{"gene":"CDCA2","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2006,"finding":"CDCA2 (Repo-Man) selectively recruits PP1γ onto mitotic chromatin at anaphase onset and into the following interphase. Mutating Repo-Man's PP1 binding domain abolishes PP1 recruitment to chromatin without disrupting Repo-Man's own chromatin binding. Knockdown of Repo-Man causes large-scale apoptosis, indicating the Repo-Man/PP1γ complex is essential for cell viability.","method":"Stable isotope labeling proteomics, time-lapse fluorescence microscopy, PP1-binding domain mutagenesis, RNAi knockdown","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (proteomics, mutagenesis, live imaging, RNAi) in a single foundational study; 213 citations","pmids":["16492807"],"is_preprint":false},{"year":2006,"finding":"Repo-Man-PP1 inactivates a chromosome architecture-maintaining activity (termed RCA) at anaphase onset; preventing PP1 recruitment by Repo-Man rescues compact chromosome structure and anaphase segregation in condensin-depleted cells, placing Repo-Man-PP1 downstream of condensin in chromosome compaction control.","method":"Conditional knockout (DT40 cells), live-cell imaging, genetic epistasis (condensin depletion rescued by Repo-Man mutant)","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1–2 — genetic epistasis with conditional KO and live imaging, 178 citations","pmids":["16998479"],"is_preprint":false},{"year":2011,"finding":"PP1γ/Repo-Man complex directly and specifically dephosphorylates histone H3T3ph on chromosome arms, opposing Haspin-mediated H3T3 phosphorylation; this in turn modulates chromosomal targeting of Aurora kinase B and its substrate MCAK in a PP1-dependent manner.","method":"In vitro phosphatase assays, RNAi, immunofluorescence, dominant-negative and PP1-binding mutants","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro phosphatase assay combined with mutagenesis and functional epistasis; 162 citations","pmids":["21514157"],"is_preprint":false},{"year":2011,"finding":"Repo-Man has two functionally distinct domains: a C-terminal domain recruits it to bulk chromatin in early anaphase and targets PP1 for dephosphorylation of H3T3, H3S10, and H3S28; an N-terminal domain localizes Repo-Man to the chromosome periphery later in anaphase and recruits nuclear envelope components Importin β and Nup153 in a PP1-independent manner, coordinating chromatin remodeling with nuclear envelope reformation.","method":"Domain deletion/mutagenesis, live-cell imaging, co-immunoprecipitation, phospho-specific antibodies, RNAi rescue","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 1–2 — domain dissection with multiple orthogonal methods; 161 citations","pmids":["21820363"],"is_preprint":false},{"year":2010,"finding":"Repo-Man interacts with ATM and PP1 through distinct domains in Xenopus egg extracts, leading to PP1-dependent dephosphorylation and inactivation of ATM. Repo-Man thereby sets the activation threshold for the ATM-dependent DNA damage checkpoint; expression of PP1-binding-deficient Repo-Man fails to attenuate DNA damage-induced ATM activation, and Repo-Man dissociates from active ATM at damage sites.","method":"Xenopus egg extract biochemistry, co-immunoprecipitation, domain-specific mutants, RNAi in human cells, soft-agar assay","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 1–2 — biochemical reconstitution in Xenopus extracts plus domain mutagenesis and cellular validation; 84 citations","pmids":["20188555"],"is_preprint":false},{"year":2012,"finding":"Repo-Man (together with Sds22) acts as a PP1-targeting subunit that counteracts Aurora B-dependent phosphorylation of the outer kinetochore component Dsn1 during anaphase; depletion of Repo-Man causes transient pauses in poleward chromosome movement and high-frequency chromosome missegregation.","method":"RNAi screen using a phosphorylation biosensor, immunofluorescence, live-cell imaging","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — RNAi screen with phospho-biosensor and live imaging; 72 citations","pmids":["22801782"],"is_preprint":false},{"year":2013,"finding":"Aurora B phosphorylates Repo-Man at S893, preventing its recruitment to histones and thus its chromosomal targeting. PP2A dephosphorylates S893 to promote Repo-Man chromatin loading. This reciprocal feedback between Aurora B/Haspin and Repo-Man generates a bistable switch that concentrates the CPC at centromeres during prometaphase.","method":"Site-specific mutagenesis (S893), co-immunoprecipitation, phospho-specific antibodies, kinase/phosphatase assays","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 1–2 — site-specific mutagenesis combined with biochemical assays and mechanistic epistasis; 71 citations","pmids":["23746640"],"is_preprint":false},{"year":2017,"finding":"Repo-Man/PP1 is enriched at the nuclear periphery on condensed chromatin via Nup153 in interphase; it dephosphorylates H3S28 and is necessary and sufficient for HP1 binding and H3K27me3 recruitment, thereby regulating heterochromatin formation and repression of polycomb telomeric genes.","method":"Chromatin fractionation, immunofluorescence, ChIP-seq (proteogenomics), RNAi depletion with rescue","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (proteogenomics, ChIP, IF, fractionation) in a single study","pmids":["28091603"],"is_preprint":false},{"year":2017,"finding":"p37/UBXN2B limits cortical NuMA levels in metaphase via PP1 and its regulatory subunit Repo-Man; in anaphase, PP1/Repo-Man promotes NuMA accumulation at the cortex to regulate spindle orientation, acting independently of Gαi, Aurora A, and PP2A.","method":"RNAi, live-cell imaging, co-immunoprecipitation, spindle orientation assay","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 — RNAi with functional phenotype and co-IP, single lab","pmids":["29222185"],"is_preprint":false},{"year":2020,"finding":"Aurora B phosphorylates Repo-Man to dissociate PP1γ from chromosomes; overexpression of phospho-deficient Repo-Man mutants or Aurora B inhibition retains PP1γ on chromatin and prolongs the chromosome condensation state, demonstrating that Aurora B regulates chromosome condensation by disrupting PP1γ–Repo-Man interaction.","method":"Co-immunoprecipitation, immunofluorescence microscopy, Aurora B inhibition, phospho-deficient/mimetic mutants","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP and mutagenesis with functional phenotype, single lab","pmids":["32938714"],"is_preprint":false},{"year":2022,"finding":"Repo-Man is SUMOylated, and this SUMOylation mediates its interaction with lamin A. Repo-Man/PP1 dephosphorylates lamin A at serine 22; depletion of Repo-Man causes nuclear envelope defects and lamin A S22 hyperphosphorylation, which is rescued by wild-type but not SUMOylation-deficient Repo-Man.","method":"In vivo and in vitro interaction assays, SUMOylation mutants, RNAi rescue, immunofluorescence","journal":"Open biology","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro interaction plus mutagenesis and cellular rescue, single lab","pmids":["35414260"],"is_preprint":false},{"year":2013,"finding":"CDCA2 knockdown in oral squamous cell carcinoma cells induces G1 cell-cycle arrest via upregulation of CDK inhibitors (p21, p27, p15, p16) and promotes apoptosis after cisplatin treatment, consistent with CDCA2's role in suppressing ATM-dependent p53/p21 signaling.","method":"shRNA knockdown, flow cytometry, Western blot","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — clean KD with defined cell-cycle phenotype linked to known molecular pathway","pmids":["23418564"],"is_preprint":false},{"year":2021,"finding":"CDCA2 promotes BRCA1 chromatin relocalization to the NRF2 locus, activating NRF2-driven antioxidant signaling (HO-1, TXNRD1, NQO1) and reducing reactive oxygen species; transcription of CDCA2 itself is activated by E2F2/E2F8 binding to its promoter.","method":"RNA-seq, RNAi, ChIP, co-immunoprecipitation, antioxidant rescue (NAC/GSH)","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP and co-IP with functional rescue, single lab","pmids":["34103686"],"is_preprint":false},{"year":2023,"finding":"CDCA2 inhibits SMURF1-mediated ubiquitination and proteasomal degradation of Aurora kinase A (AURKA), stabilizing AURKA protein; AURKA downregulation reverses the pro-proliferative and pro-migratory effects of CDCA2 overexpression in melanoma cells.","method":"Co-immunoprecipitation, ubiquitination assay, protein stability assay, RNAi rescue, in vivo xenograft","journal":"European journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP with ubiquitination assay and epistatic rescue, single lab","pmids":["37196484"],"is_preprint":false},{"year":2026,"finding":"CDCA2 (Repo-Man) is required for cMYC and MYCN protein stabilization in cancer cells; proximity ligation assays show CDCA2 is in close proximity to both MYC and MYCN in vivo. ChIP and promoter mutation studies establish that CDCA2 is a bona fide MYC target gene, forming a positive feedback loop. Degron-mediated CDCA2 depletion reduces viability of triple-negative breast cancer, neuroblastoma, and colon cancer cells.","method":"RNAi, degron-mediated protein degradation, proximity ligation assay, ChIP, promoter mutagenesis","journal":"Open biology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (PLA, ChIP, degron) in a single study, single lab","pmids":["41844234"],"is_preprint":false},{"year":2025,"finding":"PHD1 hydroxylates Repo-Man (CDCA2) at proline 604; this modification promotes the interaction of Repo-Man with PP2A-B56γ. A P604A mutant shows reduced PP2A-B56γ binding, fails to restore normal H3T3 phosphorylation patterns in prometaphase, and causes delayed mitotic completion, chromosome alignment defects, and increased cell death.","method":"Mass spectrometry (proline hydroxylation), siRNA depletion of PHD isoforms, phospho-specific immunofluorescence, site-directed mutagenesis (P604A), live-cell imaging, co-immunoprecipitation","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1–2 — MS identification of modification + mutagenesis + functional phenotype, preprint single lab","pmids":["bio_10.1101_2025.05.06.652400"],"is_preprint":true}],"current_model":"CDCA2 (Repo-Man) is a chromatin-targeting regulatory subunit for PP1γ that recruits the phosphatase to chromosomes at anaphase onset to dephosphorylate histone H3 (T3, S10, S28) and lamin A (S22), thereby coordinating chromosome architecture, nuclear envelope reformation, heterochromatin establishment, and Aurora B/CPC centromeric targeting; it also suppresses ATM-dependent DNA damage checkpoint activation, stabilizes MYC oncoproteins, and inhibits AURKA ubiquitination, with its activity regulated by Aurora B phosphorylation (S893), PP2A-mediated dephosphorylation, and PHD1-mediated prolyl hydroxylation (P604)."},"narrative":{"teleology":[{"year":2006,"claim":"The identity of the factor that recruits PP1γ to chromatin at anaphase was unknown; discovery of CDCA2/Repo-Man as a selective PP1γ-chromatin targeting subunit established the molecular basis for mitotic exit dephosphorylation on chromosomes.","evidence":"Stable isotope labeling proteomics, PP1-binding domain mutagenesis, live-cell imaging, and RNAi in human cells","pmids":["16492807"],"confidence":"High","gaps":["Structural basis of Repo-Man–PP1γ interaction not determined","Substrates beyond bulk chromatin not identified"]},{"year":2006,"claim":"Whether Repo-Man–PP1 had downstream targets beyond chromatin was unclear; genetic epistasis showed it inactivates a condensin-dependent chromosome compaction activity (RCA) at anaphase, placing Repo-Man–PP1 in the condensin pathway.","evidence":"Conditional knockout in DT40 cells with live imaging and condensin depletion rescue","pmids":["16998479"],"confidence":"High","gaps":["Molecular identity of the RCA substrate not defined","Whether this applies to mammalian somatic cells not shown"]},{"year":2010,"claim":"Whether Repo-Man functions outside mitosis was unknown; biochemical reconstitution revealed that Repo-Man directly interacts with ATM and directs PP1-dependent dephosphorylation/inactivation of ATM, establishing a role in tuning the DNA damage checkpoint activation threshold.","evidence":"Xenopus egg extract biochemistry, co-immunoprecipitation, domain mutants, and RNAi in human cells","pmids":["20188555"],"confidence":"High","gaps":["Whether ATM dephosphorylation occurs at physiological damage sites in vivo not resolved","Specific ATM phosphosites targeted by Repo-Man–PP1 not mapped"]},{"year":2011,"claim":"The phosphatase responsible for removing histone H3T3 phosphorylation from chromosome arms—critical for CPC centromeric focusing—was unidentified; in vitro and cellular assays demonstrated that Repo-Man–PP1γ directly dephosphorylates H3T3, H3S10, and H3S28, and that this opposes Haspin to regulate Aurora B and MCAK chromosomal targeting.","evidence":"In vitro phosphatase assays, RNAi, immunofluorescence, dominant-negative and PP1-binding mutants; domain deletion/mutagenesis with live imaging and co-IP","pmids":["21514157","21820363"],"confidence":"High","gaps":["Whether other PP1 targeting subunits contribute to arm H3T3 dephosphorylation not excluded","Quantitative contribution of each histone mark to CPC redistribution unclear"]},{"year":2011,"claim":"How chromatin remodeling is coupled to nuclear envelope reformation was unclear; domain dissection showed that Repo-Man's N-terminal domain independently recruits Importin β and Nup153 to the chromosome periphery in a PP1-independent manner, physically linking histone dephosphorylation to nuclear envelope reassembly.","evidence":"Domain deletion/mutagenesis, live-cell imaging, co-immunoprecipitation, RNAi rescue","pmids":["21820363"],"confidence":"High","gaps":["How Repo-Man N-terminal domain is spatially restricted to chromosome periphery not explained","Direct binding versus indirect recruitment of NE components not fully resolved"]},{"year":2012,"claim":"Whether Repo-Man–PP1 acts at kinetochores during anaphase was unknown; an RNAi screen revealed that Repo-Man counteracts Aurora B phosphorylation of the outer kinetochore component Dsn1, and its depletion causes chromosome missegregation.","evidence":"RNAi screen with phosphorylation biosensor, immunofluorescence, live-cell imaging","pmids":["22801782"],"confidence":"High","gaps":["Whether Repo-Man directly targets PP1 to kinetochores or acts indirectly not distinguished","Relative contribution of Repo-Man versus other PP1 targeting subunits (e.g., KNL1) at kinetochores not defined"]},{"year":2013,"claim":"How Repo-Man's chromatin loading is temporally restricted to anaphase was unknown; identification of Aurora B phosphorylation at S893 as a chromatin-exclusion signal, reversed by PP2A, established a bistable switch mechanism governing Repo-Man's mitotic timing.","evidence":"Site-specific mutagenesis (S893), co-IP, phospho-specific antibodies, kinase/phosphatase assays","pmids":["23746640"],"confidence":"High","gaps":["Whether additional phosphosites contribute to chromatin exclusion not systematically tested","Spatial distribution of PP2A activity relative to Aurora B gradient not mapped"]},{"year":2017,"claim":"Whether Repo-Man–PP1 has interphase chromatin functions beyond checkpoint control was unknown; ChIP and fractionation studies showed it localizes to the nuclear periphery via Nup153 where it dephosphorylates H3S28 to promote HP1 binding and H3K27me3 deposition, establishing a direct role in heterochromatin formation and polycomb-mediated gene silencing.","evidence":"Chromatin fractionation, immunofluorescence, ChIP-seq, RNAi with rescue","pmids":["28091603"],"confidence":"High","gaps":["Genome-wide identification of Repo-Man–dependent heterochromatin domains incomplete","Mechanism of specificity for peripheral versus internal heterochromatin not resolved"]},{"year":2022,"claim":"How Repo-Man targets lamin A for dephosphorylation during NE reformation was unknown; SUMOylation of Repo-Man was shown to mediate its interaction with lamin A, and Repo-Man–PP1 dephosphorylates lamin A at S22, with SUMOylation-deficient mutants failing to rescue NE defects.","evidence":"In vivo and in vitro interaction assays, SUMOylation mutants, RNAi rescue, immunofluorescence","pmids":["35414260"],"confidence":"Medium","gaps":["The SUMO E3 ligase responsible for Repo-Man SUMOylation not identified","Whether other lamin phosphosites are also Repo-Man–PP1 substrates not tested","Single-lab finding awaits independent confirmation"]},{"year":2023,"claim":"Whether CDCA2 has PP1-independent oncogenic functions was unclear; CDCA2 was shown to stabilize AURKA by inhibiting SMURF1-mediated ubiquitination, with epistatic rescue demonstrating AURKA mediates CDCA2's pro-proliferative effects in melanoma.","evidence":"Co-immunoprecipitation, ubiquitination assay, protein stability assay, RNAi rescue, in vivo xenograft","pmids":["37196484"],"confidence":"Medium","gaps":["Whether CDCA2 directly binds SMURF1 or AURKA not resolved","PP1 dependence of this stabilization mechanism not tested","Single cancer type studied"]},{"year":2026,"claim":"Whether CDCA2 stabilizes other oncoproteins and is itself transcriptionally regulated by its targets was unknown; proximity ligation and ChIP studies revealed that CDCA2 stabilizes MYC and MYCN proteins and is a direct MYC transcriptional target, forming a positive feedback loop essential for viability in multiple cancer types.","evidence":"PLA, ChIP, promoter mutagenesis, degron-mediated depletion across TNBC, neuroblastoma, and colon cancer lines","pmids":["41844234"],"confidence":"Medium","gaps":["Mechanism by which CDCA2 stabilizes MYC proteins (ubiquitin-dependent or not) not determined","Whether MYC stabilization requires PP1 activity not tested","Single-lab study"]},{"year":null,"claim":"Key open questions include: the structural basis of the Repo-Man–PP1γ holocomplex on chromatin, the full catalogue of Repo-Man–PP1 substrates genome-wide, the mechanism by which CDCA2 stabilizes oncoproteins (MYC, AURKA) and whether these require PP1 activity, and the in vivo physiological consequences of CDCA2 loss in organismal development.","evidence":"","pmids":[],"confidence":"High","gaps":["No crystal or cryo-EM structure of Repo-Man–PP1γ on nucleosomes","Comprehensive substrate identification via phosphoproteomics not performed","No knockout mouse or in vivo developmental phenotype reported"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,2,3,6,7]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,3,5,10]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[2,3,7]}],"localization":[{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[0,1,2,3,6,9]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,7,10]},{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[3,10]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,1,2,5,6,9]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[2,3,7]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[4]}],"complexes":["Repo-Man–PP1γ holoenzyme"],"partners":["PPP1CC","AURKB","NUP153","KPNB1","LMNA","ATM","AURKA","MYC"],"other_free_text":[]},"mechanistic_narrative":"CDCA2 (Repo-Man) is a PP1γ-targeting regulatory subunit that orchestrates chromatin dephosphorylation during mitotic exit and interphase to coordinate chromosome architecture, centromeric Aurora B localization, nuclear envelope reformation, and heterochromatin establishment. It recruits PP1γ to anaphase chromosomes to dephosphorylate histone H3 at T3, S10, and S28, thereby removing the CPC from chromosome arms to concentrate it at centromeres and enabling HP1 binding and H3K27me3-dependent heterochromatin formation; its N-terminal domain independently recruits Importin β, Nup153, and lamin A (via SUMOylation-dependent interaction) to reassemble the nuclear envelope, with PP1-mediated dephosphorylation of lamin A S22 required for proper lamina reassembly [PMID:16492807, PMID:21820363, PMID:21514157, PMID:28091603, PMID:35414260]. Aurora B phosphorylation of CDCA2 at S893 excludes it from chromatin during prometaphase, and PP2A-mediated dephosphorylation of this site creates a bistable switch that governs its timely chromosomal loading at anaphase onset [PMID:23746640, PMID:32938714]. Beyond mitosis, CDCA2 suppresses ATM-dependent DNA damage signaling by directing PP1 to dephosphorylate ATM, stabilizes MYC/MYCN and AURKA oncoproteins through inhibition of their ubiquitin-dependent degradation, and forms a transcriptional positive feedback loop as a direct MYC target gene [PMID:20188555, PMID:41844234, PMID:37196484]."},"prefetch_data":{"uniprot":{"accession":"Q69YH5","full_name":"Cell division cycle-associated protein 2","aliases":["Recruits PP1 onto mitotic chromatin at anaphase protein","Repo-Man"],"length_aa":1023,"mass_kda":112.7,"function":"Regulator of chromosome structure during mitosis required for condensin-depleted chromosomes to retain their compact architecture through anaphase. Acts by mediating the recruitment of phosphatase PP1-gamma subunit (PPP1CC) to chromatin at anaphase and into the following interphase. At anaphase onset, its association with chromatin targets a pool of PPP1CC to dephosphorylate substrates","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q69YH5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CDCA2","classification":"Not Classified","n_dependent_lines":13,"n_total_lines":1208,"dependency_fraction":0.01076158940397351},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"KPNB1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CDCA2","total_profiled":1310},"omim":[{"mim_id":"618785","title":"CELL DIVISION CYCLE-ASSOCIATED PROTEIN 2; CDCA2","url":"https://www.omim.org/entry/618785"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"bone marrow","ntpm":6.1},{"tissue":"lymphoid tissue","ntpm":10.6},{"tissue":"testis","ntpm":18.2}],"url":"https://www.proteinatlas.org/search/CDCA2"},"hgnc":{"alias_symbol":["Repo-Man","PPP1R81"],"prev_symbol":[]},"alphafold":{"accession":"Q69YH5","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q69YH5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q69YH5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q69YH5-F1-predicted_aligned_error_v6.png","plddt_mean":46.22},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CDCA2","jax_strain_url":"https://www.jax.org/strain/search?query=CDCA2"},"sequence":{"accession":"Q69YH5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q69YH5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q69YH5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q69YH5"}},"corpus_meta":[{"pmid":"16492807","id":"PMC_16492807","title":"Repo-Man recruits PP1 gamma to chromatin and is essential for cell viability.","date":"2006","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/16492807","citation_count":213,"is_preprint":false},{"pmid":"16998479","id":"PMC_16998479","title":"Condensin and Repo-Man-PP1 co-operate in the regulation of chromosome architecture during mitosis.","date":"2006","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/16998479","citation_count":178,"is_preprint":false},{"pmid":"21514157","id":"PMC_21514157","title":"PP1/Repo-man dephosphorylates mitotic histone H3 at T3 and regulates chromosomal aurora B targeting.","date":"2011","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/21514157","citation_count":162,"is_preprint":false},{"pmid":"21820363","id":"PMC_21820363","title":"Repo-Man coordinates chromosomal reorganization with nuclear envelope reassembly during mitotic exit.","date":"2011","source":"Developmental 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Apoptosis and Promotes Cell Proliferation in Prostate Cancer and Is Directly Regulated by HIF-1α Pathway.","date":"2020","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/32509575","citation_count":34,"is_preprint":false},{"pmid":"34103686","id":"PMC_34103686","title":"CDCA2 protects against oxidative stress by promoting BRCA1-NRF2 signaling in hepatocellular carcinoma.","date":"2021","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/34103686","citation_count":30,"is_preprint":false},{"pmid":"24563358","id":"PMC_24563358","title":"Repo-man at the intersection of chromatin remodelling, DNA repair, nuclear envelope organization, and cancer progression.","date":"2014","source":"Advances in experimental medicine and biology","url":"https://pubmed.ncbi.nlm.nih.gov/24563358","citation_count":28,"is_preprint":false},{"pmid":"22555598","id":"PMC_22555598","title":"Repo-Man-PP1: a link between chromatin remodelling and nuclear envelope 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(Amsterdam)","url":"https://pubmed.ncbi.nlm.nih.gov/36588796","citation_count":7,"is_preprint":false},{"pmid":"35694386","id":"PMC_35694386","title":"Cell division cycle associated 2 (CDCA2) upregulation promotes the progression of hepatocellular carcinoma in a p53-dependant manner.","date":"2022","source":"PeerJ","url":"https://pubmed.ncbi.nlm.nih.gov/35694386","citation_count":7,"is_preprint":false},{"pmid":"34036376","id":"PMC_34036376","title":"CDCA2 promotes tumorigenesis and induces radioresistance in oesophageal squamous cell carcinoma cells.","date":"2021","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/34036376","citation_count":6,"is_preprint":false},{"pmid":"32938714","id":"PMC_32938714","title":"Aurora B regulates PP1γ-Repo-Man interactions to maintain the chromosome condensation state.","date":"2020","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/32938714","citation_count":6,"is_preprint":false},{"pmid":"37750838","id":"PMC_37750838","title":"E2F3/CDCA2 reduces radiosensitivity in gastric adenocarcinoma by activating PI3K/AKT pathway.","date":"2023","source":"The British journal of radiology","url":"https://pubmed.ncbi.nlm.nih.gov/37750838","citation_count":6,"is_preprint":false},{"pmid":"34268949","id":"PMC_34268949","title":"CDCA2 triggers in vivo and in vitro proliferation of hepatocellular carcinoma by activating the AKT/CCND1 signaling.","date":"2021","source":"Journal of B.U.ON. : official journal of the Balkan Union of Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34268949","citation_count":6,"is_preprint":false},{"pmid":"39844908","id":"PMC_39844908","title":"DEPDC1B, CDCA2, APOBEC3B, and TYMS are potential hub genes and therapeutic targets for diagnosing dialysis patients with heart failure.","date":"2025","source":"Frontiers in cardiovascular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39844908","citation_count":2,"is_preprint":false},{"pmid":"37083601","id":"PMC_37083601","title":"PPP1R81 correlates with the survival and cell proliferation in lower-grade glioma.","date":"2023","source":"Bioscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/37083601","citation_count":1,"is_preprint":false},{"pmid":"40565058","id":"PMC_40565058","title":"Overexpression of CDCA2 in Diffuse Large B-Cell Lymphoma Promotes Cell Proliferation and Bortezomib Sensitivity.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40565058","citation_count":0,"is_preprint":false},{"pmid":"41844234","id":"PMC_41844234","title":"A CDCA2-MYC positive feedback loop controls cancer cells survival.","date":"2026","source":"Open biology","url":"https://pubmed.ncbi.nlm.nih.gov/41844234","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.02.28.640789","title":"A CDCA2 - MYC positive feedback loop controls cancer cells survival","date":"2025-02-28","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.28.640789","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.05.06.652400","title":"PHD1-dependent hydroxylation of RepoMan (CDCA2) on P604 modulates the control of mitotic progression","date":"2025-05-07","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.06.652400","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15705,"output_tokens":3823,"usd":0.05223},"stage2":{"model":"claude-opus-4-6","input_tokens":7296,"output_tokens":3288,"usd":0.17802},"total_usd":0.23025,"stage1_batch_id":"msgbatch_011kfMfE81o6CTcyhVUqumuW","stage2_batch_id":"msgbatch_01DTputS6WNkH745x1nVSoBo","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2006,\n      \"finding\": \"CDCA2 (Repo-Man) selectively recruits PP1γ onto mitotic chromatin at anaphase onset and into the following interphase. Mutating Repo-Man's PP1 binding domain abolishes PP1 recruitment to chromatin without disrupting Repo-Man's own chromatin binding. Knockdown of Repo-Man causes large-scale apoptosis, indicating the Repo-Man/PP1γ complex is essential for cell viability.\",\n      \"method\": \"Stable isotope labeling proteomics, time-lapse fluorescence microscopy, PP1-binding domain mutagenesis, RNAi knockdown\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (proteomics, mutagenesis, live imaging, RNAi) in a single foundational study; 213 citations\",\n      \"pmids\": [\"16492807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Repo-Man-PP1 inactivates a chromosome architecture-maintaining activity (termed RCA) at anaphase onset; preventing PP1 recruitment by Repo-Man rescues compact chromosome structure and anaphase segregation in condensin-depleted cells, placing Repo-Man-PP1 downstream of condensin in chromosome compaction control.\",\n      \"method\": \"Conditional knockout (DT40 cells), live-cell imaging, genetic epistasis (condensin depletion rescued by Repo-Man mutant)\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — genetic epistasis with conditional KO and live imaging, 178 citations\",\n      \"pmids\": [\"16998479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PP1γ/Repo-Man complex directly and specifically dephosphorylates histone H3T3ph on chromosome arms, opposing Haspin-mediated H3T3 phosphorylation; this in turn modulates chromosomal targeting of Aurora kinase B and its substrate MCAK in a PP1-dependent manner.\",\n      \"method\": \"In vitro phosphatase assays, RNAi, immunofluorescence, dominant-negative and PP1-binding mutants\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro phosphatase assay combined with mutagenesis and functional epistasis; 162 citations\",\n      \"pmids\": [\"21514157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Repo-Man has two functionally distinct domains: a C-terminal domain recruits it to bulk chromatin in early anaphase and targets PP1 for dephosphorylation of H3T3, H3S10, and H3S28; an N-terminal domain localizes Repo-Man to the chromosome periphery later in anaphase and recruits nuclear envelope components Importin β and Nup153 in a PP1-independent manner, coordinating chromatin remodeling with nuclear envelope reformation.\",\n      \"method\": \"Domain deletion/mutagenesis, live-cell imaging, co-immunoprecipitation, phospho-specific antibodies, RNAi rescue\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — domain dissection with multiple orthogonal methods; 161 citations\",\n      \"pmids\": [\"21820363\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Repo-Man interacts with ATM and PP1 through distinct domains in Xenopus egg extracts, leading to PP1-dependent dephosphorylation and inactivation of ATM. Repo-Man thereby sets the activation threshold for the ATM-dependent DNA damage checkpoint; expression of PP1-binding-deficient Repo-Man fails to attenuate DNA damage-induced ATM activation, and Repo-Man dissociates from active ATM at damage sites.\",\n      \"method\": \"Xenopus egg extract biochemistry, co-immunoprecipitation, domain-specific mutants, RNAi in human cells, soft-agar assay\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — biochemical reconstitution in Xenopus extracts plus domain mutagenesis and cellular validation; 84 citations\",\n      \"pmids\": [\"20188555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Repo-Man (together with Sds22) acts as a PP1-targeting subunit that counteracts Aurora B-dependent phosphorylation of the outer kinetochore component Dsn1 during anaphase; depletion of Repo-Man causes transient pauses in poleward chromosome movement and high-frequency chromosome missegregation.\",\n      \"method\": \"RNAi screen using a phosphorylation biosensor, immunofluorescence, live-cell imaging\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — RNAi screen with phospho-biosensor and live imaging; 72 citations\",\n      \"pmids\": [\"22801782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Aurora B phosphorylates Repo-Man at S893, preventing its recruitment to histones and thus its chromosomal targeting. PP2A dephosphorylates S893 to promote Repo-Man chromatin loading. This reciprocal feedback between Aurora B/Haspin and Repo-Man generates a bistable switch that concentrates the CPC at centromeres during prometaphase.\",\n      \"method\": \"Site-specific mutagenesis (S893), co-immunoprecipitation, phospho-specific antibodies, kinase/phosphatase assays\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — site-specific mutagenesis combined with biochemical assays and mechanistic epistasis; 71 citations\",\n      \"pmids\": [\"23746640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Repo-Man/PP1 is enriched at the nuclear periphery on condensed chromatin via Nup153 in interphase; it dephosphorylates H3S28 and is necessary and sufficient for HP1 binding and H3K27me3 recruitment, thereby regulating heterochromatin formation and repression of polycomb telomeric genes.\",\n      \"method\": \"Chromatin fractionation, immunofluorescence, ChIP-seq (proteogenomics), RNAi depletion with rescue\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (proteogenomics, ChIP, IF, fractionation) in a single study\",\n      \"pmids\": [\"28091603\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"p37/UBXN2B limits cortical NuMA levels in metaphase via PP1 and its regulatory subunit Repo-Man; in anaphase, PP1/Repo-Man promotes NuMA accumulation at the cortex to regulate spindle orientation, acting independently of Gαi, Aurora A, and PP2A.\",\n      \"method\": \"RNAi, live-cell imaging, co-immunoprecipitation, spindle orientation assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RNAi with functional phenotype and co-IP, single lab\",\n      \"pmids\": [\"29222185\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Aurora B phosphorylates Repo-Man to dissociate PP1γ from chromosomes; overexpression of phospho-deficient Repo-Man mutants or Aurora B inhibition retains PP1γ on chromatin and prolongs the chromosome condensation state, demonstrating that Aurora B regulates chromosome condensation by disrupting PP1γ–Repo-Man interaction.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence microscopy, Aurora B inhibition, phospho-deficient/mimetic mutants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP and mutagenesis with functional phenotype, single lab\",\n      \"pmids\": [\"32938714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Repo-Man is SUMOylated, and this SUMOylation mediates its interaction with lamin A. Repo-Man/PP1 dephosphorylates lamin A at serine 22; depletion of Repo-Man causes nuclear envelope defects and lamin A S22 hyperphosphorylation, which is rescued by wild-type but not SUMOylation-deficient Repo-Man.\",\n      \"method\": \"In vivo and in vitro interaction assays, SUMOylation mutants, RNAi rescue, immunofluorescence\",\n      \"journal\": \"Open biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro interaction plus mutagenesis and cellular rescue, single lab\",\n      \"pmids\": [\"35414260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CDCA2 knockdown in oral squamous cell carcinoma cells induces G1 cell-cycle arrest via upregulation of CDK inhibitors (p21, p27, p15, p16) and promotes apoptosis after cisplatin treatment, consistent with CDCA2's role in suppressing ATM-dependent p53/p21 signaling.\",\n      \"method\": \"shRNA knockdown, flow cytometry, Western blot\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with defined cell-cycle phenotype linked to known molecular pathway\",\n      \"pmids\": [\"23418564\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CDCA2 promotes BRCA1 chromatin relocalization to the NRF2 locus, activating NRF2-driven antioxidant signaling (HO-1, TXNRD1, NQO1) and reducing reactive oxygen species; transcription of CDCA2 itself is activated by E2F2/E2F8 binding to its promoter.\",\n      \"method\": \"RNA-seq, RNAi, ChIP, co-immunoprecipitation, antioxidant rescue (NAC/GSH)\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP and co-IP with functional rescue, single lab\",\n      \"pmids\": [\"34103686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CDCA2 inhibits SMURF1-mediated ubiquitination and proteasomal degradation of Aurora kinase A (AURKA), stabilizing AURKA protein; AURKA downregulation reverses the pro-proliferative and pro-migratory effects of CDCA2 overexpression in melanoma cells.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, protein stability assay, RNAi rescue, in vivo xenograft\",\n      \"journal\": \"European journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP with ubiquitination assay and epistatic rescue, single lab\",\n      \"pmids\": [\"37196484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CDCA2 (Repo-Man) is required for cMYC and MYCN protein stabilization in cancer cells; proximity ligation assays show CDCA2 is in close proximity to both MYC and MYCN in vivo. ChIP and promoter mutation studies establish that CDCA2 is a bona fide MYC target gene, forming a positive feedback loop. Degron-mediated CDCA2 depletion reduces viability of triple-negative breast cancer, neuroblastoma, and colon cancer cells.\",\n      \"method\": \"RNAi, degron-mediated protein degradation, proximity ligation assay, ChIP, promoter mutagenesis\",\n      \"journal\": \"Open biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (PLA, ChIP, degron) in a single study, single lab\",\n      \"pmids\": [\"41844234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PHD1 hydroxylates Repo-Man (CDCA2) at proline 604; this modification promotes the interaction of Repo-Man with PP2A-B56γ. A P604A mutant shows reduced PP2A-B56γ binding, fails to restore normal H3T3 phosphorylation patterns in prometaphase, and causes delayed mitotic completion, chromosome alignment defects, and increased cell death.\",\n      \"method\": \"Mass spectrometry (proline hydroxylation), siRNA depletion of PHD isoforms, phospho-specific immunofluorescence, site-directed mutagenesis (P604A), live-cell imaging, co-immunoprecipitation\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 — MS identification of modification + mutagenesis + functional phenotype, preprint single lab\",\n      \"pmids\": [\"bio_10.1101_2025.05.06.652400\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"CDCA2 (Repo-Man) is a chromatin-targeting regulatory subunit for PP1γ that recruits the phosphatase to chromosomes at anaphase onset to dephosphorylate histone H3 (T3, S10, S28) and lamin A (S22), thereby coordinating chromosome architecture, nuclear envelope reformation, heterochromatin establishment, and Aurora B/CPC centromeric targeting; it also suppresses ATM-dependent DNA damage checkpoint activation, stabilizes MYC oncoproteins, and inhibits AURKA ubiquitination, with its activity regulated by Aurora B phosphorylation (S893), PP2A-mediated dephosphorylation, and PHD1-mediated prolyl hydroxylation (P604).\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CDCA2 (Repo-Man) is a PP1γ-targeting regulatory subunit that orchestrates chromatin dephosphorylation during mitotic exit and interphase to coordinate chromosome architecture, centromeric Aurora B localization, nuclear envelope reformation, and heterochromatin establishment. It recruits PP1γ to anaphase chromosomes to dephosphorylate histone H3 at T3, S10, and S28, thereby removing the CPC from chromosome arms to concentrate it at centromeres and enabling HP1 binding and H3K27me3-dependent heterochromatin formation; its N-terminal domain independently recruits Importin β, Nup153, and lamin A (via SUMOylation-dependent interaction) to reassemble the nuclear envelope, with PP1-mediated dephosphorylation of lamin A S22 required for proper lamina reassembly [PMID:16492807, PMID:21820363, PMID:21514157, PMID:28091603, PMID:35414260]. Aurora B phosphorylation of CDCA2 at S893 excludes it from chromatin during prometaphase, and PP2A-mediated dephosphorylation of this site creates a bistable switch that governs its timely chromosomal loading at anaphase onset [PMID:23746640, PMID:32938714]. Beyond mitosis, CDCA2 suppresses ATM-dependent DNA damage signaling by directing PP1 to dephosphorylate ATM, stabilizes MYC/MYCN and AURKA oncoproteins through inhibition of their ubiquitin-dependent degradation, and forms a transcriptional positive feedback loop as a direct MYC target gene [PMID:20188555, PMID:41844234, PMID:37196484].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"The identity of the factor that recruits PP1γ to chromatin at anaphase was unknown; discovery of CDCA2/Repo-Man as a selective PP1γ-chromatin targeting subunit established the molecular basis for mitotic exit dephosphorylation on chromosomes.\",\n      \"evidence\": \"Stable isotope labeling proteomics, PP1-binding domain mutagenesis, live-cell imaging, and RNAi in human cells\",\n      \"pmids\": [\"16492807\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of Repo-Man–PP1γ interaction not determined\", \"Substrates beyond bulk chromatin not identified\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Whether Repo-Man–PP1 had downstream targets beyond chromatin was unclear; genetic epistasis showed it inactivates a condensin-dependent chromosome compaction activity (RCA) at anaphase, placing Repo-Man–PP1 in the condensin pathway.\",\n      \"evidence\": \"Conditional knockout in DT40 cells with live imaging and condensin depletion rescue\",\n      \"pmids\": [\"16998479\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular identity of the RCA substrate not defined\", \"Whether this applies to mammalian somatic cells not shown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Whether Repo-Man functions outside mitosis was unknown; biochemical reconstitution revealed that Repo-Man directly interacts with ATM and directs PP1-dependent dephosphorylation/inactivation of ATM, establishing a role in tuning the DNA damage checkpoint activation threshold.\",\n      \"evidence\": \"Xenopus egg extract biochemistry, co-immunoprecipitation, domain mutants, and RNAi in human cells\",\n      \"pmids\": [\"20188555\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ATM dephosphorylation occurs at physiological damage sites in vivo not resolved\", \"Specific ATM phosphosites targeted by Repo-Man–PP1 not mapped\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"The phosphatase responsible for removing histone H3T3 phosphorylation from chromosome arms—critical for CPC centromeric focusing—was unidentified; in vitro and cellular assays demonstrated that Repo-Man–PP1γ directly dephosphorylates H3T3, H3S10, and H3S28, and that this opposes Haspin to regulate Aurora B and MCAK chromosomal targeting.\",\n      \"evidence\": \"In vitro phosphatase assays, RNAi, immunofluorescence, dominant-negative and PP1-binding mutants; domain deletion/mutagenesis with live imaging and co-IP\",\n      \"pmids\": [\"21514157\", \"21820363\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other PP1 targeting subunits contribute to arm H3T3 dephosphorylation not excluded\", \"Quantitative contribution of each histone mark to CPC redistribution unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"How chromatin remodeling is coupled to nuclear envelope reformation was unclear; domain dissection showed that Repo-Man's N-terminal domain independently recruits Importin β and Nup153 to the chromosome periphery in a PP1-independent manner, physically linking histone dephosphorylation to nuclear envelope reassembly.\",\n      \"evidence\": \"Domain deletion/mutagenesis, live-cell imaging, co-immunoprecipitation, RNAi rescue\",\n      \"pmids\": [\"21820363\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Repo-Man N-terminal domain is spatially restricted to chromosome periphery not explained\", \"Direct binding versus indirect recruitment of NE components not fully resolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Whether Repo-Man–PP1 acts at kinetochores during anaphase was unknown; an RNAi screen revealed that Repo-Man counteracts Aurora B phosphorylation of the outer kinetochore component Dsn1, and its depletion causes chromosome missegregation.\",\n      \"evidence\": \"RNAi screen with phosphorylation biosensor, immunofluorescence, live-cell imaging\",\n      \"pmids\": [\"22801782\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Repo-Man directly targets PP1 to kinetochores or acts indirectly not distinguished\", \"Relative contribution of Repo-Man versus other PP1 targeting subunits (e.g., KNL1) at kinetochores not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"How Repo-Man's chromatin loading is temporally restricted to anaphase was unknown; identification of Aurora B phosphorylation at S893 as a chromatin-exclusion signal, reversed by PP2A, established a bistable switch mechanism governing Repo-Man's mitotic timing.\",\n      \"evidence\": \"Site-specific mutagenesis (S893), co-IP, phospho-specific antibodies, kinase/phosphatase assays\",\n      \"pmids\": [\"23746640\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether additional phosphosites contribute to chromatin exclusion not systematically tested\", \"Spatial distribution of PP2A activity relative to Aurora B gradient not mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Whether Repo-Man–PP1 has interphase chromatin functions beyond checkpoint control was unknown; ChIP and fractionation studies showed it localizes to the nuclear periphery via Nup153 where it dephosphorylates H3S28 to promote HP1 binding and H3K27me3 deposition, establishing a direct role in heterochromatin formation and polycomb-mediated gene silencing.\",\n      \"evidence\": \"Chromatin fractionation, immunofluorescence, ChIP-seq, RNAi with rescue\",\n      \"pmids\": [\"28091603\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genome-wide identification of Repo-Man–dependent heterochromatin domains incomplete\", \"Mechanism of specificity for peripheral versus internal heterochromatin not resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"How Repo-Man targets lamin A for dephosphorylation during NE reformation was unknown; SUMOylation of Repo-Man was shown to mediate its interaction with lamin A, and Repo-Man–PP1 dephosphorylates lamin A at S22, with SUMOylation-deficient mutants failing to rescue NE defects.\",\n      \"evidence\": \"In vivo and in vitro interaction assays, SUMOylation mutants, RNAi rescue, immunofluorescence\",\n      \"pmids\": [\"35414260\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The SUMO E3 ligase responsible for Repo-Man SUMOylation not identified\", \"Whether other lamin phosphosites are also Repo-Man–PP1 substrates not tested\", \"Single-lab finding awaits independent confirmation\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Whether CDCA2 has PP1-independent oncogenic functions was unclear; CDCA2 was shown to stabilize AURKA by inhibiting SMURF1-mediated ubiquitination, with epistatic rescue demonstrating AURKA mediates CDCA2's pro-proliferative effects in melanoma.\",\n      \"evidence\": \"Co-immunoprecipitation, ubiquitination assay, protein stability assay, RNAi rescue, in vivo xenograft\",\n      \"pmids\": [\"37196484\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether CDCA2 directly binds SMURF1 or AURKA not resolved\", \"PP1 dependence of this stabilization mechanism not tested\", \"Single cancer type studied\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Whether CDCA2 stabilizes other oncoproteins and is itself transcriptionally regulated by its targets was unknown; proximity ligation and ChIP studies revealed that CDCA2 stabilizes MYC and MYCN proteins and is a direct MYC transcriptional target, forming a positive feedback loop essential for viability in multiple cancer types.\",\n      \"evidence\": \"PLA, ChIP, promoter mutagenesis, degron-mediated depletion across TNBC, neuroblastoma, and colon cancer lines\",\n      \"pmids\": [\"41844234\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which CDCA2 stabilizes MYC proteins (ubiquitin-dependent or not) not determined\", \"Whether MYC stabilization requires PP1 activity not tested\", \"Single-lab study\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include: the structural basis of the Repo-Man–PP1γ holocomplex on chromatin, the full catalogue of Repo-Man–PP1 substrates genome-wide, the mechanism by which CDCA2 stabilizes oncoproteins (MYC, AURKA) and whether these require PP1 activity, and the in vivo physiological consequences of CDCA2 loss in organismal development.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal or cryo-EM structure of Repo-Man–PP1γ on nucleosomes\", \"Comprehensive substrate identification via phosphoproteomics not performed\", \"No knockout mouse or in vivo developmental phenotype reported\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 2, 3, 6, 7]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 3, 5, 10]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [2, 3, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [0, 1, 2, 3, 6, 9]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 7, 10]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [3, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 1, 2, 5, 6, 9]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [2, 3, 7]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"complexes\": [\n      \"Repo-Man–PP1γ holoenzyme\"\n    ],\n    \"partners\": [\n      \"PPP1CC\",\n      \"AURKB\",\n      \"NUP153\",\n      \"KPNB1\",\n      \"LMNA\",\n      \"ATM\",\n      \"AURKA\",\n      \"MYC\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}