Affinage

CENPA

Histone H3-like centromeric protein A · UniProt P49450

Length
140 aa
Mass
16.0 kDa
Annotated
2026-06-09
100 papers in source corpus 45 papers cited in narrative 45 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CENP-A is a centromere-specific histone H3 variant that epigenetically marks centromere identity and is essential for building a functional kinetochore; its loss in mouse embryos causes early lethality with mitotic catastrophe and abolishes recruitment of CENP-C and downstream kinetochore components (PMID:10655499, PMID:15870271). Centromeric CENP-A chromatin forms octameric nucleosomes that protect ~133 bp of DNA with characteristic loose entry/exit wrapping (PMID:28235947), and these nucleosomes directly nucleate the inner kinetochore: they assemble a nucleosome-associated complex of CCAN proteins (CENP-M/N/T/U/C/H) whose integrity is required for accurate chromosome alignment and segregation (PMID:16622419), with cryo-EM showing CCAN making edge-on contacts and topologically entrapping linker DNA to resist spindle forces (PMID:35420891). CENP-C reads the CENP-A nucleosome through an extended hydrophobic interface (CENP-A V532/V533), reshapes and rigidifies the histone core, and unwraps terminal DNA via the H2A C-terminal tail, a collaboration required to retain CENP-A at centromeres (PMID:25954010, PMID:31475439). CENP-A also cooperates with CENP-B to generate an open, dynamic centromeric chromatin state accessible to kinetochore factors (PMID:25916850, PMID:38086807). CENP-A deposition is strictly cell-cycle-restricted to mitotic exit/G1 by a dedicated machinery: the chaperone HJURP caps a pre-nucleosomal CENP-A–H4 heterodimer (PMID:21478274) and is licensed by the Plk1-recruited Mis18/M18BP1 complex, while CDK activity inhibits assembly by phosphorylating M18BP1 and sequestering HJURP (PMID:25036634, PMID:28017591). Multiple CENP-A modifications gate this process — Cdk1 phosphorylation of Ser68 blocks premature HJURP binding (PMID:25556658), and CUL4A-RBX1-COPS8-mediated K124 monoubiquitylation is required for HJURP interaction and centromere loading (PMID:25727006). Once incorporated, CENP-A nucleosomes are retained through DNA replication by an HJURP–MCM2 mechanism (PMID:30293838), protected during centromeric transcription by Spt6 (PMID:32522980), and stabilized in S phase through CENP-A recognition of m6A-modified centromeric RNA via Leu61/Arg63 (PMID:39305902); CENP-A chromatin also suppresses R-loops and protects centromeric replication, preventing breakage and translocations (PMID:33653953). Beyond the centromere, CENP-A overexpression drives ectopic, DAXX-dependent deposition that occludes CTCF and confers DNA-damage tolerance (PMID:24530302), and contributes to chromosomal instability and tumor phenotypes (PMID:33620383).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2000 High

    Established that CENP-A is genetically upstream of centromere organization, answering whether it is required to build the kinetochore at all.

    Evidence Cenpa knockout mouse embryos with immunofluorescence of centromere proteins

    PMID:10655499

    Open questions at the time
    • Did not resolve which kinetochore proteins bind CENP-A directly versus indirectly
    • No molecular mechanism for CENP-C recruitment
  2. 2005 High

    Defined the hierarchy of kinetochore assembly, showing CENP-A is required for both inner CCAN and outer kinetochore recruitment and for checkpoint competence.

    Evidence Conditional CENP-A disruption in chicken DT40 cells with systematic component localization

    PMID:15870271

    Open questions at the time
    • Did not distinguish direct from indirect recruitment
    • Mechanism of BubR1 maintenance defect unresolved
  3. 2006 High

    Identified the CENP-A nucleosome-associated complex (NAC/CCAN), defining the molecular bridge from CENP-A chromatin to the kinetochore.

    Evidence Mass spectrometry interactome, reciprocal Co-IP, and RNAi with mitotic phenotype

    PMID:16622419

    Open questions at the time
    • Did not determine atomic contacts between CENP-A and CCAN
    • Role of FACT and nucleophosmin-1 left undefined
  4. 2011 High

    Resolved how the dedicated chaperone HJURP selectively recognizes CENP-A, answering the basis of CENP-A-specific assembly.

    Evidence X-ray crystallography of HJURP–CENP-A–H4 with in vitro binding

    PMID:21478274

    Open questions at the time
    • Did not address how HJURP is delivered to centromeres
    • Mechanism of DNA deposition not captured by structure
  5. 2014 High

    Built the cell-cycle control logic of CENP-A deposition, showing a two-step Plk1-activating/CDK-inhibiting paradigm and CENP-A Ser68 phosphorylation as a brake on premature HJURP binding.

    Evidence RNAi/inhibitor, FRAP, degron, phosphomutant kinase assays and rescue in human cells

    PMID:25001279 PMID:25036634 PMID:25556658

    Open questions at the time
    • Did not enumerate all CDK substrates in the pathway
    • Phosphatase regulation of multiple sites incompletely mapped
  6. 2015 High

    Established post-translational gating and stabilization of CENP-A: K124 monoubiquitylation by CUL4A-RBX1-COPS8 is required for HJURP binding/loading, and CENP-C and CENP-B stabilize incorporated nucleosomes.

    Evidence In vitro ubiquitylation, CRISPR knockin, reconstitution/FRET, single-molecule PIFE, and in vivo stability assays

    PMID:25727006 PMID:25916850 PMID:25954010

    Open questions at the time
    • Did not define the deubiquitylase or full PTM crosstalk
    • CENP-C-induced reshaping not yet linked to atomic interface (resolved later)
  7. 2017 High

    Resolved the long-standing octamer-versus-tetramer debate, establishing CENP-A chromatin as an octameric nucleosome at all cell-cycle phases with characteristic DNA unwrapping.

    Evidence ChIP-seq with new reference models, MNase protection, nanopore, and quantitative mass spectrometry

    PMID:28235947

    Open questions at the time
    • Does not reconcile earlier in vivo transition observations (idx 14)
    • Dynamics of unwrapping in living cells not directly measured
  8. 2018 High

    Explained how CENP-A survives DNA replication, identifying an HJURP–MCM2 retention mechanism coupling CENP-A inheritance to the replication fork.

    Evidence BioID, reciprocal Co-IP, auxin-inducible depletion, and quantitative imaging

    PMID:30293838

    Open questions at the time
    • Did not quantify fraction of CENP-A retained versus newly deposited
    • Coordination with leading/lagging strand not resolved
  9. 2019 High

    Provided atomic-level mechanism for CENP-C reading and unwrapping the CENP-A nucleosome and for licensing factor (KNL2) discrimination of CENP-A from H3.

    Evidence Cryo-EM, in vitro binding, and mutagenesis of specific residues

    PMID:31475439 PMID:31676716 PMID:36744604

    Open questions at the time
    • Functional consequence of H4 tail rigidification on K20me1 not fully tested in vivo
    • Did not capture full CCAN engagement
  10. 2021 High

    Defined a genome-protective role for CENP-A in S phase, showing CENP-A chromatin suppresses R-loops and protects centromeric replication against breakage.

    Evidence Cell-cycle-specific auxin degron, DRIP, DNA fiber assays, and cytogenetics

    PMID:33653953

    Open questions at the time
    • Mechanism linking CENP-A nucleosome to R-loop resolution unknown
    • Did not identify the transcription/replication conflict resolving factors
  11. 2022 High

    Revealed how the inner kinetochore mechanically couples to the CENP-A nucleosome, showing CCAN topologically entraps linker DNA to withstand spindle forces.

    Evidence Cryo-EM of reconstituted CCAN–CENP-A nucleosome on α-satellite DNA

    PMID:35420891

    Open questions at the time
    • Static structure does not show force response dynamics
    • Outer kinetochore connection not in the reconstitution
  12. 2024 High

    Identified an RNA-reading function of CENP-A, showing it binds m6A-modified centromeric RNA via Leu61/Arg63 to stabilize centromere localization in S phase.

    Evidence m6A mapping, CENP-A mutagenesis, RNA-protein binding, live-cell imaging, and xenografts

    PMID:39305902

    Open questions at the time
    • m6A writer/eraser controlling cenRNA at centromeres not defined here
    • Structural basis of CENP-A–RNA contact not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the diverse CENP-A modifications (Ser68/Ser7/K124 ubiquitylation, acetylation, methylation), RNA-reading, and chaperone choices are integrated into a single quantitative inheritance program — and how ectopic/overexpressed CENP-A is normally restrained — remains incompletely defined.
  • No unified model reconciling competing PTM functions (e.g. S7 phosphorylation dispensability)
  • Mechanism restricting ectopic DAXX/MCM2-driven deposition only partially mapped
  • Disease relevance of CENP-A overexpression in cancer lacks causal in vivo proof

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 3 GO:0003677 DNA binding 2 GO:0140110 transcription regulator activity 2 GO:0003723 RNA binding 1
Localization
GO:0000228 nuclear chromosome 3 GO:0005634 nucleus 2 GO:0005694 chromosome 2
Pathway
R-HSA-1640170 Cell Cycle 4 R-HSA-4839726 Chromatin organization 3 R-HSA-73894 DNA Repair 2
Partners
CENP-BCENP-CCENP-NCENP-THJURPM18BP1MCM2SPT6
Complex memberships
CCAN/NAC (inner kinetochore)CENP-A nucleosome

Evidence

Reading pass · 45 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 CENP-A nucleosomes directly recruit a proximal nucleosome-associated complex (NAC) comprising CENP-M, CENP-N, CENP-T, CENP-U(50), CENP-C, and CENP-H. Assembly of the NAC requires CENP-M, CENP-N, and CENP-T. FACT and nucleophosmin-1 are stably recruited to CENP-A nucleosomes independently of the NAC. Seven distal CAD components (CENP-K, -L, -O, -P, -Q, -R, -S) assemble on the NAC. Disruption of the NAC causes chromosome alignment and segregation errors. Mass spectrometry, co-immunoprecipitation, RNAi depletion with mitotic phenotype readout Nature cell biology High 16622419
2000 Cenpa null mouse embryos fail to survive beyond E6.5 with severe mitotic defects. Cenpa is required for kinetochore targeting of Cenpc; loss of Cenpa causes diffuse Cenpb foci and complete loss of discrete Cenpc centromere signal, indicating Cenpa organizes centromeric chromatin and is epistatic to Cenpc localization. Gene targeting (knockout mouse), immunofluorescence microscopy Proceedings of the National Academy of Sciences of the United States of America High 10655499
2011 Crystal structure of HJURP bound to a CENP-A–H4 heterodimer shows HJURP binds a pre-nucleosomal CENP-A–H4 heterodimer; the C-terminal β-sheet domain of HJURP caps the DNA-binding surface of CENP-A–H4, preventing spontaneous DNA association. A novel CENP-A-specific surface distinguishes it from H3 in HJURP binding. X-ray crystallography, in vitro binding assays Genes & development High 21478274
2015 CENP-C binds CENP-A nucleosomes and reshapes the octameric histone core: it rigidifies both surface and internal nucleosome structure and modulates terminal DNA to match the loose DNA wrap characteristic of native centromeric CENP-A nucleosomes. CENP-C depletion leads to rapid removal of CENP-A from centromeres, demonstrating collaboration between CENP-C and CENP-A in maintaining centromere identity. Purified-component reconstitution, FRET, single-molecule PIFE, auxin-inducible degron depletion Science (New York, N.Y.) High 25954010
2014 Polo-like kinase 1 (Plk1) is required to initiate CENP-A deposition in human cells by promoting localization of the Mis18 complex to centromeres. CDK inhibits Mis18 complex assembly. A two-step Plk1/CDK regulatory paradigm controls cell-cycle-restricted CENP-A deposition; bypassing both steps uncouples deposition from cell-cycle progression and causes mitotic defects. RNAi/chemical inhibition, FRAP, auxin-inducible degron, epistasis with phosphomutants Cell High 25036634
2014 Cdk1 phosphorylates CENP-A at Ser68 during early mitosis, which eliminates binding of CENP-A to its assembly chaperone HJURP, thereby preventing premature centromeric loading before mitotic exit. PP1α dephosphorylates Ser68 at mitotic exit, enabling HJURP-mediated centromeric deposition. In vitro kinase assay, phosphomutant rescue, co-immunoprecipitation, cell synchronization Developmental cell High 25556658
2015 CUL4A-RBX1-COPS8 E3 ligase monoubiquitylates CENP-A on K124, which is required for CENP-A interaction with chaperone HJURP and for centromere localization. The K124R mutation reduces HJURP binding and abolishes centromere loading; addition of monoubiquitin to K124R restores both HJURP interaction and centromere localization. In vitro ubiquitylation assay, co-immunoprecipitation, CRISPR knockin, immunofluorescence Developmental cell High 25727006
2018 HJURP transiently associates with pre-existing CENP-A nucleosomes during S phase and is required for CENP-A nucleosome inheritance through DNA replication. HJURP co-purifies with the MCM2-7 helicase complex, and MCM2 and HJURP simultaneously bind CENP-A, defining a mechanism for retaining CENP-A during replication fork passage. BioID proximity labeling, co-immunoprecipitation, conditional depletion (auxin), quantitative imaging Developmental cell High 30293838
2022 Cryo-EM structures of the human inner kinetochore CCAN complex bound to a CENP-A nucleosome reconstituted on α-satellite DNA show that CCAN forms edge-on contacts with the CENP-A nucleosome; a linker DNA segment threads through the central CENP-LN channel; CENP-TWSX partially wraps linker DNA. This topological entrapment of linker DNA by CCAN provides a mechanism for kinetochores to withstand spindle forces. Cryo-electron microscopy, reconstitution of CENP-A nucleosome on α-satellite DNA Science (New York, N.Y.) High 35420891
2016 Cell-cycle control of CENP-A assembly requires two targets: a single Cdk phosphorylation site in licensing factor M18BP1 and a cyclin A binding site in HJURP. Simultaneous mutation of both sites completely uncouples CENP-A assembly from cell-cycle phase, allowing assembly under high Cdk activity indistinguishable from G1 assembly. Cdk-mediated inhibition works by sequestering active factors away from the centromere. Phosphomutant expression, quantitative live-cell imaging, CENP-A incorporation assays, cell-cycle staging Molecular cell High 28017591
2005 In CENP-A-depleted chicken DT40 cells, inner kinetochore proteins CENP-I, CENP-H, and CENP-C and outer components Nuf2/Hec1, Mad2, and CENP-E are mislocalised, whereas BubR1 and INCENP are efficiently recruited. CENP-A-depleted cells show chromosome congression defects and a specific defect in maintaining BubR1 at kinetochores under checkpoint activation, indicating CENP-A is required for a mitotic-checkpoint-competent kinetochore. Conditional gene disruption (DT40), immunofluorescence, epistasis of kinetochore component localization Molecular and cellular biology High 15870271
2001 CENP-A is phosphorylated at a serine residue (equivalent to H3 Ser10) in a cell-cycle-dependent manner distinct from histone H3. CENP-A phosphorylation begins in prophase, peaks in prometaphase, and disappears in telophase—after both pericentric and genome-wide H3 phosphorylation. Prekinetochore duplication (CENP-A foci doubling) occurs before complete H3 phosphorylation in G2. Phospho-specific antibody ELISA, western blot, quantitative immunocytochemistry Journal of cell science Medium 11171370
2009 CENP-A is rapidly recruited to DNA double-strand breaks (DSBs) in human and mouse cells, along with centromere-associated proteins CENP-N, CENP-T, and CENP-U. The centromere-targeting domain (CATD) of CENP-A is necessary and sufficient for recruitment to DSBs. CENP-A accumulation at breaks is enhanced by active NHEJ but does not require DNA-PKcs, Ligase IV, or H2AX. Multiphoton laser microirradiation, I-SceI endonuclease-induced DSBs, CENP-A domain truncation/mutation, immunofluorescence Proceedings of the National Academy of Sciences of the United States of America Medium 19717431
2014 CENP-A overexpression leads to ectopic enrichment at sites of active histone turnover in a heterotypic CENP-A/H3.3–H4 tetramer. Ectopic localization depends on H3.3 chaperone DAXX rather than the dedicated CENP-A chaperone HJURP. Ectopic CENP-A nucleosomes occlude CTCF binding and confer DNA damage tolerance, both dependent on DAXX. ChIP-seq, co-immunoprecipitation, RNAi knockdown, CTCF binding assay, cell survival assay Molecular cell High 24530302
2012 Human CENP-A nucleosomes undergo cell-cycle-dependent structural transitions in vivo: they exist as tetramers (half-nucleosomes) after replication and convert to octamers before the next replication, accompanied by reversible chaperone binding, chromatin fiber folding changes, and histone fold domain modifications on CENP-A and H4. AFM, mass spectrometry of PTMs, chromatin fractionation, cell-cycle synchronization Cell Medium 22817894
2017 Human centromeric CENP-A chromatin is exclusively an octameric nucleosome at all cell-cycle phases (G1 and G2), containing equimolar CENP-A, H2A, H2B, and H4 with no H3. CENP-A nucleosomes protect DNA lengths centered on 133 bp, consistent with octamers with DNA unwrapping at entry and exit. Solid-state nanopore analyses confirm nucleosomal size. ChIP-seq with new reference models, MNase protection assay, nanopore analysis, quantitative mass spectrometry The Journal of cell biology High 28235947
2019 Cryo-EM structures of centromeric tri-nucleosomes show that H3-CENP-A-H3 tri-nucleosomes adopt an untwisted architecture with outward-facing linker DNA path between nucleosomes, distinct from H3-H3-H3 tri-nucleosomes with inward-facing DNA. This exposes the CENP-A nucleosome to solvent in condensed chromatin. Cryo-electron microscopy, tri-nucleosome reconstitution Structure (London, England : 1993) High 31711756
2018 Aurora A kinase phosphorylates CENP-A at serine 7 (S7) at inner centromeres in mitosis, protecting bioriented chromosomes against cohesion fatigue. Expression of non-phosphorylatable CENP-A S7A weakens sister chromatid cohesion only when centromeres are under spindle tension. Aurora A is recruited to centromeres in a Bub1-dependent manner. Phosphomutant CENP-A expression, chromosome cohesion assays, Aurora A inhibition, immunofluorescence Nature communications Medium 29760389
2019 Phosphorylation of CENP-A on serine 7 is dispensable for correct CENP-C recruitment, faithful chromosome segregation, and long-term cell viability, as demonstrated by gene targeting at both endogenous CENP-A alleles and gene replacement with S7A in human cells. Gene targeting at endogenous loci (CRISPR), gene replacement, immunofluorescence, live-cell imaging Nature communications High 30635586
2019 CENP-C unwraps the human CENP-A nucleosome through the H2A C-terminal tail. The CENP-C central region (CENP-C_CR) binds the CENP-A nucleosome with high affinity via an extended hydrophobic area involving CENP-A V532 and V533. CENP-C binding further loosens terminal DNA wrapping (through H2A C-tail destabilization) and rigidifies the H4 N-terminal tail in a conformation favoring H4K20 monomethylation. Cryo-EM, in vitro binding assays, nucleosome reconstitution, mutagenesis EMBO reports High 31475439
2019 CDK1 phosphorylates CENP-C in its C-terminal CENP-A binding motif, which facilitates CENP-C binding to the CENP-A nucleosome in vitro and in vivo. This phosphorylation promotes CENP-C kinetochore localization during mitosis. The CENP-A–CENP-C interaction is critical for long-term cell viability in human RPE-1 cells. In vitro kinase assay, co-immunoprecipitation, phosphomutant rescue, immunofluorescence, cell viability assays The Journal of cell biology High 31676716
2015 CENP-B forms a stable complex with the CENP-A nucleosome in vitro, preferentially when the CENP-B box DNA is located at the proximal edge of the nucleosome. The CENP-B DNA-binding domain specifically interacts with the CENP-A–H4 complex (but not H3.1–H4). In vivo, CENP-B binding near the CENP-A nucleosome substantially stabilizes CENP-A on alphoid DNA. In vitro nucleosome reconstitution, pulldown assay, in vivo chromatin stability assay Nucleic acids research High 25916850
2018 Centromeric transcription by RNA Pol II temporally coincides with de novo dCENP-A deposition in Drosophila. Short inhibition of transcription impairs CENP-A incorporation into stable (salt-resistant) chromatin but does not prevent initial targeting to centromeres, revealing two stability states of newly loaded CENP-A: a salt-sensitive association and a salt-resistant incorporated form. Transcription-mediated chromatin remodeling drives the transition to fully incorporated nucleosomes. Drosophila tissue culture, transcription inhibitor treatment, SNAP-tag pulse-chase, chromatin fractionation The Journal of cell biology High 29626011
2020 Spt6, a histone chaperone and transcription elongation factor, prevents loss of old CENP-A nucleosomes during centromeric transcription. Spt6 directly binds dCENP-A in vitro; phosphomimetic dCENP-A mutants reduce Spt6 association, and non-phosphorylatable dCENP-A accumulates at centromeres. Spt6 acts as a conserved CENP-A maintenance factor in both Drosophila and human cells. Co-immunoprecipitation/direct binding assay, SNAP-tag pulse-chase, phosphomutant analysis, immunofluorescence Nature communications High 32522980
2021 CENP-A chromatin protects centromeric alpha-satellite DNA from replication stress during S phase. Rapid CENP-A removal specifically in S phase causes R-loop accumulation with increased centromeric transcripts, impaired replication fork progression, recombination at alpha-satellites, and anaphase bridges leading to chromosome breakage and translocations at centromeric regions. Auxin-inducible degron for cell-cycle-specific CENP-A removal, DNA-RNA immunoprecipitation, DNA fiber assay, cytogenetics Proceedings of the National Academy of Sciences of the United States of America High 33653953
2016 CENP-A ubiquitylation (K124) is inherited between cell divisions through CENP-A dimerization. Pre-existing ubiquitylated CENP-A is necessary for recruitment of newly synthesized CENP-A to the centromere. In vivo and in vitro experiments with dimerization mutants show that inheritance of K124 ubiquitylation requires CENP-A dimerization. Overexpression of monoubiquitin-fused CENP-A induces neocentromeres at non-centromeric regions. In vivo and in vitro dimerization mutant analysis, co-immunoprecipitation, immunofluorescence, ectopic CENP-A expression Cell reports Medium 27052173
2019 CENP-A HJURP nucleosome clusters form rosette-like structures (~250–300 nm) around HJURP during G1 phase. 2D/3D super-resolution microscopy shows HJURP localizes to the center of these rosettes and acts as a nucleation point for CENP-A deposition, providing structural insight into centromeric chromatin organization during loading. Super-resolution microscopy (STORM/PALM), co-localization analysis, segmentation Nature communications Medium 31570711
2014 Cell-cycle-dependent recruitment of HJURP to centromeres depends on timely CDK-mediated phosphorylation of HJURP. A non-phosphorylatable HJURP mutant localizes prematurely to centromeres in S and G2, causing premature CENP-A loading and cell-cycle delays. Once at centromeres, HJURP promotes CENP-A deposition through a unique DNA-binding domain. Phosphomutant expression, cell-cycle synchronization, immunofluorescence, DNA binding assays Cell reports High 25001279
2015 In a cell-free CENP-A assembly system, two distinct domains of CENP-A within existing nucleosomes are required for new CENP-A assembly. CENP-A nucleosomes recruit CENP-C and M18BP1 independently, and CENP-C recruitment depends on the density of underlying CENP-A nucleosomes. Cell-free CENP-A assembly system (Xenopus extract), domain truncation analysis, chromatin binding assays The Journal of cell biology High 26076692
2017 At yeast centromeres, Cse4/CENP-A histone-fold domain interacts with inner kinetochore protein Mif2/CENP-C. Mif2 contacts one side of the nucleosome dyad engaging both Cse4 residues and AT-rich centromeric DNA through a contiguous DNA- and histone-binding domain (DHBD) containing the CENP-C motif, an AT hook, and RK clusters. Human CENP-C has two related DHBDs with preference for AT-rich DNA. Biochemical binding assays, mutagenesis, ChIP, structural modeling Genes & development High 29074736
2002 PARP-2 co-immunoprecipitates with CENP-A (Cenpa) and CENP-B (Cenpb) at active centromeres in a cell-cycle-dependent manner (accumulating prometaphase/metaphase, disassociating by telophase). PARP-2 does not interact with CENP-C. PARP-2 centromere binding is sequence-independent and enhanced by microtubule-inhibiting drugs. Co-immunoprecipitation, immunofluorescence, pseudodicentric chromosome analysis Human molecular genetics Medium 12217960
2012 In Saccharomyces cerevisiae, Cse4/CENP-A (centromeric H3 variant) is methylated on arginine 37 (R37). Absence of R37 methylation reduces levels of Mtw1/MIND and Ctf19 complex components at the centromere (but not Cse4 itself), causing growth defects, G2/M arrest, and chromosome segregation errors. This modification regulates recruitment of linker kinetochore components. Mass spectrometry, methylation mutants, genetic epistasis with kinetochore mutants, ChIP Proceedings of the National Academy of Sciences of the United States of America Medium 22615363
2017 CENPT bridges adjacent CENPA nucleosomes on young human α-satellite dimers. Sequential ChIP-seq shows CENPT is centered between two well-positioned CENPA nucleosomes over the CENPB box, forming a CENPA/CENPB/CENPC/CENPT complex nuclease-protected over an α-satellite dimer. CENPT interacts with CENPB/CENPC complex rather than H3 nucleosomes in vivo. Comparative and sequential ChIP-seq, base-pair-resolution genomic readout of protein-protein interactions Genome research Medium 27384170
2024 CENP-A functions as an m6A reader of centromeric RNA (cenRNA): m6A-modified cenRNA stabilizes centromeric localization of CENP-A during S phase. Mutations at CENP-A Leu61 and Arg63 abolish cenRNA binding and cause loss of centromere-bound CENP-A during S phase, compromised centromere integrity, and abnormal chromosome separation. m6A methylation mapping, CENP-A mutagenesis, RNA-protein binding assays, live-cell imaging, tumor xenograft Cell High 39305902
2021 CENP-A overexpression causes CIN with lagging chromosomes and micronuclei due to reduced localization of kinetochore proteins, resulting in defective kinetochore integrity and unstable kinetochore-microtubule attachments. CENP-A OE also reduces cell adhesion gene expression and increases invasion. Inducible overexpression, kinetochore protein quantification by immunofluorescence, live-cell imaging, xenograft The Journal of cell biology Medium 33620383
2021 CENPA overexpression promotes prostate cancer cell growth through a non-centromeric function as a transcriptional regulator that modulates expression of proliferation, cell-cycle, and centromere/kinetochore genes, as revealed by integrated ChIP-seq and RNA-seq experiments. ChIP-seq, RNA-seq, gain/loss-of-function experiments, tissue microarray The Journal of biological chemistry Medium 32371391
2021 CENPA recruits histone acetyltransferase GCN-5 to the promoter of KPNA2 to induce transcription activation in colon cancer cells. This non-centromeric transcriptional activity of CENPA promotes glycolysis and growth. H3K27ac modification is detected at the KPNA2 promoter upon CENPA binding. ChIP assay, co-immunoprecipitation, RNAi knockdown, rescue experiments, metabolic assays The American journal of pathology Medium 34508688
2021 Phosphorylation of CENP-A Ser68 primes polyubiquitin-mediated proteasomal degradation of CENP-A during mitotic phase. DCAF11 (WDR23) is the E3 ligase mediating this polyubiquitination via K49 and K124. Mutation of K49R/K124R or DCAF11 deletion abrogates proper degradation and causes CENP-A mislocalization. In vivo ubiquitination assay, proteasome inhibitor treatment, DCAF11 depletion/knockout, immunofluorescence Cell reports Medium 34758320
2023 HJURP phosphorylation by CDK prevents HJURP interaction with CENP-C in metaphase, blocking delivery of soluble CENP-A to centromeres. Non-phosphorylatable HJURP constitutively binds CENP-C in metaphase but is insufficient for new CENP-A assembly. M18BP1.S subunit of the Mis18 complex competitively inhibits HJURP access to CENP-C. Two inhibitory activities together repress CENP-A assembly in metaphase. X. laevis egg extract cell-free assembly system, phosphomutant analysis, co-immunoprecipitation, competitive binding assays The Journal of cell biology High 37141119
2023 Cryo-EM structure of chicken CENP-A nucleosome bound to ggKNL2 (Mis18 complex component with CENP-C-like motif) shows ggKNL2 simultaneously recognizes the CENP-A C-terminal tail and the RG-loop using its CENP-C-like motif to distinguish CENP-A from H3. ggKNL2 changes its centromere binding partner during cell cycle progression. Cryo-EM structure, biochemical binding assays, cell biology validation, cell-cycle analysis The EMBO journal High 36744604
2023 CENP-A and CENP-B collaborate to establish an open centromeric chromatin state. CENP-A incorporation increases chromatin fiber dynamics. This increased dynamics allow CENP-B DNA access; bound CENP-B further opens chromatin fiber structure and induces nucleosomal DNA unwrapping. Removal of CENP-A increases CENP-B mobility in cells. Single-molecule fluorescence, cryo-EM, FRAP (in cells), chromatin fiber reconstitution Nature communications High 38086807
2024 DNAJC9 (a J-domain protein for H3-H4 folding) restricts CENP-A mislocalization. Its depletion promotes CENP-A interaction with MCM2, which drives CENP-A deposition at ectopic sites. H3.3 depletion also causes CENP-A mislocalization. This defines MCM2 as a driver of ectopic CENP-A deposition when H3-H4 supply chains are disrupted. Genome-wide RNAi screen, global interactome analysis, MCM2 depletion epistasis, immunofluorescence The EMBO journal Medium 38600242
2016 Diaphanous formin mDia2 is required for stable replenishment of new CENP-A at centromeres in G1. Depletion of mDia2 causes prolonged centromere association of HJURP. mDia2 acts downstream of the MgcRacGAP-dependent small GTPase pathway in regulating CENP-A nucleosome assembly. Nuclear localization of mDia2 is required for this function. Quantitative imaging, pulse-chase, constitutively active mutant rescue, RNAi epistasis The Journal of cell biology Medium 27185834
2019 Quiescent cells (G0-arrested and prophase I-arrested oocytes) actively and continuously incorporate new CENP-A at centromeres using the canonical CENP-A deposition machinery. Plk1 is required specifically for G1 (not quiescent) CENP-A deposition, while transcription promotes CENP-A incorporation in quiescent oocytes. Preventing CENP-A deposition during quiescence reduces CENP-A levels and perturbs chromosome segregation upon re-entry into division. Pulse-chase labeling, chemical inhibitors (Plk1/transcription), conditional depletion, quantitative imaging Developmental cell Medium 31422918
2017 CENP-A acetylation at K124 causes tightening of the histone core and diminishes CENP-C binding (by computational modeling and CENP-A K124Q/K124A mutants). CENP-A K124 switches from acetylation at G1/S to monomethylation during early/mid-S phase. The HAT p300 is implicated in K124 acetylation. K124 mutations alter centromeric replication timing and cause modest increases in mitotic errors. Computational modeling, in vivo phosphomutant analysis, mass spectrometry of native CENP-A, HAT inhibitor experiments Epigenetics & chromatin Medium 28396698

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 The human CENP-A centromeric nucleosome-associated complex. Nature cell biology 594 16622419
2000 Early disruption of centromeric chromatin organization in centromere protein A (Cenpa) null mice. Proceedings of the National Academy of Sciences of the United States of America 328 10655499
2002 Centromeric retroelements and satellites interact with maize kinetochore protein CENH3. The Plant cell 296 12417704
2014 Mislocalization of the centromeric histone variant CenH3/CENP-A in human cells depends on the chaperone DAXX. Molecular cell 211 24530302
2015 Chromosomes. CENP-C reshapes and stabilizes CENP-A nucleosomes at the centromere. Science (New York, N.Y.) 182 25954010
2005 CENP-A is required for accurate chromosome segregation and sustained kinetochore association of BubR1. Molecular and cellular biology 164 15870271
2014 Polo-like kinase 1 licenses CENP-A deposition at centromeres. Cell 153 25036634
2011 Structure of a CENP-A-histone H4 heterodimer in complex with chaperone HJURP. Genes & development 153 21478274
2009 Double-strand DNA breaks recruit the centromeric histone CENP-A. Proceedings of the National Academy of Sciences of the United States of America 131 19717431
2009 CENPA overexpression promotes genome instability in pRb-depleted human cells. Molecular cancer 121 20003272
2014 CAL1 is the Drosophila CENP-A assembly factor. The Journal of cell biology 116 24469636
2012 Cell-cycle-dependent structural transitions in the human CENP-A nucleosome in vivo. Cell 116 22817894
2008 The histone variant CENP-A and centromere specification. Current opinion in cell biology 115 18226513
2015 Naturally occurring differences in CENH3 affect chromosome segregation in zygotic mitosis of hybrids. PLoS genetics 113 25622028
2018 Centromere transcription allows CENP-A to transit from chromatin association to stable incorporation. The Journal of cell biology 105 29626011
2015 Point mutation impairs centromeric CENH3 loading and induces haploid plants. Proceedings of the National Academy of Sciences of the United States of America 100 26294252
2021 Haploid induction by a maize cenh3 null mutant. Science advances 93 33523932
2022 Structure of the human inner kinetochore bound to a centromeric CENP-A nucleosome. Science (New York, N.Y.) 92 35420891
2014 Dynamic phosphorylation of CENP-A at Ser68 orchestrates its cell-cycle-dependent deposition at centromeres. Developmental cell 90 25556658
2001 Differential regulation of CENP-A and histone H3 phosphorylation in G2/M. Journal of cell science 90 11171370
2015 CENP-A K124 Ubiquitylation Is Required for CENP-A Deposition at the Centromere. Developmental cell 84 25727006
2018 Inheritance of CENP-A Nucleosomes during DNA Replication Requires HJURP. Developmental cell 80 30293838
2002 Poly(ADP-ribose) polymerase 2 localizes to mammalian active centromeres and interacts with PARP-1, Cenpa, Cenpb and Bub3, but not Cenpc. Human molecular genetics 80 12217960
2020 The centromere comes into focus: from CENP-A nucleosomes to kinetochore connections with the spindle. Open biology 79 32516549
2007 The CENP-A NAC/CAD kinetochore complex controls chromosome congression and spindle bipolarity. The EMBO journal 77 18007590
2014 Phosphorylation and DNA binding of HJURP determine its centromeric recruitment and function in CenH3(CENP-A) loading. Cell reports 76 25001279
2021 CENP-A chromatin prevents replication stress at centromeres to avoid structural aneuploidy. Proceedings of the National Academy of Sciences of the United States of America 74 33653953
2016 A Dual Inhibitory Mechanism Sufficient to Maintain Cell-Cycle-Restricted CENP-A Assembly. Molecular cell 72 28017591
2012 Putting CENP-A in its place. Cellular and molecular life sciences : CMLS 67 22729156
2019 Quiescent Cells Actively Replenish CENP-A Nucleosomes to Maintain Centromere Identity and Proliferative Potential. Developmental cell 61 31422918
2021 CENPA promotes clear cell renal cell carcinoma progression and metastasis via Wnt/β-catenin signaling pathway. Journal of translational medicine 60 34627268
2019 CENP-C unwraps the human CENP-A nucleosome through the H2A C-terminal tail. EMBO reports 57 31475439
2019 Centromeric and ectopic assembly of CENP-A chromatin in health and cancer: old marks and new tracks. Nucleic acids research 55 30590707
2015 CENP-C and CENP-I are key connecting factors for kinetochore and CENP-A assembly. Journal of cell science 54 26527398
2012 Methylation of CenH3 arginine 37 regulates kinetochore integrity and chromosome segregation. Proceedings of the National Academy of Sciences of the United States of America 54 22615363
2020 The role of the histone H3 variant CENPA in prostate cancer. The Journal of biological chemistry 53 32371391
2020 CenH3-Independent Kinetochore Assembly in Lepidoptera Requires CCAN, Including CENP-T. Current biology : CB 52 32032508
2017 Human centromeric CENP-A chromatin is a homotypic, octameric nucleosome at all cell cycle points. The Journal of cell biology 52 28235947
2015 Stable complex formation of CENP-B with the CENP-A nucleosome. Nucleic acids research 52 25916850
2019 Cryo-EM Structures of Centromeric Tri-nucleosomes Containing a Central CENP-A Nucleosome. Structure (London, England : 1993) 50 31711756
2019 CDK1-mediated CENP-C phosphorylation modulates CENP-A binding and mitotic kinetochore localization. The Journal of cell biology 48 31676716
2017 Molecular basis of CENP-C association with the CENP-A nucleosome at yeast centromeres. Genes & development 48 29074736
2014 Characterization of two CENH3 genes and their roles in wheat evolution. The New phytologist 48 25557089
2018 HJURP antagonizes CENP-A mislocalization driven by the H3.3 chaperones HIRA and DAXX. PloS one 45 30365520
2021 CENP-A overexpression promotes aneuploidy with karyotypic heterogeneity. The Journal of cell biology 43 33620383
2025 Single-cell and bulk RNA sequencing analysis reveals CENPA as a potential biomarker and therapeutic target in cancers. PloS one 42 39820192
2013 Octameric CENP-A nucleosomes are present at human centromeres throughout the cell cycle. Current biology : CB 42 23623556
2020 Formation of the CenH3-Deficient Holocentromere in Lepidoptera Avoids Active Chromatin. Current biology : CB 41 33125865
2018 Posttranslational modifications of CENP-A: marks of distinction. Chromosoma 41 29569072
2020 CENP-B creates alternative epigenetic chromatin states permissive for CENP-A or heterochromatin assembly. Journal of cell science 40 32661090
2016 Co-evolving CENP-A and CAL1 Domains Mediate Centromeric CENP-A Deposition across Drosophila Species. Developmental cell 40 27093083
2015 A cell-free CENP-A assembly system defines the chromatin requirements for centromere maintenance. The Journal of cell biology 40 26076692
2011 Characterization of CENH3 proteins and centromere-associated DNA sequences in diploid and allotetraploid Brassica species. Chromosoma 40 21394438
2011 Immunohistochemical Assessment of Expression of Centromere Protein-A (CENPA) in Human Invasive Breast Cancer. Cancers 39 24213134
2017 CENP-A chromatin disassembly in stressed and senescent murine cells. Scientific reports 38 28186195
2016 CENPT bridges adjacent CENPA nucleosomes on young human α-satellite dimers. Genome research 38 27384170
2016 No longer a nuisance: long non-coding RNAs join CENP-A in epigenetic centromere regulation. Cellular and molecular life sciences : CMLS 37 26748759
2022 CENP-A Regulation and Cancer. Frontiers in cell and developmental biology 36 35721491
2020 Spt6 is a maintenance factor for centromeric CENP-A. Nature communications 36 32522980
2024 m6A-modified cenRNA stabilizes CENPA to ensure centromere integrity in cancer cells. Cell 35 39305902
2021 CENP-A overexpression promotes distinct fates in human cells, depending on p53 status. Communications biology 35 33772115
2018 Nanoscale dynamics of centromere nucleosomes and the critical roles of CENP-A. Nucleic acids research 34 29040671
2017 Internal modifications in the CENP-A nucleosome modulate centromeric dynamics. Epigenetics & chromatin 32 28396698
2009 CENPA a genomic marker for centromere activity and human diseases. Current genomics 32 20119530
2013 Hypermorphic expression of centromeric retroelement-encoded small RNAs impairs CENP-A loading. Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology 31 23392618
2018 Aurora A-dependent CENP-A phosphorylation at inner centromeres protects bioriented chromosomes against cohesion fatigue. Nature communications 30 29760389
2000 Fine-specificity of the anti-CENP-A B-cell autoimmune response. Journal of molecular medicine (Berlin, Germany) 30 11097115
2021 High-throughput AFM analysis reveals unwrapping pathways of H3 and CENP-A nucleosomes. Nanoscale 28 33683227
2020 Structural basis for centromere maintenance by Drosophila CENP-A chaperone CAL1. The EMBO journal 27 32134144
2020 Stable inheritance of CENP-A chromatin: Inner strength versus dynamic control. The Journal of cell biology 27 32931551
2016 CENP-A Ubiquitylation Is Inherited through Dimerization between Cell Divisions. Cell reports 27 27052173
2009 Epigenetic specification of centromeres by CENP-A. Experimental cell research 27 19660450
2019 CENP-A nucleosome clusters form rosette-like structures around HJURP during G1. Nature communications 26 31570711
2012 Cell cycle-dependent deposition of CENP-A requires the Dos1/2-Cdc20 complex. Proceedings of the National Academy of Sciences of the United States of America 26 23267073
2003 Partially functional Cenpa-GFP fusion protein causes increased chromosome missegregation and apoptosis during mouse embryogenesis. Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology 26 12906131
1999 CENP-A associated complex satellite DNA in the kinetochore of the Indian muntjac. Chromosoma 25 10591996
2021 Centromere Protein A (CENPA) Regulates Metabolic Reprogramming in the Colon Cancer Cells by Transcriptionally Activating Karyopherin Subunit Alpha 2 (KPNA2). The American journal of pathology 24 34508688
2019 The deposition of CENH3 in maize is stringently regulated. The Plant journal : for cell and molecular biology 24 31713923
2012 Replicating centromeric chromatin: spatial and temporal control of CENP-A assembly. Experimental cell research 24 22561213
2012 The CENP-A nucleosome: a dynamic structure and role at the centromere. Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology 24 22825424
2020 Unequal contribution of two paralogous CENH3 variants in cowpea centromere function. Communications biology 23 33319863
2022 The ins and outs of CENP-A: Chromatin dynamics of the centromere-specific histone. Seminars in cell & developmental biology 22 35422390
2019 In vitro BioID: mapping the CENP-A microenvironment with high temporal and spatial resolution. Molecular biology of the cell 21 30892990
2013 The CENP-A nucleosome: a battle between Dr Jekyll and Mr Hyde. Nucleus (Austin, Tex.) 21 23324462
2021 Phosphorylation at Ser68 facilitates DCAF11-mediated ubiquitination and degradation of CENP-A during the cell cycle. Cell reports 20 34758320
2013 CENP-A is essential for cardiac progenitor cell proliferation. Cell cycle (Georgetown, Tex.) 20 24362315
2020 Hap2-Ino80-facilitated transcription promotes de novo establishment of CENP-A chromatin. Genes & development 19 31919190
2020 CENP-A nucleosome-a chromatin-embedded pedestal for the centromere: lessons learned from structural biology. Essays in biochemistry 19 32720682
2017 CENP-A and topoisomerase-II antagonistically affect chromosome length. The Journal of cell biology 19 28733327
2016 CENP-A and H3 Nucleosomes Display a Similar Stability to Force-Mediated Disassembly. PloS one 19 27820823
2016 Diaphanous formin mDia2 regulates CENP-A levels at centromeres. The Journal of cell biology 18 27185834
2024 Cyto-swapping in maize by haploid induction with a cenh3 mutant. Nature plants 17 38499777
2024 DNAJC9 prevents CENP-A mislocalization and chromosomal instability by maintaining the fidelity of histone supply chains. The EMBO journal 17 38600242
2022 CENPA regulates tumor stemness in lung adenocarcinoma. Aging 17 35816352
2019 Phosphorylation of CENP-A on serine 7 does not control centromere function. Nature communications 17 30635586
2023 The cryo-EM structure of the CENP-A nucleosome in complex with ggKNL2. The EMBO journal 16 36744604
2023 Repression of CENP-A assembly in metaphase requires HJURP phosphorylation and inhibition by M18BP1. The Journal of cell biology 15 37141119
2023 The CENP-A nucleosome: where and when it happens during the inner kinetochore's assembly. Trends in biochemical sciences 15 37596196
2019 CENP-A Ubiquitylation Is Indispensable to Cell Viability. Developmental cell 15 31550462
2023 CENP-A and CENP-B collaborate to create an open centromeric chromatin state. Nature communications 14 38086807

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