The Flexible Ends of CENP-A Nucleosome Are Required for Mitotic Fidelity

Roulland, Yohan; Ouararhni, Khalid; Naidenov, Mladen; Ramos, Lorrie; Shuaib, Muhammad; Syed, Sajad Hussain; Lone, Imtiaz Nisar; Boopathi, Ramachandran; Fontaine, Emeline; Pápai, Gábor; Tachiwana, Hiroaki; Gautier, Thierry; Skoufias, Dimitrios A.; Padmanabhan, Kiran; Bednář, Jan; Kurumizaka, Hitoshi; Schultz, Patrick; Angelov, Dimitar; Hamiche, Ali; Dimitrov, Stéfan

doi:10.1016/j.molcel.2016.06.023

Cited by 83 publications

(100 citation statements)

References 40 publications

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“…We employed a well-established approach for nucleosomes424344, recently extended to CENP-A nucleosomes assembled with a synthetic positioning sequence45 that employs hydroxyl radical-mediated cleavage of DNA. We used the same natural CENP-A nucleosome-positioning sequence from human centromeres1146 used in our HXMS experiments, but where it is end-labelled20 for hydroxyl radical footprinting (Fig.…”

Section: Resultsmentioning

confidence: 99%

Centromeres are maintained by fastening CENP-A to DNA and directing an arginine anchor-dependent nucleosome transition

et al. 2017

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Maintaining centromere identity relies upon the persistence of the epigenetic mark provided by the histone H3 variant, centromere protein A (CENP-A), but the molecular mechanisms that underlie its remarkable stability remain unclear. Here, we define the contributions of each of the three candidate CENP-A nucleosome-binding domains (two on CENP-C and one on CENP-N) to CENP-A stability using gene replacement and rapid protein degradation. Surprisingly, the most conserved domain, the CENP-C motif, is dispensable. Instead, the stability is conferred by the unfolded central domain of CENP-C and the folded N-terminal domain of CENP-N that becomes rigidified 1,000-fold upon crossbridging CENP-A and its adjacent nucleosomal DNA. Disrupting the ‘arginine anchor' on CENP-C for the nucleosomal acidic patch disrupts the CENP-A nucleosome structural transition and removes CENP-A nucleosomes from centromeres. CENP-A nucleosome retention at centromeres requires a core centromeric nucleosome complex where CENP-C clamps down a stable nucleosome conformation and CENP-N fastens CENP-A to the DNA.

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Section: Resultsmentioning

confidence: 99%

Centromeres are maintained by fastening CENP-A to DNA and directing an arginine anchor-dependent nucleosome transition

et al. 2017

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“…It has been suggested that the centromeric H3 variant CENP-A might not need histone H1 to interact with the linker DNA, as CENP-A contains a conserved domain that shows highly similarity with motifs present on the H1 tails. The results of the recent study by Roulland et al confirms these suggestions as they show a low binding affinity between CENP-A and H1 as a result of the flexible histone tails of CENP-A (Roulland et al, 2016). …”

Section: Mitotic Bookmarking and Epigenetic Memorymentioning

confidence: 61%

“…A recent study by Roulland et al showed the importance of the flexible tails of CENP-A in mitosis. When the flexible tail of CENP-A is switched with the more rigid tail of the canonical H3, several kinetochore proteins dislocate and severe mitotic and cytokinetic defects like aneuploidy are observed (Roulland et al, 2016). Although DNA sequences in centromeres have been shown not to be conserved, the centromeric H3 histone variant shows high levels of similarity across species (Cheeseman et al, 2004).…”

Section: Mitotic Bookmarking and Epigenetic Memorymentioning

confidence: 99%

Epigenetic characteristics of the mitotic chromosome in 1D and 3D

Oomen

Dekker

2017

Critical Reviews in Biochemistry and Molecular Biology

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While chromatin characteristics in interphase are widely studied, characteristics of mitotic chromatin and their inheritance through mitosis are still poorly understood. During mitosis chromatin undergoes dramatic changes: Transcription stalls, chromatin binding factors leave the chromatin, histone modifications change and chromatin becomes highly condensed. Many key insights into mitotic chromosome state and conformation have come from extensive microscopy studies over the last century. Over the last decade the development of 3C-based techniques has enabled the study of higher order chromosome organization during mitosis in a genome-wide manner. During mitosis chromosomes lose their cell type specific and locus-dependent chromatin organization that characterizes interphase chromatin and fold into randomly positioned loop arrays. Upon exit of mitosis cells are capable of quickly rearranging the chromosome conformation to form the cell type specific interphase organization again. The information that enables this rearrangement after mitotic exit is thought to be encoded at least in part in mitotic bookmarks, e.g. histone modifications and variants, histone remodelers, chromatin factors and non-coding RNA. Here we give an overview of the chromosomal organization and epigenetic characteristics of the interphase and mitotic chromatin in vertebrates. Second, we describe different ways in which mitotic bookmarking enables epigenetic memory of the features of the interphase chromatin through mitosis. And third, we explore the role of epigenetic modifications and mitotic bookmarking in cell differentiation.

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“…The incorporation of different species of histone variants into nucleosomes provides further differentiation and epigenetic chromatin diversity [1, 8]. The differentiation and specific functions of chromatin directed by a histone variant is especially conspicuous at centromeres, where the H3 variant, CENP-A, is assembled into specialized nucleosomes that form the foundation for the kinetochore assembly [9–11]. The crystal structure of CENP-A revealed that it is quite similar to the structure of histone H3 variants and consists of an unstructured amino terminal αN-helix, α1 helix, Loop1, β1-sheet, β2-sheet, α2 helix, and α3-helix [12].…”

Section: Introductionmentioning

confidence: 99%

“…A domain found in the HFD of CENP-A, called the CENP-A targeting domain (CATD), mediates the specific interaction of CENP-A with HJURP and to date is the only domain identified essential for CENP-A centromeric localization [28]. Some modifications in the amino-terminus of CENP-A have recently been identified as regulatory signals for its centromeric targeting and chromosome segregation [9, 13, 29, 30]. However, the role of the amino-terminus of CENP-A is poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Motifs in the amino-terminus of CENP-A are required for its accumulation within the nucleus and at the centromere

Jing¹,

Xi²,

Leng³

et al. 2017

Oncotarget

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Centromere protein A (CENP-A) is a variant of core histone H3 that marks the centromere's location on the chromosome. The mechanisms that target the protein to the nucleus and the centromere have not been defined. In this study, we found that deletion of the first 53 but not the first 29 residues of CENP-A from the amino-terminus, resulted in its cytoplasmic localization. Two motifs, R42R43R44 and K49R52K53K56, which are reported to be required for DNA contact in the centromere nucleosome, were found to be critical for CENP-A nuclear accumulation. These two motifs potentially mediated its interaction with Importin-β but were not involved in CENP-A centromeric localization. A third novel motif, L60L61I62R63K64, was found to be essential for the centromeric accumulation of CENP-A. The nonpolar hydrophobic residues L60L61I62, but not the basic residues R63K64, were found to be the most important residues. A protein interaction assay suggested that this motif is not involved in the interaction of CENP-A with its deposition factors but potentially mediates its interaction with core histone H4 and CENP-B. Our study uncovered the role of the amino-terminus of CENP-A in localization.

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The Flexible Ends of CENP-A Nucleosome Are Required for Mitotic Fidelity

Cited by 83 publications

References 40 publications

Centromeres are maintained by fastening CENP-A to DNA and directing an arginine anchor-dependent nucleosome transition

Centromeres are maintained by fastening CENP-A to DNA and directing an arginine anchor-dependent nucleosome transition

Epigenetic characteristics of the mitotic chromosome in 1D and 3D

Motifs in the amino-terminus of CENP-A are required for its accumulation within the nucleus and at the centromere

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