromatin assembled with the histone H3 variant CENP-A. Recent studies offer conflicting evidence for the structure of CENP-A-containing chromatin, including the histone composition and handedness of the DNA wrapped around the histones. We present a model for the assembly and deposition of centromeric nucleosomes that couples these processes to the cell cycle. This model reconciles divergent data for CENP-A-containing nucleosomes and provides a basis for how centromere identity is stably inherited. Centromeres direct chromosome inheritance, but in multicellular organisms their positions on chromosomes are primarily specified epigenetically rather than by a DNA sequence. The major candidate for the epigenetic mark is chromatin assembled with the histone H3 variant CENP-A. Recent studies offer conflicting evidence for the structure of CENP-A-containing chromatin, including the histone composition and handedness of the DNA wrapped around the histones. We present a model for the assembly and deposition of centromeric nucleosomes that couples these processes to the cell cycle. This model reconciles divergent data for CENP-A-containing nucleosomes and provides a basis for how centromere identity is stably inherited. The centromere is a specialized region on each chromosome that ensures the faithful inheritance of the chromosome during cell division. Specifically, the centromere mediates the chromosome's attachment to the mitotic spindle, and it also serves as the location of final cohesion between the duplicated copies of a chromosome (i.e., chromatids) prior to their complete separation and movement to opposite spindle poles near the end of mitosis. Centromeric DNA usually contains a repetitive sequence with a repeating unit, typically 160–180 bp, that is slightly smaller than the average spacing between nucleosomes on chromosomal arms (i.e., ∼200 bp). The repeating sequences found in centromeric DNA evolve rapidly relative to the rest of the chromosome (Figure 1), and they are likely to have a role in maintaining the large heterochromatin domains typically found at centromeres. In the budding yeast Saccharomyces cerevisiae, centromeric DNA is a single domain of 125 bp (bottom, Figure 1), and its position is specified by sequence-specific recruitment of a centromere binding complex, which contains four proteins (Ndc10, Cep3, Ctf13, and Skp1) (Lechner and Carbon, 1991Lechner J. Carbon J. A 240 kd multisubunit protein complex, CBF3, is a major component of the budding yeast centromere.Cell. 1991; 64: 717-725Abstract Full Text PDF PubMed Scopus (250) Google Scholar). In all other species studied, centromeric DNA spans thousands to millions of base pairs and contains repetitive DNA motifs that sharply diverge between species, making these repeats sequence unique for each species. Surprisingly, however, the presence of these repeats does not specify centromere location, and they are not required for the general function of centromeres. Rather, the epigenetic information that specifies centromeres tracks with the chromatin underlying the mitotic kinetochore, the protein complex that physically connects each chromosome to the microtubule-based spindle apparatus. In all eukaryotes, a key component of the chromatin that specifies centromeres is the incorporation of a variant of histone H3, named CENP-A in mammals, CID in flies, and Cse4 in budding yeast. In all likely models of centromere inheritance, CENP-A or its homolog is what physically distinguishes centromeric chromatin from the rest of the chromosome. In addition, after DNA replication in S phase, the presence of CENP-A is also probably responsible for directing the deposition of newly expressed CENP-A and other centromere components, which in mammals include CENP-C, M, N, U, and T (Foltz et al., 2006Foltz D.R. Jansen L.E.T. Black B.E. Bailey A.O. Yates 3rd, J.R. Cleveland D.W. The human CENP-A centromeric nucleosome-associated complex.Nat. Cell Biol. 2006; 8: 458-469Crossref PubMed Scopus (492) Google Scholar). A consistent observation is that centromere-specifying chromatin vacates “silenced” centromeres that no longer function (Earnshaw and Migeon, 1985Earnshaw W.C. Migeon B.R. Three related centromere proteins are absent from the inactive centromere of a stable isodicentric chromosome.Chromosoma. 1985; 92: 290-296Crossref PubMed Scopus (181) Google Scholar, Warburton et al., 1997Warburton P.E. Cooke C.A. Bourassa S. Vafa O. Sullivan B.A. Stetten G. Gimelli G. Warburton D. Tyler-Smith C. Sullivan K.F. et al.Immunolocalization of CENP-A suggests a distinct nucleosome structure at the inner kinetochore plate of active centromeres.Curr. Biol. 1997; 7: 901-904Abstract Full Text Full Text PDF PubMed Scopus (287) Google Scholar). The best examples of these “silenced” centromeres are produced by rare chromosomal translocations in which both initial centromeres end up on one chromosome (which has been called a “pseudodicentric” chromosome). Invariably, one of the centromeres is silenced and loses all centromere proteins, including CENP-A. In other examples in humans, centromere silencing (or loss through germline chromosomal rearrangement) at a normal chromosomal location has been accompanied by activation of a new centromere at a different position on the same chromosome, creating what is referred to as a neocentromere. Neocentromeres form at sites without the typical repetitive DNA found at the original centromeres and without any DNA sequence changes (Lo et al., 2001Lo A.W. Craig J.M. Saffery R. Kalitsis P. Irvine D.V. Earle E. Magliano D.J. Choo K.H. A 330 kb CENP-A binding domain and altered replication timing at a human neocentromere.EMBO J. 2001; 20: 2087-2096Crossref PubMed Scopus (114) Google Scholar). Even more remarkably, the locations of such neocentromeres are faithfully maintained through the human germline (Amor et al., 2004Amor D.J. Bentley K. Ryan J. Perry J. Wong L. Slater H. Choo K.H. Human centromere repositioning “in progress”.Proc. Natl. Acad. Sci. USA. 2004; 101: 6542-6547Crossref PubMed Scopus (152) Google Scholar, Depinet et al., 1997Depinet T.W. Zackowski J.L. Earnshaw W.C. Kaffe S. Sekhon G.S. Stallard R. Sullivan B.A. Vance G.H. Van Dyke D.L. Willard H.F. et al.Characterization of neo-centromeres in marker chromosomes lacking detectable alpha-satellite DNA.Hum. Mol. Genet. 1997; 6: 1195-1204Crossref PubMed Scopus (130) Google Scholar, du Sart et al., 1997du Sart D. Cancilla M.R. Earle E. Mao J.I. Saffery R. Tainton K.M. Kalitsis P. Martyn J. Barry A.E. Choo K.H. A functional neo-centromere formed through activation of a latent human centromere and consisting of non-alpha-satellite DNA.Nat. Genet. 1997; 16: 144-153Crossref PubMed Scopus (266) Google Scholar, Warburton et al., 1997Warburton P.E. Cooke C.A. Bourassa S. Vafa O. Sullivan B.A. Stetten G. Gimelli G. Warburton D. Tyler-Smith C. Sullivan K.F. et al.Immunolocalization of CENP-A suggests a distinct nucleosome structure at the inner kinetochore plate of active centromeres.Curr. Biol. 1997; 7: 901-904Abstract Full Text Full Text PDF PubMed Scopus (287) Google Scholar). Furthermore, centromeric chromatin can spread linearly along DNA (Maggert and Karpen, 2001Maggert K.A. Karpen G.H. The activation of a neocentromere in Drosophila requires proximity to an endogenous centromere.Genetics. 2001; 158: 1615-1628PubMed Google Scholar). It is poorly understood how epigenetic information encoded by chromatin at specific sites is retained during major chromosomal events, including DNA replication and transcription. Of these epigenetic marks, the centromere mark is the longest lived (i.e., through evolutionary timescales). Nevertheless, there is no consensus on what are the most crucial questions to address concerning the epigenetic basis of centromere identity: What is the structure of centromeric chromatin? What is the likely epigenetic mark? Or, how is that mark replicated and maintained through centromere DNA duplication? Instead, a set of seemingly inconsistent models for the structure of CENP-A-containing chromatin have been proposed (Camahort et al., 2009Camahort R. Shivaraju M. Mattingly M. Li B. Nakanishi S. Zhu D. Shilatifard A. Workman J.L. Gerton J.L. Cse4 is part of an octameric nucleosome in budding yeast.Mol. Cell. 2009; 35: 794-805Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar, Furuyama and Henikoff, 2009Furuyama T. Henikoff S. Centromeric nucleosomes induce positive DNA supercoils.Cell. 2009; 138: 104-113Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar, Lavelle et al., 2009Lavelle C. Recouvreux P. Wong H. Bancaud A. Viovy J.L. Prunell A. Victor J.M. Right-handed nucleosome: myth or reality?.Cell. 2009; 139 (author reply 1217–1218): 1216-1217Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar, Mizuguchi et al., 2007Mizuguchi G. Xiao H. Wisniewski J. Smith M.M. Wu C. Nonhistone Scm3 and histones CenH3-H4 assemble the core of centromere-specific nucleosomes.Cell. 2007; 129: 1153-1164Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar, Sekulic et al., 2010Sekulic N. Bassett E.A. Rogers D.J. Black B.E. The structure of (CENP-A-H4)2 reveals physical features that mark centromeres.Nature. 2010; 467: 347-351Crossref PubMed Scopus (160) Google Scholar, Williams et al., 2009Williams J.S. Hayashi T. Yanagida M. Russell P. Fission yeast Scm3 mediates stable assembly of Cnp1/CENP-A into centromeric chromatin.Mol. Cell. 2009; 33: 287-298Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar). Reconciling the disparate data on the structure of centromeric chromatin and generating testable models—two primary goals of this essay—are critical for understanding the molecular mechanisms that drive the self-propagation of the epigenetic mark underling centromere inheritance. Here we consider the merits (and weaknesses) of each model. Building on the discovery that in metazoans, the assembly of centromeric chromatin occurs only after exit from mitosis (i.e., half a cell cycle after centromeric DNA replication) (Jansen et al., 2007Jansen L.E. Black B.E. Foltz D.R. Cleveland D.W. Propagation of centromeric chromatin requires exit from mitosis.J. Cell Biol. 2007; 176: 795-805Crossref PubMed Scopus (424) Google Scholar, Schuh et al., 2007Schuh M. Lehner C.F. Heidmann S. Incorporation of Drosophila CID/CENP-A and CENP-C into centromeres during early embryonic anaphase.Curr. Biol. 2007; 17: 237-243Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar), we propose a model for cell-cycle-dependent maturation of centromeric nucleosomes. Perhaps the most central, unresolved question regarding replication of centromere identity is how CENP-A already assembled into centromeric chromatin is retained at centromeres as nucleosomes are disrupted by DNA polymerase and then reassembled onto each daughter centromere after replication. A second, related question is when during the cell cycle is CENP-A deposited at centromeres. Surprisingly, this deposition is not contemporaneous with DNA replication. Evidence in human cells (Jansen et al., 2007Jansen L.E. Black B.E. Foltz D.R. Cleveland D.W. Propagation of centromeric chromatin requires exit from mitosis.J. Cell Biol. 2007; 176: 795-805Crossref PubMed Scopus (424) Google Scholar) and fly embryos (Schuh et al., 2007Schuh M. Lehner C.F. Heidmann S. Incorporation of Drosophila CID/CENP-A and CENP-C into centromeres during early embryonic anaphase.Curr. Biol. 2007; 17: 237-243Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar) indicates that deposition of newly synthesized CENP-A onto centromeric DNA starts late in mitosis and extends through the G1 phase of the following cycle. Temporal separation of the assembly of new CENP-A chromatin from the replication of centromeric DNA raises the likelihood that distinct forms of centromeric chromatin exist during different portions of the cell cycle. In particular, the current evidence suggests that restoration of complete loading of CENP-A occurs in G1. However, after DNA replication in S phase, despite complete reloading of previously centromere-bound CENP-A, there are twice as many centromeres, resulting in half as many CENP-A at each centromere (Jansen et al., 2007Jansen L.E. Black B.E. Foltz D.R. Cleveland D.W. Propagation of centromeric chromatin requires exit from mitosis.J. Cell Biol. 2007; 176: 795-805Crossref PubMed Scopus (424) Google Scholar, Schuh et al., 2007Schuh M. Lehner C.F. Heidmann S. Incorporation of Drosophila CID/CENP-A and CENP-C into centromeres during early embryonic anaphase.Curr. Biol. 2007; 17: 237-243Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar). This CENP-A loading at half the maximal level persists through the G2 and mitosis phases. Such distinct forms of centromeric chromatin could include variations in the histone (or nonhistone) composition of nucleosomes or even alterations in higher-order chromatin structure. Regardless of the answers to these crucial questions, two steps must occur to separate the deposition of CENP-A at centromeres from pathways depositing bulk histones at noncentromeric chromatin: the sorting of newly synthesized CENP-A away from bulk H3 and the selective recognition of centromeric chromatin for assembling new CENP-A protein into it. Newly synthesized histones are thought to rapidly bind to their partners: H3 binds to H4 and H2A to H2B. In addition, prior to assembly, the histone complexes are bound by “chaperones” that prevent promiscuous association of the highly basic proteins with highly acidic nucleic acids (Ransom et al., 2010Ransom M. Dennehey B.K. Tyler J.K. Chaperoning histones during DNA replication and repair.Cell. 2010; 140: 183-195Abstract Full Text Full Text PDF PubMed Scopus (242) Google Scholar). The chaperone that sorts the (CENP-A:H4)2 heterotetramer away from bulk histone is called HJURP in humans (Dunleavy et al., 2009Dunleavy E.M. Roche D. Tagami H. Lacoste N. Ray-Gallet D. Nakamura Y. Daigo Y. Nakatani Y. Almouzni-Pettinotti G. HJURP is a cell-cycle-dependent maintenance and deposition factor of CENP-A at centromeres.Cell. 2009; 137: 485-497Abstract Full Text Full Text PDF PubMed Scopus (416) Google Scholar, Foltz et al., 2009Foltz D.R. Jansen L.E.T. Bailey A.O. Yates 3rd, J.R. Bassett E.A. Wood S. Black B.E. Cleveland D.W. Centromere specific assembly of CENP-A nucleosomes is mediated by HJURP.Cell. 2009; 137: 472-484Abstract Full Text Full Text PDF PubMed Scopus (421) Google Scholar) and Scm3 in budding (Camahort et al., 2007Camahort R. Li B. Florens L. Swanson S.K. Washburn M.P. Gerton J.L. Scm3 is essential to recruit the histone h3 variant cse4 to centromeres and to maintain a functional kinetochore.Mol. Cell. 2007; 26: 853-865Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar, Mizuguchi et al., 2007Mizuguchi G. Xiao H. Wisniewski J. Smith M.M. Wu C. Nonhistone Scm3 and histones CenH3-H4 assemble the core of centromere-specific nucleosomes.Cell. 2007; 129: 1153-1164Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar, Stoler et al., 2007Stoler S. Rogers K. Weitze S. Morey L. Fitzgerald-Hayes M. Baker R.E. Scm3, an essential Saccharomyces cerevisiae centromere protein required for G2/M progression and Cse4 localization.Proc. Natl. Acad. Sci. USA. 2007; 104: 10571-10576Crossref PubMed Scopus (151) Google Scholar) and fission (Pidoux et al., 2009Pidoux A.L. Choi E.S. Abbott J.K. Liu X. Kagansky A. Castillo A.G. Hamilton G.L. Richardson W. Rappsilber J. He X. et al.Fission yeast Scm3: A CENP-A receptor required for integrity of subkinetochore chromatin.Mol. Cell. 2009; 33: 299-311Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar, Williams et al., 2009Williams J.S. Hayashi T. Yanagida M. Russell P. Fission yeast Scm3 mediates stable assembly of Cnp1/CENP-A into centromeric chromatin.Mol. Cell. 2009; 33: 287-298Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar) yeasts. This chaperone is part of the pathway that couples CENP-A deposition to the cell cycle and targets CENP-A to centromeres. Human HJURP forms a complex with newly synthesized CENP-A protein (i.e., before it integrates into a nucleosome) by recognizing the CENP-A Targeting Domain (CATD) on the CENP-A:H4 tetramer (Foltz et al., 2009Foltz D.R. Jansen L.E.T. Bailey A.O. Yates 3rd, J.R. Bassett E.A. Wood S. Black B.E. Cleveland D.W. Centromere specific assembly of CENP-A nucleosomes is mediated by HJURP.Cell. 2009; 137: 472-484Abstract Full Text Full Text PDF PubMed Scopus (421) Google Scholar). The CATD consists of 22 amino acid substitutions within the classic histone fold domain (Black et al., 2004Black B.E. Foltz D.R. Chakravarthy S. Luger K. Woods V.L. Cleveland D.W. Structural determinants for generating centromeric chromatin.Nature. 2004; 430: 578-582Crossref PubMed Scopus (313) Google Scholar). When it is substituted into histone H3, it not only is sufficient to confer centromere targeting capabilities to H3 (Black et al., 2004Black B.E. Foltz D.R. Chakravarthy S. Luger K. Woods V.L. Cleveland D.W. Structural determinants for generating centromeric chromatin.Nature. 2004; 430: 578-582Crossref PubMed Scopus (313) Google Scholar), but it also enables the hybrid H3-CATD to maintain centromere function when CENP-A is reduced (Black et al., 2007bBlack B.E. Jansen L.E.T. Maddox P.S. Foltz D.R. Desai A.B. Shah J.V. Cleveland D.W. Centromere identity maintained by nucleosomes assembled with histone H3 containing the CENP-A targeting domain.Mol. Cell. 2007; 25: 309-322Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar). Substantial structural differences distinguish CENP-A:H4 from its histone counterpart, H3:H4. These include several alterations in surface-exposed side chains; a bulged loop (loop L1) that generates a different shape and oppositely charged surface as found on H3; a rigid interface with H4; and a rotated CENP-A:CENP-A interface that compacts the overall size of the (CENP-A:H4)2 heterotetramers (Sekulic et al., 2010Sekulic N. Bassett E.A. Rogers D.J. Black B.E. The structure of (CENP-A-H4)2 reveals physical features that mark centromeres.Nature. 2010; 467: 347-351Crossref PubMed Scopus (160) Google Scholar). Following incorporation into chromosomes, CENP-A must mark the chromatin as centromeric, thus distinguishing the centromere from the rest of the chromosome. One or a few nucleosomes with CENP-A substituting for the conventional H3 histone is apparently insufficient to generate a functional centromere, except in budding yeast in which a DNA sequence element is used for identifying centromeres (Figure 1). This view is built upon several observations. First, CENP-A accumulation at noncentromeric sites of DNA damage is transient (Zeitlin et al., 2009Zeitlin S.G. Baker N.M. Chapados B.R. Soutoglou E. Wang J.Y. Berns M.W. Cleveland D.W. Double-strand DNA breaks recruit the centromeric histone CENP-A.Proc. Natl. Acad. Sci. USA. 2009; 106: 15762-15767Crossref PubMed Scopus (104) Google Scholar). Second, when CENP-A is massively overproduced, it deposits onto chromosomal arms, but these sites only occasionally recruit one or more kinetochore components even when incorporated into expansive ectopic loci (Heun et al., 2006Heun P. Erhardt S. Blower M.D. Weiss S. Skora A.D. Karpen G.H. Mislocalization of the Drosophila centromere-specific histone CID promotes formation of functional ectopic kinetochores.Dev. Cell. 2006; 10: 303-315Abstract Full Text Full Text PDF PubMed Scopus (254) Google Scholar). Mechanisms that reinforce centromere identity probably rely on recognizing the foundational mark that CENP-A confers to nucleosomes. This could occur either by CENP-A nucleosomes recognizing other CENP-A nucleosomes in higher-order chromatin folding (Blower et al., 2002Blower M.D. Sullivan B.A. Karpen G.H. Conserved organization of centromeric chromatin in flies and humans.Dev. Cell. 2002; 2: 319-330Abstract Full Text Full Text PDF PubMed Scopus (404) Google Scholar, Ribeiro et al., 2010Ribeiro S.A. Vagnarelli P. Dong Y. Hori T. McEwen B.F. Fukagawa T. Flors C. Earnshaw W.C. A super-resolution map of the vertebrate kinetochore.Proc. Natl. Acad. Sci. USA. 2010; 107: 10484-10489Crossref PubMed Scopus (146) Google Scholar) or direct recognition of CENP-A-containing nucleosomes by other centromere components (Carroll et al., 2009Carroll C.W. Silva M.C.C. Godek K.M. Jansen L.E.T. Straight A.F. Centromere assembly requires the direct recognition of CENP-A nucleosomes by CENP-N.Nat. Cell Biol. 2009; 11: 896-902Crossref PubMed Scopus (192) Google Scholar, Carroll et al., 2010Carroll C.W. Milks K.J. Straight A.F. Dual recognition of CENP-A nucleosomes is required for centromere assembly.J. Cell Biol. 2010; 189: 1143-1155Crossref PubMed Scopus (212) Google Scholar). Recent studies have uncovered additional mechanisms that prevent CENP-A from stably incorporating into chromosome arms. For example, in the budding yeast, ubiquitination by the E3 ligase Psh1, which specifically recognizes CENP-A through the CATD (Ranjitkar et al., 2010Ranjitkar P. Press M.O. Yi X. Baker R. MacCoss M.J. Biggins S. An E3 ubiquitin ligase prevents ectopic localization of the centromeric histone H3 variant via the centromere targeting domain.Mol. Cell. 2010; 40: 455-464Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar), triggers subsequent degradation of CENP-A at noncentromeric locations (Hewawasam et al., 2010Hewawasam G. Shivaraju M. Mattingly M. Venkatesh S. Martin-Brown S. Florens L. Workman J.L. Gerton J.L. Psh1 is an E3 ubiquitin ligase that targets the centromeric histone variant Cse4.Mol. Cell. 2010; 40: 444-454Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar, Ranjitkar et al., 2010Ranjitkar P. Press M.O. Yi X. Baker R. MacCoss M.J. Biggins S. An E3 ubiquitin ligase prevents ectopic localization of the centromeric histone H3 variant via the centromere targeting domain.Mol. Cell. 2010; 40: 455-464Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar). Throughout the genome, epigenetic marks encoded by nucleosomes are generally thought to exist as posttranslational modifications of conventional histones, the incorporation of histone variants, or a combination of both. A major challenge has been to define how the variant CENP-A physically alters chromatin to specify and maintain centromere location on the chromosome. In fact, several recent studies have provided evidence that support seemingly contradictory models for the structure of chromatin containing CENP-A (Figure 2): (1) The most conventional view is of an octameric nucleosome with two copies of each histone, H2A, H2B, H4, and CENP-A (in place of H3) (Camahort et al., 2009Camahort R. Shivaraju M. Mattingly M. Li B. Nakanishi S. Zhu D. Shilatifard A. Workman J.L. Gerton J.L. Cse4 is part of an octameric nucleosome in budding yeast.Mol. Cell. 2009; 35: 794-805Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar, Conde e Silva et al., 2007Conde e Silva N. Black B.E. Sivolob A. Filipski J. Cleveland D.W. Prunell A. CENP-A-containing nucleosomes: easier disassembly versus exclusive centromeric localization.J. Mol. Biol. 2007; 370: 555-573Crossref PubMed Scopus (105) Google Scholar, Foltz et al., 2006Foltz D.R. Jansen L.E.T. Black B.E. Bailey A.O. Yates 3rd, J.R. Cleveland D.W. The human CENP-A centromeric nucleosome-associated complex.Nat. Cell Biol. 2006; 8: 458-469Crossref PubMed Scopus (492) Google Scholar, Palmer and Margolis, 1985Palmer D.K. Margolis R.L. Kinetochore components recognized by human autoantibodies are present on mononucleosomes.Mol. Cell. Biol. 1985; 5: 173-186Crossref PubMed Scopus (43) Google Scholar, Sekulic et al., 2010Sekulic N. Bassett E.A. Rogers D.J. Black B.E. The structure of (CENP-A-H4)2 reveals physical features that mark centromeres.Nature. 2010; 467: 347-351Crossref PubMed Scopus (160) Google Scholar, Shelby et al., 1997Shelby R.D. Vafa O. Sullivan K.F. Assembly of CENP-A into centromeric chromatin requires a cooperative array of nucleosomal DNA contact sites.J. Cell Biol. 1997; 136: 501-513Crossref PubMed Scopus (249) Google Scholar). As with conventional nucleosomes in noncentromeric chromatin, the DNA wraps around the histones with a left-hand twist (Sekulic et al., 2010Sekulic N. Bassett E.A. Rogers D.J. Black B.E. The structure of (CENP-A-H4)2 reveals physical features that mark centromeres.Nature. 2010; 467: 347-351Crossref PubMed Scopus (160) Google Scholar). (2) A tetrasome with two copies of CENP-A and H4 but lacking H2A:H2B dimers (Williams et al., 2009Williams J.S. Hayashi T. Yanagida M. Russell P. Fission yeast Scm3 mediates stable assembly of Cnp1/CENP-A into centromeric chromatin.Mol. Cell. 2009; 33: 287-298Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar). (3) A hemisome, or other non-nucleosomal complex assembled onto DNA, with one copy of each histone instead of the two copies found in conventional nucleosomes (Dalal et al., 2007Dalal Y. Wang H. Lindsay S. Henikoff S. Tetrameric structure of centromeric nucleosomes in interphase Drosophila cells.PLoS Biol. 2007; 5: e218Crossref PubMed Scopus (192) Google Scholar, Williams et al., 2009Williams J.S. Hayashi T. Yanagida M. Russell P. Fission yeast Scm3 mediates stable assembly of Cnp1/CENP-A into centromeric chromatin.Mol. Cell. 2009; 33: 287-298Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar). In addition, the DNA wraps around the histones with a right-hand twist instead of the traditional left-hand twist (Furuyama and Henikoff, 2009Furuyama T. Henikoff S. Centromeric nucleosomes induce positive DNA supercoils.Cell. 2009; 138: 104-113Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar). (4) An octameric “reversome” with the same stoichiometry as in a conventional nucleosome but with right-handed wrapping of DNA (Lavelle et al., 2009Lavelle C. Recouvreux P. Wong H. Bancaud A. Viovy J.L. Prunell A. Victor J.M. Right-handed nucleosome: myth or reality?.Cell. 2009; 139 (author reply 1217–1218): 1216-1217Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar). (5) A hexameric complex that resembles a nucleosome but in which H2A:H2B dimers are replaced by recruitment of two molecules of Scm3 (as proposed for the centromere of budding yeast) (Mizuguchi et al., 2007Mizuguchi G. Xiao H. Wisniewski J. Smith M.M. Wu C. Nonhistone Scm3 and histones CenH3-H4 assemble the core of centromere-specific nucleosomes.Cell. 2007; 129: 1153-1164Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar). (6) A trisome of Cse4, H4, and Scm3 (again proposed in budding yeast) with right-handed wrapping of DNA (Furuyama and Henikoff, 2009Furuyama T. Henikoff S. Centromeric nucleosomes induce positive DNA supercoils.Cell. 2009; 138: 104-113Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar). Several lines of evidence in diverse species support the conventional view that centromeric nucleosomes consist of the octameric configuration found elsewhere in the genome but with CENP-A replacing H3 (Figure 2A) (Camahort et al., 2009Camahort R. Shivaraju M. Mattingly M. Li B. Nakanishi S. Zhu D. Shilatifard A. Workman J.L. Gerton J.L. Cse4 is part of an octameric nucleosome in budding yeast.Mol. Cell. 2009; 35: 794-805Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar, Erhardt et al., 2008Erhardt S. Mellone B.G. Betts C.M. Zhang W. Karpen G.H. Straight A.F. Genome-wide analysis reveals a cell cycle-dependent mechanism controlling centromere propagation.J. Cell Biol. 2008; 183: 805-818Crossref PubMed Scopus (138) Google Scholar, Sekulic et al., 2010Sekulic N. Bassett E.A. Rogers D.J. Black B.E. The structure of (CENP-A-H4)2 reveals physical features that mark centromeres.Nature. 2010; 467: 347-351Crossref PubMed Scopus (160) Google Scholar, Shelby et al., 1997Shelby R.D. Vafa O. Sullivan K.F. Assembly of CENP-A into centromeric chromatin requires a cooperative array of nucleosomal DNA contact sites.J. Cell Biol. 1997; 136: 501-513Crossref PubMed Scopus (249) Google Scholar). In humans, for instance, CENP-A-containing chromatin isolated from cultured cells contains stoichiometric amounts of CENP-A, H4, H2A, and H2B, including two CENP-A molecules (Foltz et al., 2006Foltz D.R. Jansen L.E.T. Black B.E. Bailey A.O. Yates 3rd, J.R. Cleveland D.W. The human CENP-A centromeric nucleosome-associated complex.Nat. Cell Biol. 2006; 8: 458-469Crossref PubMed Scopus (492) Google Scholar, Shelby et al., 1997Shelby R.D. Vafa O. Sullivan K.F. Assembly of CENP-A into centromeric chromatin requires a cooperative array of nucleosomal DNA contact sites.J. Cell Biol. 1997; 136: 501-513Crossref PubMed Scopus (249) Google Scholar). Octameric nucleosomes are also readily reconstituted from purified components (Black et al., 2007aBlack B.E. Brock M.A. Bédard S. Woods V.L. Cleveland D.W. An epigenetic mark generated by the incorporation of CENP-A into centromeric nucleosomes.Proc. Natl. Acad. Sci. 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