Affinage

CHAMP1

Chromosome alignment-maintaining phosphoprotein 1 · UniProt Q96JM3

Length
812 aa
Mass
89.1 kDa
Annotated
2026-06-09
25 papers in source corpus 14 papers cited in narrative 16 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CHAMP1 is a chromatin-associated zinc-finger phosphoprotein that operates across mitotic fidelity, heterochromatin assembly, and DNA double-strand break (DSB) repair (PMID:21063390, PMID:39962076). During mitosis it localizes to chromosomes, kinetochores, and the spindle under CDK1-dependent phosphorylation of its FPE region, which counteracts the negative regulation imposed by its C-terminal zinc fingers and is required for proper chromosome alignment; loss of CHAMP1 destabilizes kinetochore-microtubule attachments and reduces kinetochore loading of CENP-E and CENP-F (PMID:21063390). CHAMP1 forms a stable complex with POGZ, HP1α, and the H3K9 methyltransferase SETDB1 that drives H3K9me3-marked heterochromatin assembly at centromeres and telomeres and is recruited, via the adaptor CDYL2, to pericentromeric H3K9me3 to sustain mitotic accuracy (PMID:36658409, PMID:39962076). This complex also supports genome stability under replication stress, depositing H3K9me3 at stalled forks to shield them from MRE11-mediated degradation and promote ORC2 recruitment and fork restart (PMID:41481470, PMID:40799599). In DSB repair, CHAMP1 binds the REV7 seatbelt domain to displace the Shieldin complex and, together with POGZ, promotes CtIP/pRPA2-dependent end resection and BRCA1 recruitment, biasing repair toward homologous recombination (PMID:36044844, PMID:35393543). CHAMP1 additionally maintains Mcl-1 by suppressing its proteasomal degradation, promoting survival during mitotic arrest (PMID:34107118), and acts as a MyoD cofactor through its C2H2 zinc fingers to activate Myomaker and drive myoblast fusion (PMID:41540007). Loss-of-function CHAMP1 mutations cause an intellectual disability disorder, with patient cells showing delocalized protein, impaired heterochromatin clustering, and HR deficiency through haploinsufficiency (PMID:26751395, PMID:39738383, PMID:39962076).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2010 High

    Established CHAMP1's foundational mitotic role by showing it is a CDK1-phosphorylated kinetochore/spindle protein whose domains govern chromosome alignment and kinetochore-microtubule attachment.

    Evidence Immunofluorescence, CDK1 phosphorylation assays, domain-deletion mutants, and siRNA depletion with alignment/tension phenotypes in human cells

    PMID:21063390

    Open questions at the time
    • Structural basis of FPE-mediated localization not resolved
    • Direct kinase-substrate stoichiometry of CDK1 phosphosites not mapped
  2. 2015 Medium

    Linked the C-terminal zinc fingers to localization control by mapping patient truncating mutations onto the domain structure.

    Evidence Functional inference from patient mutations mapped to domains, consistent with prior deletion experiments

    PMID:26340335

    Open questions at the time
    • No direct biochemical reconstitution in this study
    • Does not establish DNA/chromatin binding partners of the zinc fingers
  3. 2016 Medium

    Provided a molecular mechanism for pathogenicity by showing disease variants lose chromatin localization and binding to POGZ and HP1.

    Evidence Co-IP/binding assays and localization with patient-derived CHAMP1 variants

    PMID:26751395

    Open questions at the time
    • Single lab, no reciprocal structural mapping of POGZ/HP1 interfaces
    • Functional consequence on downstream pathways not tested here
  4. 2017 Medium

    Extended CHAMP1 function beyond alignment to cytokinesis, showing depletion causes centrosome amplification and multipolar spindles.

    Evidence Depletion in culture cells plus patient lymphoblastoid cell analysis with immunofluorescence

    PMID:28944241

    Open questions at the time
    • Mechanism linking CHAMP1 to cytokinesis machinery undefined
    • Single lab
  5. 2021 Medium

    Identified a survival function by showing CHAMP1 maintains Mcl-1 levels and suppresses its proteasomal degradation during mitotic arrest.

    Evidence siRNA depletion, live-cell imaging, proteasome inhibitor rescue, RT-PCR/Western blot

    PMID:34107118

    Open questions at the time
    • Direct mechanism of Mcl-1 protein stabilization not defined
    • Whether CHAMP1 acts directly on Mcl-1 or via intermediates unknown
  6. 2022 High

    Defined a direct DSB repair-choice mechanism: CHAMP1 binds the REV7 seatbelt domain to displace Shieldin and promote end resection, and with POGZ drives CtIP/pRPA2 recruitment and BRCA1 loading toward HR.

    Evidence Direct binding/pulldown to REV7, Shieldin/end-resection assays, laser micro-irradiation recruitment, and depletion epistasis for BRCA1/53BP1/pRPA2/CtIP

    PMID:35393543 PMID:36044844

    Open questions at the time
    • Structural detail of CHAMP1-REV7-Shieldin competition not resolved
    • Quantitative contribution relative to other anti-Shieldin factors unclear
  7. 2022 Medium

    Established a cell-autonomous developmental role by showing CHAMP1 loss delays neuronal differentiation and increases mitotic cells in cortex.

    Evidence CHAMP1 knockout mouse, NSC differentiation assays, in vivo knockdown

    PMID:36106092

    Open questions at the time
    • Molecular link between mitotic/repair functions and differentiation timing undefined
    • Single lab
  8. 2023 Medium

    Identified CDYL2 as an upstream adaptor coupling pericentromeric H3K9me3 to the CHAMP1-POGZ complex for mitotic fidelity.

    Evidence Mass spectrometry interactome, CDYL2 domain-mapping RNAi rescue, immunofluorescence for CHAMP1 pericentromeric localization

    PMID:36658409

    Open questions at the time
    • Direct vs. indirect CDYL2-CHAMP1 contact not structurally resolved
    • Single lab
  9. 2025 High

    Unified the heterochromatin and repair functions by defining a CHAMP1-POGZ-HP1α-SETDB1 complex that assembles H3K9me3 heterochromatin at centromeres/telomeres and protects stalled forks from MRE11 degradation while enabling HR in heterochromatic regions.

    Evidence Co-IP/complex reconstitution, ChIP, fork-protection and MRE11 degradation assays, ORC2 recruitment, ALT telomere and DSB repair assays in cell lines and patient lymphocytes

    PMID:39962076 PMID:40799599 PMID:41481470

    Open questions at the time
    • Order of complex assembly and SETDB1 recruitment hierarchy not fully resolved
    • How fork protection integrates with the REV7/Shieldin axis unclear
  10. 2024 Medium

    Demonstrated that intellectual disability-associated PTC mutations cause an HR defect through haploinsufficiency, linking the repair function to disease.

    Evidence HR assays in patient lymphoblastoid cells and fibroblasts, U2OS mutant rescue, heterozygous depletion in DLD-1 cells

    PMID:39738383

    Open questions at the time
    • Causal contribution of HR defect to neurodevelopmental phenotype not directly shown
    • Single lab
  11. 2026 High

    Revealed a transcriptional role: CHAMP1 zinc fingers bind MyoD to activate Myomaker and drive myoblast fusion, with patient cells showing rescuable fusion defects.

    Evidence Co-IP/ChIP for CHAMP1-MyoD, Myomaker expression assays, domain mutation analysis, patient-cell rescue, in vitro and in vivo fusion assays

    PMID:41540007

    Open questions at the time
    • Whether CHAMP1 binds DNA directly at the Myomaker locus vs. via MyoD unclear
    • Relationship between transcriptional and mitotic/repair roles undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CHAMP1's distinct activities — kinetochore attachment, heterochromatin/fork protection, HR repair-choice, Mcl-1 stability, and MyoD-driven transcription — are coordinated by a single protein and which is most relevant to neurodevelopmental disease remains unresolved.
  • No integrated structural model of CHAMP1 across its functions
  • Tissue-specific partitioning of functions not established
  • Causal hierarchy linking molecular defects to clinical phenotype unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0003677 DNA binding 1 GO:0140110 transcription regulator activity 1
Localization
GO:0005634 nucleus 2 GO:0005694 chromosome 2 GO:0005815 microtubule organizing center 2 GO:0000228 nuclear chromosome 1
Pathway
R-HSA-73894 DNA Repair 5 R-HSA-1640170 Cell Cycle 4 R-HSA-4839726 Chromatin organization 3 R-HSA-1266738 Developmental Biology 2 R-HSA-74160 Gene expression (Transcription) 1
Partners
CDYL2HP1ΑMYODPOGZREV7SETDB1
Complex memberships
CHAMP1-POGZ-HP1α-SETDB1 complex

Evidence

Reading pass · 16 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 CHAMP1 (CAMP/C13orf8/ZNF828) localizes to chromosomes, the mitotic spindle, and kinetochores, and undergoes CDK1-dependent phosphorylation at multiple sites during mitosis. The FPE region is responsible for spindle and kinetochore localization and is essential for proper chromosome alignment. The C-terminal zinc-finger domain negatively regulates chromosome alignment, and phosphorylation in the FPE region counteracts this negative regulation. Immunofluorescence localization, CDK1 phosphorylation assays, domain-deletion/mutation analysis, siRNA depletion The EMBO journal High 21063390
2010 CHAMP1 depletion causes severe chromosome misalignment associated with poor resistance of K-fibres to tension during sister kinetochore bi-orientation, establishing CHAMP1 as required for maintaining kinetochore-microtubule attachment. siRNA depletion, live-cell imaging, chromosome alignment assays The EMBO journal High 21063390
2010 CHAMP1 depletion reduces kinetochore localization of CENP-E and CENP-F, placing these proteins as downstream effectors of CHAMP1 in the kinetochore-microtubule attachment pathway. siRNA depletion, immunofluorescence, CHAMP1 mutant rescue experiments The EMBO journal High 21063390
2015 The C-terminal zinc-finger domains of CHAMP1 regulate its localization to chromosomes and the mitotic spindle; truncating mutations predicted to remove these domains are loss-of-function mutations causing mislocalization. Functional inference from patient mutations mapped to known domain structure; consistent with prior domain-deletion experiments American journal of human genetics Medium 26340335
2016 CHAMP1 disease-causing protein variants are delocalized from chromatin and are unable to bind two direct partners, POGZ and HP1, providing a molecular mechanism for pathogenicity. Co-immunoprecipitation / binding assays using patient-derived CHAMP1 variants; localization assays Human mutation Medium 26751395
2017 CHAMP1-depleted human cells and patient-derived lymphoblastoid cells show increased centrosome number and multipolar spindle formation, attributed to cytokinesis failure, establishing a role for CHAMP1 in cytokinesis and centrosome number maintenance. CHAMP1 depletion in culture cells, patient lymphoblastoid cell analysis, immunofluorescence microscopy Molecular genetics & genomic medicine Medium 28944241
2021 CHAMP1 maintains Mcl-1 expression at both the mRNA and protein level independently of the cell cycle; at the protein level, CHAMP1 suppresses proteasome-dependent degradation of Mcl-1, thereby promoting cell survival during mitotic arrest. siRNA depletion, live-cell imaging, proteasome inhibitor rescue, RT-PCR/Western blot for Mcl-1 levels Cancer science Medium 34107118
2022 CHAMP1 binds directly to REV7 via the REV7 C-terminal seatbelt domain. This binding reduces the level of the Shieldin complex, causing increased double-strand break end resection, thereby activating homologous recombination (HR) repair instead of NHEJ. Direct binding assay (Co-IP/pulldown), Shieldin complex level measurement, end-resection assays Cell reports High 36044844
2022 CHAMP1 is recruited to laser-micro-irradiation-induced DSB sites and promotes HR but not NHEJ. CHAMP1 depletion suppresses BRCA1 recruitment but not 53BP1 recruitment at DSB sites, placing CHAMP1 upstream of BRCA1 in DSB repair pathway choice. Laser micro-irradiation, live-cell imaging, siRNA depletion, immunofluorescence for repair factors at DSBs Oncogene Medium 35393543
2022 CHAMP1, in complex with POGZ, promotes DNA end resection for HR: depletion of either CHAMP1 or POGZ impairs recruitment of phosphorylated RPA2 and CtIP at DSB sites. siRNA depletion of CHAMP1 or POGZ, immunofluorescence for pRPA2 and CtIP at laser-induced DSBs Oncogene Medium 35393543
2022 CHAMP1 deficiency causes delayed neuronal differentiation in neural stem cells in vitro and in vivo, and increased mitotic cells in the cerebral cortex, establishing a cell-autonomous role in neuronal development. CHAMP1 knockout mouse (homozygous and heterozygous), neural stem cell culture differentiation assays, CHAMP1 knockdown in vivo Brain communications Medium 36106092
2023 CDYL2 interacts directly with CHAMP1 and POGZ via a central non-conserved region, and CDYL2 depletion causes loss of CHAMP1 localization at pericentromeres, placing CDYL2 as an upstream adaptor that connects pericentromeric H3K9me3 to the CHAMP1-POGZ complex for mitotic fidelity. Mass spectrometry interactome analysis, RNAi rescue assays (CDYL2 domain mapping), immunofluorescence for CHAMP1 pericentromeric localization Cellular and molecular life sciences : CMLS Medium 36658409
2024 CHAMP1 premature termination codon (PTC) mutations found in intellectual disability patients are loss-of-function mutations that cause an HR defect through haploinsufficiency: heterozygous depletion of CHAMP1 in DLD-1 cells causes an HR defect, and patient-derived fibroblasts with PTC mutations show HR deficiency at induced DSBs. HR assays in patient-derived lymphoblastoid cells and fibroblasts, U2OS rescue experiments with CHAMP1 mutants, heterozygous CHAMP1 depletion in DLD-1 cells Scientific reports Medium 39738383
2025 The CHAMP1 complex (CHAMP1, POGZ, HP1α, SETDB1) promotes heterochromatin assembly at centromeres and telomeres, recruits the H3K9me3 methyltransferase SETDB1 to heterochromatin, and is required for homology-directed repair of DSBs in heterochromatic regions including ALT telomeres. Patient lymphocytes with CHAMP1 mutations show defective heterochromatin clustering and defective DSB repair. Chromatin fractionation, ChIP, Co-IP of CHAMP1-POGZ-HP1α-SETDB1 complex, DSB repair assays in patient lymphocytes and cell lines, ALT telomere assays Nature communications High 39962076
2025 Upon replication stress, the CHAMP1 complex (CHAMP1, POGZ, HP1α, SETDB1) is recruited to stalled replication forks, facilitates H3K9me3 deposition, shields forks from MRE11-mediated degradation, and promotes ORC2 recruitment; loss of CHAMP1 impairs fork restart and increases micronuclei formation. iPOND or fork protection assays, H3K9me3 ChIP at stalled forks, MRE11 fork degradation assays, ORC2 recruitment assays, micronuclei quantification Proceedings of the National Academy of Sciences of the United States of America High 40799599 41481470
2026 CHAMP1 acts as a MyoD cofactor in myoblasts: C2H2-type zinc-finger motifs of CHAMP1 directly interact with MyoD and activate transcription of the muscle fusogen Myomaker, which is required for human myoblast fusion. Patient-derived cells with CHAMP1 mutations show fusion defects rescuable by restoring Myomaker expression. Genomic and protein-interaction assays (Co-IP/ChIP for CHAMP1-MyoD interaction), Myomaker expression assays, CHAMP1 domain deletion/mutation analysis, patient-derived cell rescue experiments, in vitro and in vivo fusion assays Nature communications High 41540007

Source papers

Stage 0 corpus · 25 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 De Novo Mutations in CHAMP1 Cause Intellectual Disability with Severe Speech Impairment. American journal of human genetics 78 26340335
2010 CAMP (C13orf8, ZNF828) is a novel regulator of kinetochore-microtubule attachment. The EMBO journal 57 21063390
2016 De Novo Truncating Mutations in the Kinetochore-Microtubules Attachment Gene CHAMP1 Cause Syndromic Intellectual Disability. Human mutation 45 26751395
2016 De novo pathogenic variants in CHAMP1 are associated with global developmental delay, intellectual disability, and dysmorphic facial features. Cold Spring Harbor molecular case studies 34 27148580
2022 CHAMP1 binds to REV7/FANCV and promotes homologous recombination repair. Cell reports 26 36044844
2022 CHAMP1-POGZ counteracts the inhibitory effect of 53BP1 on homologous recombination and affects PARP inhibitor resistance. Oncogene 17 35393543
2021 Neurodevelopmental phenotypes in individuals with pathogenic variants in CHAMP1. Cold Spring Harbor molecular case studies 14 34021018
2021 Chromosome alignment-maintaining phosphoprotein CHAMP1 plays a role in cell survival through regulating Mcl-1 expression. Cancer science 11 34107118
2017 Disturbed chromosome segregation and multipolar spindle formation in a patient with CHAMP1 mutation. Molecular genetics & genomic medicine 11 28944241
2025 CHAMP1 complex directs heterochromatin assembly and promotes homology-directed DNA repair. Nature communications 9 39962076
2023 CHAMP1-related disorders: pathomechanisms triggered by different genomic alterations define distinct nosological categories. European journal of human genetics : EJHG 9 36797464
2022 Deficiency of CHAMP1, a gene related to intellectual disability, causes impaired neuronal development and a mild behavioural phenotype. Brain communications 5 36106092
2023 Chromodomain on Y-like 2 (CDYL2) implicated in mitosis and genome stability regulation via interaction with CHAMP1 and POGZ. Cellular and molecular life sciences : CMLS 4 36658409
2024 CHAMP1 premature termination codon mutations found in individuals with intellectual disability cause a homologous recombination defect through haploinsufficiency. Scientific reports 3 39738383
2021 First Chinese patient with mental retardation-40 due to a de novo CHAMP1 frameshift mutation: Case report and literature review. Experimental and therapeutic medicine 3 34257719
2021 Intellectual disability and microcephaly associated with a novel CHAMP1 mutation. Human genome variation 3 34404773
2023 Prospective phenotyping of CHAMP1 disorder indicates that coding mutations may not act through haploinsufficiency. Human genetics 2 37454340
2023 CHAMP1-Related Disorder: Sharing 20 Years of thorough Clinical Follow-Up and Review of the Literature. Genes 2 37628598
2020 [Autosomal dominant intellectual disability-40 caused by a de novo mutation of the CHAMP1 gene: a case report]. Zhongguo dang dai er ke za zhi = Chinese journal of contemporary pediatrics 2 33059813
2023 [Analysis of a child with autosomal dominant mental retardation type 40 due to variant of CHAMP1 gene]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 1 36585000
2026 CHAMP1 complex promotes heterochromatin assembly and reduces replication stress. Proceedings of the National Academy of Sciences of the United States of America 0 41481470
2026 CHAMP1 is an essential regulator for human myoblast fusion and muscle development. Nature communications 0 41540007
2026 CHAMP1-Related Neurodevelopmental Disorder: Two Turkish Cases with Novel Truncating Variants and Literature Review. Molecular syndromology 0 42125344
2025 CHAMP1 Complex Promotes Heterochromatin Assembly and Reduces Replication Stress. bioRxiv : the preprint server for biology 0 40799599
2025 Clinical characteristics, molecular mechanisms, and exploration of association with gastrointestinal symptoms in CHAMP1 gene variation-related neurodevelopmental disorders. Frontiers in neurology 0 41111978

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