CENP-A Ubiquitylation Is Inherited through Dimerization between Cell Divisions

Niikura, Yohei; Kitagawa, Risa; Kitagawa, Katsumi

doi:10.1016/j.celrep.2016.03.010

Cited by 29 publications

(34 citation statements)

References 56 publications

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“…A complete turnover of all preexisting CENP-A molecules has been only previously observed in holocentric organisms (Gassmann et al, 2012). Our findings further demonstrate that post-translational modifications on preexisting centromeric CENP-A are not essential to guide new CENP-A deposition at the centromere in contrast to previously described models (Niikura et al, 2015(Niikura et al, , 2016.…”

Section: Discussionsupporting

confidence: 58%

A genetic memory initiates the epigenetic loop necessary to preserve centromere position

et al. 2020

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Centromeres are built on repetitive DNA sequences (CenDNA) and a specific chromatin enriched with the histone H3 variant CENP-A, the epigenetic mark that identifies centromere position. Here, we interrogate the importance of CenDNA in centromere specification by developing a system to rapidly remove and reactivate CENP-A (CENP-A OFF/ ON). Using this system, we define the temporal cascade of events necessary to maintain centromere position. We unveil that CENP-B bound to CenDNA provides memory for maintenance on human centromeres by promoting de novo CENP-A deposition. Indeed, lack of CENP-B favors neocentromere formation under selective pressure. Occasionally, CENP-B triggers centromere re-activation initiated by CENP-C, but not CENP-A, recruitment at both ectopic and native centromeres. This is then sufficient to initiate the CENP-A-based epigenetic loop. Finally, we identify a population of CENP-A-negative, CENP-B/C-positive resting CD4 + T cells capable to re-express and reassembles CENP-A upon cell cycle entry, demonstrating the physiological importance of the genetic memory.

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Section: Discussionsupporting

confidence: 58%

A genetic memory initiates the epigenetic loop necessary to preserve centromere position

et al. 2020

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“…Whereas molecular steps allowing eviction of overloaded pool of CENP-A are largely unknown, there are reports of stabilization of nascent CENP-A occurring in G1 (Lagana et al, 2010;Liu and Mao, 2016;Perpelescu et al, 2009), suggesting that addition of CENP-A ´´stabilization´´ mark would happen prior to DNA synthesis. A recent addition to this theme is the report of ubiquitylation of parental CENP-A as a requirement to recruit nascent CENP-A (Niikura et al, 2016). Centromeric CENP-A levels could also be normalized during S phase passage, in which the mix of parental and G1-loaded pools of CENP-A would be coordinately and preferentially segregated to the granddaughter centromere which inherited a decreased number of CENP-A molecules from the previous generation.…”

Section: Possible Mechanisms To Maintain Homeostasis Of Cenp-a Levelsmentioning

confidence: 99%

Quantitative Microscopy Reveals Centromeric Chromatin Stability, Size, and Cell Cycle Mechanisms to Maintain Centromere Homeostasis

Stanković

Jansen

2017

Centromeres and Kinetochores

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Centromeres are chromatin domains specified by nucleosomes containing the histone H3 variant, CENP-A. This unique centromeric structure is at the heart of a strong self-templating epigenetic mechanism that renders centromeres heritable. We review how specific quantitative microscopy approaches have contributed to the determination of the copy number, architecture, size, and dynamics of centromeric chromatin and its associated centromere complex and kinetochore. These efforts revealed that the key to long-term centromere maintenance is the slow turnover of CENP-A nucleosomes, a critical size of the chromatin domain and its cell cycle-coupled replication. These features come together to maintain homeostasis of a chromatin locus that directs its own epigenetic inheritance and facilitates the assembly of the mitotic kinetochore.

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“…Of these, only three have been reported within the histone fold domain [20–23]. Using epitope-tagged CENP-A, studies have identified phosphorylation of S68 within loop 1 [23], and ubiquitination of K124 near the pseudo-dyad of the nucleosome [21, 22]. We previously analyzed chromatin-bound native CENP-A (nCENP-A) and identified acetylation of K124 (K124ac), which was enriched at G1/S phase [20].…”

Section: Introductionmentioning

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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CENP-A Ubiquitylation Is Inherited through Dimerization between Cell Divisions

Cited by 29 publications

References 56 publications

A genetic memory initiates the epigenetic loop necessary to preserve centromere position

A genetic memory initiates the epigenetic loop necessary to preserve centromere position

Quantitative Microscopy Reveals Centromeric Chromatin Stability, Size, and Cell Cycle Mechanisms to Maintain Centromere Homeostasis

Internal modifications in the CENP-A nucleosome modulate centromeric dynamics

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