Human centromere protein A (CENP-A) can replace histone H3 in nucleosome reconstitution
            <i>in vitro</i>

Yoda, Kinya; Ando, Satoshi; Morishita, Setsuo; Houmura, Kenichi; Hashimoto, Keiji; Takeyasu, Kunio; Okazaki, Tuneko

doi:10.1073/pnas.130189697

Cited by 215 publications

(188 citation statements)

References 44 publications

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“…In model 1 (Figure 6B), the kinetochore is built on a chromatin foundation of CENP-A nucleosomes (Palmer and Margolis, 1985;Palmer et al, 1991;Yoda et al, 2000;Black et al, 2007;Dalal et al, 2007;reviewed in Carroll and Straight, 2006;Cheeseman and Desai, 2008;Vagnarelli et al, 2008). In this model, eviction of CENP-A or prevention of its targeting caused by chromatin modifiers would disrupt the foundation for the kinetochore as a primary effect, and the structure would subsequently fall apart.…”

Section: Discussionmentioning

confidence: 99%

Hierarchical Inactivation of a Synthetic Human Kinetochore by a Chromatin Modifier

Cardinale

Bergmann

Kelly

et al. 2009

MBoC

114

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We previously used a human artificial chromosome (HAC) with a synthetic kinetochore that could be targeted with chromatin modifiers fused to tetracycline repressor to show that targeting of the transcriptional repressor tTS within kinetochore chromatin disrupts kinetochore structure and function. Here we show that the transcriptional corepressor KAP1, a downstream effector of the tTS, can also inactivate the kinetochore. The disruption of kinetochore structure by KAP1 subdomains does not simply result from loss of centromeric CENP-A nucleosomes. Instead it reflects a hierarchical disruption of the outer kinetochore, with CENP-C levels falling before CENP-A levels and, in certain instances, CENP-H being lost more readily than CENP-C. These results suggest that this novel approach to kinetochore dissection may reveal new patterns of protein interactions within the kinetochore. INTRODUCTIONThe centromere/kinetochore is one of the most complex cellular substructures, with more than 80 protein components described to date (reviewed in Carroll and Straight, 2006;Cheeseman and Desai, 2008;Fukagawa, 2008;Vagnarelli et al., 2008). These components perform the complex job of attaching chromosomes to the mitotic spindle; ensuring that those attachments are correct; signaling to delay mitotic progression if they are not, and regulating the movements of the chromosomes toward the spindle poles in anaphase.The kinetochore is assembled at a unique locus on each natural chromosome. However, for organisms with regional centromeres (Pluta et al., 1995), this reflects only a preference¤, and not an absolute requirement for particular DNA sequences. Kinetochores can form on a wide range of singlecopy and repeated DNA sequences, leading to the conclusion that the ultimate determinants of kinetochore assembly are epigenetic. The long-term purpose of our studies is to determine the epigenetic "landscape" that promotes kinetochore assembly and its maintenance during cell divisions.Experiments including yeast genetics, RNA interference (RNAi) studies in mammalian cells, and gene knockout analysis in mouse and chicken DT40 cells have revealed that kinetochores assemble on a foundation of specialized chromatin containing the kinetochore-specific histone H3 variant CENP-A (Earnshaw and Rothfield, 1985). CENP-A is upstream of almost all other known components in the kinetochore assembly pathway. However, that pathway is multiplex, as recent studies in chicken and Drosophila show that inner kinetochore proteins CENP-H and -C are required for normal CENP-A loading or retention (Okada et al., 2006;Goshima et al., 2007;Erhardt et al., 2008).Our work was inspired by an approach first developed a number of years ago in which cloned fragments of human centromeric DNA were used to form human artificial chromosomes (HACs) in HT1080 fibrosarcoma cells (Harrington et al., 1997;Ikeno et al., 1998). Originally, HAC formation was only achieved with regular repeated arrays of ␣-satellite DNA containing CENP-B boxes Ohzeki et al., 2002;Okada et al., 2007)....

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Section: Discussionmentioning

confidence: 99%

Hierarchical Inactivation of a Synthetic Human Kinetochore by a Chromatin Modifier

Cardinale

Bergmann

Kelly

et al. 2009

MBoC

114

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“…In centromeric chromatin, CENP-A substitutes for histone H3 in the nucleosome (Yoda et al 2000), and CENP-A was recently found to be overexpressed and mislocalized in primary human colorectal tumors, suggesting a link between CENP-A deregulation and aneuploidy (Tomonaga et al 2003). Other histone variants directly influence transcriptional activity.…”

Section: Variant Histonesmentioning

confidence: 99%

Epigenetics and cancer

Lund¹,

Lohuizen²

2004

Genes Dev.

442

318

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Epigenetic mechanisms act to change the accessibility of chromatin to transcriptional regulation locally and globally via modifications of the DNA and by modification or rearrangement of nucleosomes. Epigenetic gene regulation collaborates with genetic alterations in cancer development. This is evident from every aspect of tumor biology including cell growth and differentiation, cell cycle control, DNA repair, angiogenesis, migration, and evasion of host immunosurveillance. In contrast to genetic cancer causes, the possibility of reversing epigenetic codes may provide new targets for therapeutic intervention.Epigenetic programming is crucial in mammalian development, and stable inheritance of epigenetic settings is essential for the maintenance of tissue-and cell-typespecific functions (Li 2002). With the exception of controlled genomic rearrangements, such as those of the immunoglobulin and T-cell receptor genes in B and T cells, all other differentiation processes are initiated or maintained through epigenetic processes. Not surprisingly therefore, epigenetic gene regulation is characterized overall by a high degree of integrity and stability. Evidence is accumulating that suggests that the intrinsic stability is caused by multiple interlocking feedback mechanisms between functionally unrelated epigenetic layers, such as DNA methyltransferases (DNMTs) and histone modifying enzymes, resulting in the stable commitment of a locus to a particular activity state. In somatic cells, the transcriptional status of most genes is epigenetically fixed. However, other genes, such as cell cycle checkpoint genes and genes directly affected by exogenous stimuli such as growth factors or cell-cell contact, likely reside in a balanced state sensitive to dynamic adjustments in histone modifications, thereby allowing for rapid responses to specific stimuli. Perturbation of epigenetic balances may lead to alterations in gene expression, ultimately resulting in cellular transformation and malignant outgrowth; the involvement of deregulated epigenetic mechanisms in cancer development has received increased attention in recent years.Per definition, epigenetic regulators alter the activities and abilities of a cell without directly affecting and mutating the sequence of the DNA. In this review, we deal with epigenetic gene regulation as imposed by DNA methylation, covalent modifications of the canonical core histones, deposition of variant histone proteins, local nucleosome remodeling, and long-range epigenetic regulators. Understanding the molecular details behind "epigenetic cancer diseases" holds potentially important prospects for medical treatment, as it allows for novel strategies for drug development. A number of recent reviews have provided details on epigenetic mechanisms and their involvement in cancer, and we refer to these for more in-depth information on individual epigenetic mechanisms

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“…The above-mentioned results raise the question of how the CPC targets to the centromere. The histone H3 variant CENP-A that defines the centromere (Earnshaw and Rothfield, 1985;Howman et al, 2000;Yoda et al, 2000) has been implicated in this process. A recent study reported that human CENP-A phosphorylated by Aurora A at serine 7 is required to restrict Aurora B to the centromere (Kunitoku et al, 2003).…”

Section: Cpc Loading Onto the Centromere Is Independent Of Cenp-a Andmentioning

confidence: 99%

Centromere Targeting of the Chromosomal Passenger Complex Requires a Ternary Subcomplex of Borealin, Survivin, and the N-Terminal Domain of INCENP

Klein

Nigg

Grüneberg

2006

MBoC

164

170

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The chromosomal passenger complex (CPC), consisting of the serine/threonine kinase Aurora B, the inner centromere protein INCENP, Survivin, and Borealin/DasraB, has essential functions at the centromere in ensuring correct chromosome alignment and segregation. Despite observations that small interfering RNA-mediated knockdown of any one member of the CPC abolishes localization of the other subunits, it remains unclear how the complex is targeted to the centromere. We have now identified a ternary subcomplex of the CPC comprising Survivin, Borealin, and the N-terminal 58 amino acids of INCENP in vitro and in vivo. This subcomplex was found to be essential and sufficient for targeting to the centromere. Notably, Aurora B kinase, the enzymatic core of the CPC, was not required for centromere localization of the subcomplex. We demonstrate that CPC targeting to the centromere does not depend on CENP-A and hMis12, two core components for kinetochore/centromere assembly, and provide evidence that the CPC may be directed to centromeric DNA directly via the Borealin subunit. Our findings thus establish a functional module within the CPC that assembles on the N terminus of INCENP and controls centromere recruitment.

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Human centromere protein A (CENP-A) can replace histone H3 in nucleosome reconstitution in vitro

Cited by 215 publications

References 44 publications

Hierarchical Inactivation of a Synthetic Human Kinetochore by a Chromatin Modifier

Hierarchical Inactivation of a Synthetic Human Kinetochore by a Chromatin Modifier

Epigenetics and cancer

Centromere Targeting of the Chromosomal Passenger Complex Requires a Ternary Subcomplex of Borealin, Survivin, and the N-Terminal Domain of INCENP

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