Affinage

CENPP

Centromere protein P · UniProt Q6IPU0

Length
288 aa
Mass
33.2 kDa
Annotated
2026-06-09
20 papers in source corpus 9 papers cited in narrative 11 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/5 claims corpus-supported (80%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CENPP (CENP-P) is a constitutive subunit of the inner-kinetochore CCAN that helps ensure accurate chromosome segregation during mitosis (PMID:16622419). It functions within the CENP-O complex (CENP-O/P/Q/U/R), which is not pre-assembled in the cytoplasm but loads stepwise onto kinetochores during S-phase, with CENP-P and CENP-O entering as a heterodimer and the complex docking onto the CCAN largely through interactions with CENP-L and CENP-K (PMID:23028590). Structural work in yeast established the molecular basis of this assembly: the CENP-P ortholog (Ctf19) forms an RWD-domain heterodimer with the CENP-O ortholog (Mcm21) that binds a motif in the CENP-Q ortholog (Okp1), positioning this branch of the inner kinetochore (PMID:29046335). Within the reconstituted human kinetochore, the CENP-OPQUR module binds a joint interface on the CENP-HIKM and CENP-LN complexes, placing CENP-P in the structural bridge that connects CENP-A chromatin to the KMN microtubule-binding machinery (PMID:30174292). Functionally, CENP-P and CENP-Q are required to recruit CENP-U to kinetochores, and CENP-U in turn recruits Plk1 in parallel with Bub1 to stabilize kinetochore-microtubule attachments (PMID:24481920, PMID:25395579, PMID:34551298); loss of the CENP-O complex removes all its subunits from kinetochores and causes chromosome alignment and segregation errors (PMID:16622419, PMID:24481920).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2006 High

    Established CENP-P as a bona fide centromere component by placing it within the CENP-A-associated CCAN, defining its cellular address before any mechanism was known.

    Evidence Affinity purification/MS, co-IP, and immunofluorescence localization of the CAD/NAC group

    PMID:16622419

    Open questions at the time
    • Did not resolve CENP-P's specific binding partners within the complex
    • CENP-P was not individually depleted to define its own loss-of-function phenotype
  2. 2006 Medium

    Linked the CCAN module containing CENP-P to mitotic fidelity, showing that disruption of the assembly it depends on causes lethal chromosome alignment and segregation errors.

    Evidence RNAi knockdown of the CENP-A NAC with mitotic phenotype readout

    PMID:16622419

    Open questions at the time
    • Phenotype attributed to NAC disruption rather than CENP-P depletion specifically
    • Does not separate CENP-P's contribution from other complex subunits
  3. 2012 High

    Defined how the CENP-P-containing sub-complex assembles, showing it loads stepwise on kinetochores as CENP-O/P heterodimers rather than as a pre-formed cytoplasmic unit, with CCAN docking via CENP-L and CENP-K.

    Evidence F3H, FRET, SNAP-tag, immunostaining, and FRAP in living mammalian cells

    PMID:23028590

    Open questions at the time
    • Did not provide atomic-resolution interface details
    • Functional consequence of slow exchange dynamics not established
  4. 2012 Medium

    Placed CENP-O complex loading temporally in S-phase, identifying a late-S oligomerization maturation step for CENP-Q/CENP-U.

    Evidence SNAP-tag pulse-chase and immunostaining

    PMID:23028590

    Open questions at the time
    • Whether CENP-P itself undergoes maturation/oligomerization not addressed
    • Single-lab timing data
  5. 2014 Medium

    Demonstrated interdependence within the complex, showing CENP-P is required for CENP-U kinetochore localization and that the subunits stand or fall together for targeting.

    Evidence Conditional CENP-U knockout in mouse ES cells with immunofluorescence

    PMID:24481920

    Open questions at the time
    • Did not determine direct vs indirect basis of CENP-P-CENP-U dependence
    • Single-lab localization assay
  6. 2014 Medium

    Connected the CENP-O complex to a signaling output by showing CENP-P/Q recruit CENP-U, which targets Plk1 to kinetochores.

    Evidence RNAi depletion with Plk1 kinetochore quantification and congression assays

    PMID:25395579

    Open questions at the time
    • Direct CENP-U-Plk1 binding mode not resolved here
    • Relative contribution of CENP-P vs CENP-Q to recruitment not separated
  7. 2017 High

    Provided the structural mechanism of complex assembly, showing the CENP-P ortholog forms an RWD-domain heterodimer with the CENP-O ortholog that binds the CENP-Q ortholog to configure the inner kinetochore.

    Evidence Crystal structure of Ctf19-Mcm21 RWD domains with Okp1 peptide, HDX-MS, native MS (K. lactis)

    PMID:29046335

    Open questions at the time
    • Structure derived from yeast orthologs, not human CENP-P
    • Human CENP-P structure not solved
  8. 2018 High

    Positioned CENP-P architecturally within the human kinetochore, showing the CENP-OPQUR module bridges CENP-HIKM/CENP-LN to connect CENP-A chromatin with KMN.

    Evidence In vitro reconstitution of a 26-subunit recombinant kinetochore particle with biochemical binding assays

    PMID:30174292

    Open questions at the time
    • Reconstituted system may not capture all in vivo regulation
    • Microtubule attachment function not directly assayed
  9. 2019 High

    Revealed a regulatory function for the CENP-P ortholog C-terminus, linking it to chromosome segregation fidelity via interaction with the Aurora B/CPC core in yeast.

    Evidence Crosslink-guided in vitro reconstitution plus genetic rescue/epistasis (S. cerevisiae)

    PMID:31112132

    Open questions at the time
    • CPC interaction shown in yeast; human CENP-P-CPC interaction not established
    • 2021 work indicates the human complex does not regulate Aurora B localization, leaving species divergence unresolved
  10. 2021 High

    Refined the human signaling model, confirming CENP-P/Q recruit CENP-U and that CENP-U and Bub1 redundantly recruit Plk1 to stabilize attachments, while excluding Aurora B regulation by the human complex.

    Evidence siRNA/shRNA depletion, Plk1/Aurora B kinetochore quantification, segregation assays, pharmacological inhibition

    PMID:34551298

    Open questions at the time
    • Mechanistic basis of the species difference in Aurora B regulation not resolved
    • Direct CENP-P contacts to CENP-U not structurally defined
  11. 2021 Medium

    Identified an upstream transcriptional regulator, showing CDK4 occupies the CENPP promoter and regulates its expression in keratinocytes.

    Evidence ChIP-qPCR plus CDK4 gain/loss-of-function with CENPP mRNA readout (mouse)

    PMID:34429772

    Open questions at the time
    • Single-study, single-cell-type observation
    • Functional consequence of CDK4-driven CENPP expression not established
    • Direct vs indirect promoter regulation not distinguished

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CENP-P contributes mechanistically to microtubule attachment stability beyond Plk1 recruitment, and whether the yeast CENP-P-CPC interaction has a human counterpart, remain unresolved.
  • No human structural model of CENP-P-containing interfaces resolved at atomic detail
  • CENP-P-specific (vs whole-complex) loss-of-function phenotype not isolated
  • Species divergence in Aurora B/CPC regulation unexplained

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3
Localization
GO:0005694 chromosome 3 GO:0000228 nuclear chromosome 2
Pathway
R-HSA-1640170 Cell Cycle 3
Partners
CENPKCENPLCENPOCENPQCENPRCENPU
Complex memberships
CCANCENP-O complex (CENP-OPQUR)COMA (yeast ortholog)

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 CENP-P (CENPP) is a component of the CENP-A nucleosome distal (CAD) centromere complex, assembling on the CENP-A NAC (comprised of CENP-M, CENP-N, CENP-T, CENP-U(50), CENP-C, CENP-H). CENP-P localizes to centromeres as part of the CAD group along with CENP-K, CENP-L, CENP-O, CENP-Q, CENP-R, and CENP-S. Affinity purification / mass spectrometry, co-immunoprecipitation, immunofluorescence localization Nature cell biology High 16622419
2006 Disruption of the CENP-A NAC (which CENP-P depends on for centromere assembly) causes errors of chromosome alignment and segregation that preclude cell survival, establishing CENP-P's functional requirement in mitotic fidelity through its position in the CCAN hierarchy. RNAi knockdown with mitotic phenotype readout (chromosome alignment/segregation errors) Nature cell biology Medium 16622419
2012 CENP-P/O/R/Q/U form a tightly packed sub-complex with multifold protein-protein interactions. The sub-complex is not pre-assembled in the cytoplasm but is assembled stepwise on kinetochores, with CENP-O/P loading as heterodimers. Binding to the CCAN is largely mediated through interactions with CENP-L and CENP-K. Once assembled, CENP-P/O/R/Q/U exchanges slowly with the free nucleoplasmic pool. Fluorescent three-hybrid (F3H) assay, FRET in living mammalian cells, SNAP-tag experiments, immunostaining, FRAP PloS one High 23028590
2012 CENP-P/O/R/Q/U kinetochore loading occurs during S-phase, similar to the nucleosome-binding CCAN components CENP-T/W/N. During late S-phase, CENP-Q and CENP-U (but not CENP-R) undergo oligomerization after the kinetochore-binding step, suggesting a pre-mitotic maturation step. SNAP-tag pulse-chase experiments and immunostaining PloS one Medium 23028590
2014 CENP-P is required for kinetochore localization of CENP-U; when CENP-U is absent (or the CENP-O complex is disrupted), all CENP-O complex proteins including CENP-P disappear from kinetochores while other kinetochore proteins are unaffected, indicating interdependence within the CENP-O complex for kinetochore targeting. Conditional knockout (CENP-U deficiency in mouse ES cells) with immunofluorescence to assess kinetochore localization of complex members Chromosome research Medium 24481920
2014 The CENP-O complex (comprising CENP-O, CENP-P, CENP-Q and CENP-U) targets polo-like kinase 1 (Plk1) to kinetochores; CENP-P and CENP-Q subunits are specifically required for kinetochore recruitment of CENP-U, which in turn recruits Plk1. RNAi depletion of CENP-Q/CENP-O complex subunits with immunofluorescence quantification of Plk1 kinetochore levels and chromosome congression assays Journal of cell science Medium 25395579
2017 In yeast (Kluyveromyces lactis), the COMA complex (Ame1/Okp1/Ctf19/Mcm21, orthologs of CENP-U/Q/P/O) has a defined subunit topology: Ctf19 (CENP-P ortholog) forms an RWD domain-based heterodimer with Mcm21 (CENP-O ortholog) that binds a specific motif in Okp1 (CENP-Q ortholog), configuring a branch of the inner kinetochore and tethering Chl4/Iml3 (CENP-N/L orthologs). Crystal structure of Ctf19-Mcm21 RWD domains bound with Okp1 peptide, hydrogen-deuterium exchange MS, nanoflow ESI-MS The EMBO journal High 29046335
2018 The human CENP-OPQUR complex binds to a joint interface on the CENP-HIKM and CENP-LN complexes to form an 11-subunit CCAN core, which then connects KMN and CENP-A in a reconstituted 26-subunit particle. CENP-P is thus part of the structural bridge between CENP-A chromatin and the microtubule-binding machinery. In vitro reconstitution of recombinant 26-subunit kinetochore particle, biochemical binding assays Molecular cell High 30174292
2019 In budding yeast, the COMA complex (Ctf19/Mcm21/Ame1/Okp1, orthologs of CENP-P/O/U/Q) selectively binds Cse4 (CENP-A) nucleosomes through the Cse4 N-terminus. The Ctf19 C-terminus (CENP-P ortholog C-terminus) interacts with the Sli15/Ipl1 (INCENP/Aurora B) core-CPC in vitro, and deletion of this C-terminus affects chromosome segregation fidelity. In vitro reconstitution of kinetochore complexes guided by crosslinking MS; genetic rescue experiments (tethering Sli15 to Ame1/Okp1 rescues Ctf19 depletion synthetic lethality) eLife High 31112132
2021 CENP-U is recruited to kinetochores by the CENP-P and CENP-Q subunits of the CENP-O complex; CENP-U and Bub1 redundantly recruit Plk1 to kinetochores to stabilize kinetochore-microtubule attachments. The CENP-O complex (unlike its budding yeast homolog) does not regulate centromeric localization of Aurora B in human cells. Stable protein depletion (siRNA/shRNA), immunofluorescence quantification of Plk1 and Aurora B kinetochore levels, chromosome segregation assays, pharmacological inhibition Cell reports High 34551298
2021 CDK4 occupies the promoter region of the CENPP gene in mouse keratinocytes and regulates its transcription; gain- and loss-of-function experiments demonstrated that CDK4 participates in transcriptional regulation of CENP-P expression. Chromatin immunoprecipitation (ChIP) followed by RT-qPCR; CDK4 gain- and loss-of-function experiments with CENPP mRNA quantification Oncology letters Medium 34429772

Source papers

Stage 0 corpus · 20 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
2011 The ABCs of CENPs. Chromosoma 164 21751032
2019 The COMA complex interacts with Cse4 and positions Sli15/Ipl1 at the budding yeast inner kinetochore. eLife 67 31112132
2018 Reconstitution of a 26-Subunit Human Kinetochore Reveals Cooperative Microtubule Binding by CENP-OPQUR and NDC80. Molecular cell 62 30174292
2014 Chromosome congression is promoted by CENP-Q- and CENP-E-dependent pathways. Journal of cell science 43 25395579
2021 Bub1 and CENP-U redundantly recruit Plk1 to stabilize kinetochore-microtubule attachments and ensure accurate chromosome segregation. Cell reports 36 34551298
2012 Step-wise assembly, maturation and dynamic behavior of the human CENP-P/O/R/Q/U kinetochore sub-complex. PloS one 33 23028590
2023 Fathers' preconception smoking and offspring DNA methylation. Clinical epigenetics 32 37649101
2014 The CENP-O complex requirement varies among different cell types. Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology 32 24481920
2017 Molecular basis for inner kinetochore configuration through RWD domain-peptide interactions. The EMBO journal 27 29046335
2013 New centromere autoantigens identified in systemic sclerosis using centromere protein microarrays. The Journal of rheumatology 26 23418382
2024 Enriched Single-Nucleus RNA-Sequencing Reveals Unique Attributes of Distal Convoluted Tubule Cells. Journal of the American Society of Nephrology : JASN 15 38238903
2019 RAP-8 ameliorates liver fibrosis by modulating cell cycle and oxidative stress. Life sciences 14 31047894
2015 Exposure to fluorescent light triggers down regulation of genes involved with mitotic progression in Xiphophorus skin. Comparative biochemistry and physiology. Toxicology & pharmacology : CBP 13 26334372
2017 CENP-R acts bilaterally as a tumor suppressor and as an oncogene in the two-stage skin carcinogenesis model. Cancer science 9 28795467
2023 Immunomodulatory effect of Atractylodis macrocephala Koidz. polysaccharides in vitro. Poultry science 6 37925772
2022 Exploring a four-gene risk model based on doxorubicin resistance-associated lncRNAs in hepatocellular carcinoma. Frontiers in pharmacology 5 36457707
2021 A nomogram based on CENPP expression for survival prediction in breast cancer. Gland surgery 3 34268072
2022 A novel nonsense variant in the CENPP gene segregates in a Swiss family with autosomal dominant low-frequency sensorineural hearing loss. European journal of human genetics : EJHG 2 36071244
2021 CDK4 has the ability to regulate Aurora B and Cenpp expression in mouse keratinocytes. Oncology letters 2 34429772

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