Epigenetic regulation of centromere formation and kinetochore functionThis paper is one of a selection of papers published in this Special Issue, entitled 27th International West Coast Chromatin and Chromosome Conference, and has undergone the Journal's usual peer review process.

Department of Oncology, University of Alberta, Edmonton, AB T6G 1Z2, Canada.
Biochemistry and Cell Biology (Impact Factor: 2.15). 09/2006; 84(4):605-18. DOI: 10.1139/o06-080
Source: PubMed


In the midst of an increasingly detailed understanding of the molecular basis of genome regulation, we still only vaguely understand the relationship between molecular biochemistry and the structure of the chromatin inside of cells. The centromere is a structurally and functionally unique region of each chromosome and provides an example in which the molecular understanding far exceeds the understanding of the structure and function relationships that emerge on the chromosomal scale. The centromere is located at the primary constriction of the chromosome. During entry into mitosis, the centromere specifies the assembly site of the kinetochore, the structure that binds to microtubules to enable transport of the chromosomes into daughter cells. The epigenetic contributions to the molecular organization and function of the centromere are reviewed in the context of structural mechanisms of chromatin function.

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Available from: Michael Hendzel, Sep 12, 2014
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    • "The function of HP1 is highly important in the establishment, propagation and maintenance of constitutive heterochromatin,58 especially at the pericentromeric region that has been demonstrated to be enriched in the H3K9me3 and H4K20me3 marks, hypoacetylated histones H3 and H4, and highly methylated regions along the satellites repeats.59,60 Due to its juxtaposition next to centromeric chromatin, it has been suggested that the organization and stability of the pericentromeric region is crucial to ensuring correct chromosomal segregation during mitosis; therefore, this region is important for genome stability.59,61 "
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    ABSTRACT: The centromere is a key region for cell division where the kinetochore assembles, recognizes and attaches to microtubules so that each sister chromatid can segregate to each daughter cell. The centromeric chromatin is a unique rigid chromatin state promoted by the presence of the histone H3 variant CENP-A, in which epigenetic histone modifications of both heterochromatin or euchromatin states and associated protein elements are present. Although DNA sequence is not regarded as important for the establishment of centromere chromatin, it has become clear that this structure is formed as a result of a highly regulated epigenetic event that leads to the recruitment and stability of kinetochore proteins. We describe an integrative model for epigenetic processes that conform regional chromatin interactions indispensable for the recruitment and stability of kinetochore proteins. If alterations of these chromatin regions occur, chromosomal instability is promoted, although segregation may still take place.
    Epigenetics: official journal of the DNA Methylation Society 01/2012; 7(1):3-13. DOI:10.4161/epi.7.1.18504 · 4.78 Impact Factor
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    • "Studies on model organisms such as Saccharomyces cerevisiae and Caenorhabditis elegans as well as cultured human cells have, however, revealed a number of key kinetochore components and how they are assembled [3]-[9]. We now know that centromeric chromatin is required for the epigenetic mechanisms that specify centromere position [10]–[14]. In metazoans, centromeric DNA binds to nucleosomes in which the histone H3 is replaced with the histone H3 variant CENP-A (or CID in Drosophila) [15], [16], which then associate with two major centromeric multi-protein complexes known as the CENP-A nucleosome associated complex (NAC) and CENP-A distal complex (CAD) [17], [18]. "
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    ABSTRACT: Kinetochores are large multiprotein complexes indispensable for proper chromosome segregation. Although Drosophila is a classical model organism for studies of chromosome segregation, little is known about the organization of its kinetochores. We employed bioinformatics, proteomics and cell biology methods to identify and analyze the interaction network of Drosophila kinetochore proteins. We have shown that three Drosophila proteins highly diverged from human and yeast Ndc80, Nuf2 and Mis12 are indeed their orthologues. Affinity purification of these proteins from cultured Drosophila cells identified a further five interacting proteins with weak similarity to subunits of the SPC105/KNL-1, MIND/MIS12 and NDC80 kinetochore complexes together with known kinetochore associated proteins such as dynein/dynactin, spindle assembly checkpoint components and heterochromatin proteins. All eight kinetochore complex proteins were present at the kinetochore during mitosis and MIND/MIS12 complex proteins were also centromeric during interphase. Their down-regulation led to dramatic defects in chromosome congression/segregation frequently accompanied by mitotic spindle elongation. The systematic depletion of each individual protein allowed us to establish dependency relationships for their recruitment onto the kinetochore. This revealed the sequential recruitment of individual members of first, the MIND/MIS12 and then, NDC80 complex. The Drosophila MIND/MIS12 and NDC80 complexes and the Spc105 protein, like their counterparts from other eukaryotic species, are essential for chromosome congression and segregation, but are highly diverged in sequence. Hierarchical dependence relationships of individual proteins regulate the assembly of Drosophila kinetochore complexes in a manner similar, but not identical, to other organisms.
    PLoS ONE 02/2007; 2(5):e478. DOI:10.1371/journal.pone.0000478 · 3.23 Impact Factor
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    ABSTRACT: The specificity of RNA silencing is conferred by small RNA guides that are processed from structured RNA or dsRNA. The core components for small RNA biogenesis and effector functions have proliferated and specialized in eukaryotic lineages, resulting in diversified pathways that control expression of endogenous and exogenous genes, invasive elements and viruses, and repeated sequences. Deployment of small RNA pathways for spatiotemporal regulation of the transcriptome has shaped the evolution of eukaryotic genomes and contributed to the complexity of multicellular organisms.
    Nature Reviews Genetics 12/2007; 8(11):884-96. DOI:10.1038/nrg2179 · 36.98 Impact Factor
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