Crystal structure and stable property of the cancer-associated heterotypic nucleosome containing CENP-A and H3.3

Arimura, Yasuhiro; Shirayama, Kazuyoshi; Horikoshi, Naoki; Fujita, Ryosuke; Taguchi, Hiroyuki; Kagawa, Wataru; Fukagawa, Tatsuo; Almouzni, Geneviève; Kurumizaka, Hitoshi

doi:10.1038/srep07115

Cited by 64 publications

(86 citation statements)

References 40 publications

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“…CENP-A binds to HJURP during the G1 and G2 phases but not during the S phase (Bui et al, 2012). However, the current model of interconversion between tetrameric and octameric CENP-A nucleosomes in the cell cycle remains controversial (Fukagawa and Earnshaw, 2014; Hasson et al, 2013; Miell et al, 2013; Padeganeh et al, 2013), although the structures of the homotypic and heterotypic CENP-A particles have been solved (Arimura et al, 2014; Tachiwana et al, 2011). Therefore, we provide two models of epigenetic inheritance of CENP-A ubiquitylation: a tetramer model (Figure 7A) and an octamer model (Figure 7B).…”

Section: Discussionmentioning

confidence: 99%

“…At these ectopic loci, CENP-A forms heterotypic nucleosomes (CENP-A/H3.3) occluding CTCF binding, and their presence may increase DNA damage tolerance in cancer cells (Lacoste et al, 2014). Arimura et al revealed a “hybrid” structure of the heterotypic CENP-A/H3.3 and suggested that the stable existence of the CENP-A/H3.3 nucleosome may cause ectopic kinetochore assembly (Arimura et al, 2014), which could lead to neocentromere formation and chromosome instability in cancer cells (Biermann et al, 2007; Lacoste et al, 2014; McGovern et al, 2012; Tomonaga et al, 2003; Wu et al, 2012). Our models of epigenetic inheritance of CENP-A ubiquitylation suggest that errors in CENP-A targeting, heterodimerization, and/or ubiquitylation induce abnormal accumulation of heterotypic nucleosomes (Figure 7B, bottom).…”

Section: Discussionmentioning

confidence: 99%

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CENP-A Ubiquitylation Is Inherited through Dimerization between Cell Divisions

Niikura

Kitagawa

2016

Cell Reports

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SUMMARY The presence of chromatin containing the histone H3 variant CENP-A dictates the location of the centromere in a DNA sequence–independent manner. But the mechanism by which centromere inheritance occurs is largely unknown. We previously reported that CENP-A K124 ubiquitylation, mediated by CUL4A-RBX1-COPS8 E3 ligase activity, is required for CENP-A deposition at the centromere. Here we show that pre-existing ubiquitylated CENP-A is necessary for recruitment of newly synthesized CENP-A to the centromere and that CENP-A ubiquitylation is inherited between cell divisions. In vivo and in vitro analyses using dimerization mutants and dimerization domain fusion mutants revealed that the inheritance of CENP-A ubiquitylation requires CENP-A dimerization. Therefore, we propose models in which CENP-A ubiquitylation is inherited and, through dimerization, determines centromere location. Consistent with this model is our finding that overexpression of a monoubiquitin-fused CENP-A mutant induces neocentromeres at noncentromeric regions of chromosomes.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

CENP-A Ubiquitylation Is Inherited through Dimerization between Cell Divisions

Niikura

Kitagawa

2016

Cell Reports

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“…It has been documented that CENP-A can form a heterotypic particle with H3.3 ). Furthermore, it had been shown recently that the heterotypic CENP-A/H3.3 nucleosome forms an unexpectedly stable structure as compared with the CENP-A nucleosome (Arimura et al 2014). Previously, we reported that incorporation of H3.3 can prevent the compaction of the chromatin fiber (Chen et al 2013); thus, we hypothesized that the dynamics of H3.3 at centromeres play important roles in the regulation of the higher-order organization of centromeric chromatin during the cell cycle.…”

Section: Cenp-a Chromatin Displays a Distinct Higher-order Organizationmentioning

confidence: 91%

“…Two recent crystallographic studies of CENP-A homotypic and CENP-A/H3.3 heterotypic nucleosomes revealed that, in comparison with H3.1 and H3.3, the αN helix of CENP-A is shorter, which results in a weaker interaction between DNA at the entry/exit site of CENP-A nucleosomes and histone cores and leads to an open conformation of the linker DNA (Luger et al 1997;Tachiwana et al 2011;Arimura et al 2014). In addition, a lysine in place of H3R49 in CENP-A probably results in a less protected αN helix of CENP-A, which consequently increases the flexibility of the linker DNA at the entry/exit sites of CENP-A nucleosomes (Conde e Silva et al 2007;Panchenko et al 2011).…”

Section: Cenp-a Chromatin Displays a Distinct Higher-order Organizationmentioning

confidence: 99%

Structural transitions of centromeric chromatin regulate the cell cycle-dependent recruitment of CENP-N

et al. 2015

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Specific recognition of centromere-specific histone variant CENP-A-containing chromatin by CENP-N is an essential process in the assembly of the kinetochore complex at centromeres prior to mammalian cell division. However, the mechanisms of CENP-N recruitment to centromeres/kinetochores remain unknown. Here, we show that a CENP-A-specific RG loop (Arg80/Gly81) plays an essential and dual regulatory role in this process. The RG loop assists the formation of a compact "ladder-like" structure of CENP-A chromatin, concealing the loop and thus impairing its role in recruiting CENP-N. Upon G1/S-phase transition, however, centromeric chromatin switches from the compact to an open state, enabling the now exposed RG loop to recruit CENP-N prior to cell division. Our results provide the first insights into the mechanisms by which the recruitment of CENP-N is regulated by the structural transitions between compaction and relaxation of centromeric chromatin during the cell cycle.

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“…During energy minimization of this constructed region, one residue in the n-terminus and c-terminus directions was unconstrained. Additionally, heterogen selenomethionine residues were altered to methionine through a single-atom mutation from Se to S. As a control, the 146 base-pair α-satellite DNA of PDB ID: 3WTP [61] was aligned onto 3AN2 using the CE algorithm [62] of PyMOL [63]. To further study the effect of acetylation on CENP-C binding, the CENP-C fragment [27] was docked onto each system using the CE algorithm [62] and simulated for an additional microsecond retaining identical simulation protocols.…”

Section: Methodsmentioning

confidence: 99%

Internal modifications in the CENP-A nucleosome modulate centromeric dynamics

Bui

Pitman

Nuccio³

et al. 2017

Epigenetics & Chromatin

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BackgroundPosttranslational modifications of core histones are correlated with changes in transcriptional status, chromatin fiber folding, and nucleosome dynamics. However, within the centromere-specific histone H3 variant CENP-A, few modifications have been reported, and their functions remain largely unexplored. In this multidisciplinary report, we utilize in silico computational and in vivo approaches to dissect lysine 124 of human CENP-A, which was previously reported to be acetylated in advance of replication.ResultsComputational modeling demonstrates that acetylation of K124 causes tightening of the histone core and hinders accessibility to its C-terminus, which in turn diminishes CENP-C binding. Additionally, CENP-A K124ac/H4 K79ac containing nucleosomes are prone to DNA sliding. In vivo experiments using a CENP-A acetyl or unacetylatable mimic (K124Q and K124A, respectively) reveal alterations in CENP-C levels and a modest increase in mitotic errors. Furthermore, mutation of K124 results in alterations in centromeric replication timing. Purification of native CENP-A proteins followed by mass spectrometry analysis reveals that while CENP-A K124 is acetylated at G1/S, it switches to monomethylation during early S and mid-S phases. Finally, we provide evidence implicating the histone acetyltransferase (HAT) p300 in this cycle.ConclusionsTaken together, our data suggest that cyclical modifications within the CENP-A nucleosome contribute to the binding of key kinetochore proteins, the integrity of mitosis, and centromeric replication. These data support the paradigm that modifications in histone variants can influence key biological processes.Electronic supplementary materialThe online version of this article (doi:10.1186/s13072-017-0124-6) contains supplementary material, which is available to authorized users.

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Crystal structure and stable property of the cancer-associated heterotypic nucleosome containing CENP-A and H3.3

Cited by 64 publications

References 40 publications

CENP-A Ubiquitylation Is Inherited through Dimerization between Cell Divisions

CENP-A Ubiquitylation Is Inherited through Dimerization between Cell Divisions

Structural transitions of centromeric chromatin regulate the cell cycle-dependent recruitment of CENP-N

Internal modifications in the CENP-A nucleosome modulate centromeric dynamics

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