Kinetochore components recognized by human autoantibodies are present on mononucleosomes.

Palmer, Douglas K.; Margolis, Robert L.

doi:10.1128/mcb.5.1.173

Cited by 58 publications

(41 citation statements)

References 41 publications

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“…The single exception had a predominance of IgG3 antibody (55% of total). This is the same serum that apparently failed to bind staphylococcal protein A in immunoblots (lo), and is similar to a previously described serum sample that contained mainly IgG3 antikinetochore (11). In 16 of the sera, IgGl represented more than 95% of the total IgG ACA, and in 28 sera, IgG1 represented at least 90%.…”

supporting

confidence: 83%

Isotype analysis of the anti–CENP‐B anticentromere autoantibody: Evidence for restricted clonality

Eisenberg

Earnshaw

Bordwell

et al. 1989

Arthritis & Rheumatism

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Utilizing the centromere B fusion protein (CENP-B) and specific, matched monoclonal antiisotype reagents in an enzyme-linked immunosorbent assay, we found that anti-CENP-B autoantibodies were skewed to the IgGl isotype. The overall K : A light chain ratio was 2: I, although several individual sera showed a strong predominance of one of the light chains. Isoelectric focusing of light chain-skewed sera showed polyclonal patterns. Our findings are consistent with the anti-CENP-B autoantibody response being a chronic, antigen-driven response.Autoantibodies to centromere proteins (ACA) are characteristic of the CREST (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasias) variant of scleroderma and are associated particularly with Raynaud's phenomenon (1). Immunoblotting analysis has indicated that ACA recognize 3 chromosomal peptides: 17-19 kd From the

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supporting

confidence: 83%

Isotype analysis of the anti–CENP‐B anticentromere autoantibody: Evidence for restricted clonality

Eisenberg

Earnshaw

Bordwell

et al. 1989

Arthritis & Rheumatism

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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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“…Indirect immunofluorescence staining was performed on fixed HeLa cells using methods described previously (Palmer and Margolis 1985). Briefly, cells were fixed with paraformaldehyde, permeabilized with Triton X-100, blocked with bovine serum albumin, and incubated with affinity-purified anti-Max or polyclonal anti-Myc sera.…”

Section: Nuclear Localizationmentioning

confidence: 99%

Myc and Max associate in vivo.

Blackwood¹,

Lüscher²,

Eisenman³

1992

Genes Dev.

395

313

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Max is a helix-loop-helix zipper protein that associates in vitro with Myc family proteins to form a sequence-specific DNA-binding complex. We show here, by means of a coimmunoprecipitation assay with anti-Myc and anti-Max antibodies, that Myc and Max are associated in vivo and essentially all of the newly synthesized Myc can be detected in a complex with Max. This complex possesses specific DNA-binding activity for CACGTG-containing oligonucleotides. Although Max itself is a highly stable protein, Myc is rapidly degraded during or after its association with Max. In vivo Max is shown to be a nuclear protein phosphorylated by casein kinase II, and alternatively spliced forms of Max are expressed in cells. Furthermore, the levels of Max expression are equivalent in quiescent, mitogen-stimulated, and cycling cells. We conclude that the highly regulated rate of Myc biosynthesis is likely to be a limiting step in the formation of Myc:Max complexes.

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Kinetochore components recognized by human autoantibodies are present on mononucleosomes.

Cited by 58 publications

References 41 publications

Isotype analysis of the anti–CENP‐B anticentromere autoantibody: Evidence for restricted clonality

Isotype analysis of the anti–CENP‐B anticentromere autoantibody: Evidence for restricted clonality

Hierarchical Inactivation of a Synthetic Human Kinetochore by a Chromatin Modifier

Myc and Max associate in vivo.

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