{"gene":"CDCA7L","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2005,"finding":"CDCA7L (R1/RAM2) was identified as a novel transcriptional repressor of the MAO A gene. It was cloned by yeast one-hybrid screening using Sp1-binding sites in the MAO A core promoter. Transfection of R1 in neuroblastoma cells inhibited MAO A promoter and enzymatic activity in a dose-dependent manner. Gel-shift assay showed endogenous R1 protein interacted with the R1 binding sequence, and ChIP confirmed direct binding to the natural MAO A promoter in vivo. Immunocytochemical analysis showed R1 is expressed in both cytosol and nucleus.","method":"Yeast one-hybrid screen, luciferase reporter assay, gel-shift/EMSA, chromatin immunoprecipitation (ChIP), immunocytochemistry, transfection overexpression","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (yeast one-hybrid, EMSA, ChIP, reporter assay) in a single focused study establishing direct DNA binding and transcriptional repression","pmids":["15654081"],"is_preprint":false},{"year":2006,"finding":"Glucocorticoid (dexamethasone) induces time-dependent translocation of CDCA7L (R1) from the cytosol to the nucleus in neuroblastoma and glioblastoma cells, but not in R1 knockdown cells. R1 interacts with Sp1-binding sites in the MAO A promoter and represses MAO A gene expression. Glucocorticoid receptor interacts indirectly with the MAO A promoter via Sp1 or R1. Androgen receptor interacts with Sp1 but not R1 on Sp1 sites, revealing differential regulation.","method":"Luciferase reporter assay, gel-shift/EMSA, shRNA knockdown, immunofluorescence/immunocytochemistry for subcellular localization","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal knockdown validation, EMSA, reporter assays, and direct localization experiment with functional consequence in a single focused study","pmids":["16728402"],"is_preprint":false},{"year":2006,"finding":"In serum starvation-induced apoptosis, R1 (CDCA7L/JPO2) protein levels are reduced while MAO A and caspase-3 are increased. Using p38 kinase inhibitor, R1 overexpression, and MAO A inhibitor, R1 and MAO A were positioned downstream of p38 kinase and Bcl-2 but upstream of caspase-3 in the apoptotic signaling pathway. Immunoprecipitation and immunohistochemistry demonstrated that c-Myc co-localizes with R1 and induces R1 gene expression. R1 and MAO A were shown to act upstream of cyclin D1 and E2F1 in c-Myc-induced proliferative signaling.","method":"Pharmacological inhibition (p38 inhibitor, MAO A inhibitor), overexpression, siRNA knockdown, co-immunoprecipitation, immunohistochemistry, western blot","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis established by multiple orthogonal interventions (inhibitors, overexpression, siRNA), co-IP for c-Myc/R1 interaction, in a single focused study","pmids":["16829576"],"is_preprint":false},{"year":2006,"finding":"CDCA7L (JPO2) associates with transcriptional co-activator p75 (LEDGF/p75) both in vitro and in vivo. The PHAT domain of p75, which mediates its interaction with HIV-1 integrase, also mediates interaction with JPO2. Recombinant integrase competes with JPO2 for binding to p75 in vitro (mutually competitive). JPO2 binds p75 through a 61-residue region (amino acids 58–119) distinct from its Myc-interacting domain. In cells, JPO2 and p75 co-localize throughout the cell cycle and concentrate on condensed chromosomes during mitosis. JPO2 association with chromatin strictly depends upon p75, and p75 stabilizes intracellular steady-state levels of JPO2.","method":"In vitro binding assay, co-immunoprecipitation, competitive binding with recombinant proteins, domain mapping, live-cell co-localization (fluorescence microscopy), protein stability assay","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal in vitro and in vivo binding confirmed, competition assay, domain mapping, and live-cell co-localization with functional consequence (chromatin tethering, protein stability)","pmids":["16735438"],"is_preprint":false},{"year":2005,"finding":"CDCA7L (JPO2) was identified as a novel c-Myc NH2-terminal domain (MycNTD) binding protein by two-hybrid screening of a medulloblastoma cDNA library. JPO2 shows nuclear co-localization with c-Myc and interacts with c-Myc both in vitro and in mammalian cells. In Rat1a transformation assays, JPO2 potentiates c-Myc transforming activity and can complement a transformation-defective Myc mutant. RNAi-mediated JPO2 knockdown impairs colony formation in medulloblastoma cells.","method":"Yeast two-hybrid screen, in vitro binding, co-immunoprecipitation, immunofluorescence co-localization, Rat1a transformation assay, RNAi knockdown/colony formation assay","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — interaction confirmed by yeast two-hybrid, in vitro binding, and co-IP; functional role confirmed by transformation assay and RNAi loss-of-function with specific phenotypic readout","pmids":["15994933"],"is_preprint":false},{"year":2007,"finding":"JPO2 (CDCA7L) was identified as a binding partner of the C-terminal integrase-binding domain (IBD) of LEDGF/p75 by yeast two-hybrid screening. Specific interaction was verified by pull-down, AlphaScreen, and co-immunoprecipitation. Competition assays using recombinant proteins showed mutually exclusive binding of either JPO2 or HIV-1 integrase to LEDGF/p75. Notably, JPO2 retains binding to certain LEDGF/p75 mutants (I365A, D366A, F406A) that are totally defective for HIV-1 integrase interaction, indicating different binding mechanisms. JPO2 overexpression caused modest but reproducible inhibition of HIV-1 replication, consistent with competition for LEDGF/p75. JPO2 overexpression also activated transcription from the HIV-1 LTR.","method":"Yeast two-hybrid screen, pull-down, AlphaScreen, co-immunoprecipitation, competition assay with recombinant proteins, site-directed mutagenesis of LEDGF/p75, HIV-1 replication assay, LTR-driven reporter assay","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — interaction confirmed by three independent methods (pull-down, AlphaScreen, co-IP), mutagenesis mapping, and functional consequence in viral replication assay","pmids":["17669426"],"is_preprint":false},{"year":2010,"finding":"CDCA7L (R1/RAM2/JPO2) was identified as a novel transcriptional repressor of MAO B using Sp1-binding motifs as bait in a yeast one-hybrid screen. EMSA demonstrated that R1 competed with Sp1 for binding to the Sp1 site in the MAO B promoter in vitro. R1 reduced Sp1-activated glucocorticoid activation of MAO B promoter activity. ChIP analysis showed lower occupancy by R1 at the MAO B core promoter in response to dexamethasone.","method":"Yeast one-hybrid screen, EMSA, luciferase reporter assay, chromatin immunoprecipitation (ChIP)","journal":"Molecular pharmacology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (yeast one-hybrid, EMSA, ChIP, reporter assay) establishing direct DNA binding and competition with Sp1 at the MAO B promoter","pmids":["20980443"],"is_preprint":false},{"year":2016,"finding":"A multiple myeloma risk SNP (rs4487645 G>T) resides in an enhancer element 47 kb upstream of CDCA7L. The G-risk allele increases IRF4 binding at the enhancer, which interacts with the CDCA7L promoter by chromatin looping. The G allele is associated with increased CDCA7L expression. Suppression of CDCA7L limits myeloma cell proliferation through apoptosis.","method":"Genetic association + functional characterization: chromatin conformation capture (enhancer-promoter interaction), IRF4 ChIP, reporter assay, siRNA knockdown with proliferation/apoptosis readout","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — enhancer-promoter interaction confirmed by chromatin conformation capture, IRF4 binding by ChIP, and loss-of-function knockdown with specific apoptosis readout","pmids":["27882933"],"is_preprint":false},{"year":2016,"finding":"JPO2 (CDCA7L) and its partner LEDGF/p75 are critical modulators of PI3K/AKT signaling and metastasis in medulloblastoma. JPO2 overexpression induced metastatic medulloblastoma in vivo. Two synergistic feed-forward regulatory circuits involving LEDGF/p75 and AKT were identified as promoting metastatic phenotypes downstream of JPO2.","method":"In vivo medulloblastoma metastasis model, overexpression, identification of JPO2:LEDGF/p75 protein complex, pathway analysis (PI3K/AKT signaling readouts)","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo model with defined phenotype and protein complex identified, but pathway circuit details rely on single lab with limited orthogonal validation in abstract","pmids":["27013196"],"is_preprint":false},{"year":2011,"finding":"R1 (CDCA7L/JPO2) protein levels are significantly reduced by ~37.5% in postmortem prefrontal cortex of untreated MDD subjects compared to controls, and this reduction is significantly correlated with an approximately 40% increase in MAO A protein levels and MAO A catalytic activity within the same MDD groups. This supports an in vivo regulatory relationship between R1 and MAO A.","method":"Western blot quantification of postmortem human brain tissue, MAO A catalytic activity assay, correlation analysis","journal":"Neuropsychopharmacology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct protein quantification in human postmortem tissue with correlated MAO A activity, but purely correlative/observational rather than interventional","pmids":["21654740"],"is_preprint":false}],"current_model":"CDCA7L (JPO2/RAM2/R1) is a nuclear transcriptional repressor that binds Sp1 sites in the MAO A and MAO B promoters to suppress their expression; it interacts directly with c-Myc (via the MycNTD) to potentiate oncogenic transformation; it is tethered to chromatin and stabilized by LEDGF/p75 through its PHAT domain in a manner that competes with HIV-1 integrase binding; it participates in apoptotic and proliferative signaling downstream of p38/Bcl-2 and upstream of caspase-3/cyclin D1; its expression is regulated by an IRF4-bound enhancer element whose risk allele drives increased CDCA7L expression in multiple myeloma; and in medulloblastoma, the JPO2:LEDGF/p75 complex promotes metastasis by modulating PI3K/AKT signaling."},"narrative":{"mechanistic_narrative":"CDCA7L (also called R1/RAM2/JPO2) is a nuclear transcriptional repressor and c-Myc cofactor that links transcriptional control of monoamine oxidase genes to oncogenic proliferation and survival signaling [PMID:15654081, PMID:15994933]. It was cloned through Sp1-binding sites in the MAO A core promoter and represses MAO A transcription by binding the promoter directly, competing with Sp1; the same Sp1-competition mechanism represses MAO B, and glucocorticoid signaling drives its cytosol-to-nucleus translocation to modulate this repression [PMID:15654081, PMID:20980443, PMID:16728402]. Independently identified as a binding partner of the c-Myc NH2-terminal domain, CDCA7L co-localizes with and binds c-Myc, potentiates c-Myc transforming activity, and complements a transformation-defective Myc mutant, with its loss impairing colony formation in medulloblastoma cells [PMID:15994933]. Within apoptotic and proliferative circuits, CDCA7L acts downstream of p38 kinase and Bcl-2 but upstream of caspase-3, and upstream of cyclin D1 and E2F1 in c-Myc-induced proliferation [PMID:16829576]. CDCA7L is tethered to chromatin and stabilized by the transcriptional co-activator LEDGF/p75, binding the same PHAT/integrase-binding domain that engages HIV-1 integrase such that the two compete for LEDGF/p75; this association is required for CDCA7L chromatin loading and underlies a JPO2:LEDGF/p75 complex that promotes PI3K/AKT-driven metastasis in medulloblastoma [PMID:16735438, PMID:17669426, PMID:27013196]. Its expression is elevated by a multiple myeloma risk allele at an upstream IRF4-bound enhancer, and CDCA7L supports myeloma cell proliferation and suppresses apoptosis [PMID:27882933].","teleology":[{"year":2005,"claim":"Established CDCA7L's two foundational activities — that it is a sequence-specific transcriptional repressor of MAO A and an independent c-Myc cofactor — defining it as both a DNA-binding regulator and an oncogenic partner.","evidence":"Yeast one-hybrid via Sp1 sites with EMSA/ChIP/reporter for MAO A repression; yeast two-hybrid against MycNTD with transformation and RNAi assays for the Myc link","pmids":["15654081","15994933"],"confidence":"High","gaps":["Direct DNA-binding domain of CDCA7L not mapped","Mechanism by which it potentiates Myc transformation (cofactor recruitment vs. target gene effects) unresolved"]},{"year":2006,"claim":"Connected CDCA7L's MAO A repression to upstream glucocorticoid signaling through ligand-induced nuclear translocation, showing its repressor activity is regulated rather than constitutive.","evidence":"Reporter assays, EMSA, shRNA knockdown, and immunofluorescence localization in neuroblastoma/glioblastoma cells","pmids":["16728402"],"confidence":"High","gaps":["Signal transducing the dexamethasone cue to CDCA7L translocation not identified","Whether translocation involves post-translational modification unknown"]},{"year":2006,"claim":"Positioned CDCA7L within apoptotic and proliferative pathways by epistasis, placing it downstream of p38/Bcl-2 and upstream of caspase-3, cyclin D1, and E2F1, and confirming c-Myc induces its expression.","evidence":"Pharmacological inhibition, overexpression, siRNA, co-IP, and IHC in apoptosis and proliferation models","pmids":["16829576"],"confidence":"High","gaps":["Direct molecular targets mediating caspase-3 and cyclin D1 effects not defined","Whether the apoptotic role is dependent on MAO A activity vs. independent transcriptional targets unresolved"]},{"year":2006,"claim":"Identified LEDGF/p75 as the factor that tethers CDCA7L to chromatin and stabilizes it, revealing how a repressor lacking strong autonomous chromatin retention is loaded onto chromosomes.","evidence":"In vitro and in vivo binding, domain mapping (aa 58–119), competition with recombinant integrase, live-cell co-localization, and protein stability assays","pmids":["16735438"],"confidence":"High","gaps":["Functional consequence of chromatin tethering for specific target genes not tested","Genomic loci co-occupied by CDCA7L and LEDGF/p75 not mapped"]},{"year":2007,"claim":"Refined the CDCA7L–LEDGF/p75 interface and demonstrated functional competition with HIV-1 integrase, showing CDCA7L can interfere with viral replication and activate the HIV-1 LTR.","evidence":"Yeast two-hybrid, pull-down, AlphaScreen, co-IP, LEDGF/p75 mutagenesis, HIV-1 replication and LTR reporter assays","pmids":["17669426"],"confidence":"High","gaps":["Physiological relevance of LTR activation by CDCA7L unclear","Distinct binding determinants on LEDGF/p75 for CDCA7L vs. integrase only partially mapped"]},{"year":2010,"claim":"Generalized the Sp1-competition repressor mechanism beyond MAO A to MAO B, establishing CDCA7L as a coordinated regulator of monoamine oxidase gene expression.","evidence":"Yeast one-hybrid, EMSA Sp1-competition, ChIP, and reporter assays on the MAO B promoter","pmids":["20980443"],"confidence":"High","gaps":["Whether additional Sp1-driven promoters are targets not surveyed","Stoichiometry of CDCA7L vs. Sp1 occupancy in vivo not quantified"]},{"year":2011,"claim":"Provided in vivo human evidence for the CDCA7L–MAO A regulatory axis by correlating reduced CDCA7L with elevated MAO A in depressive disorder brain tissue.","evidence":"Western blot quantification and MAO A activity assay in postmortem prefrontal cortex with correlation analysis","pmids":["21654740"],"confidence":"Medium","gaps":["Correlative/observational, not interventional","Causality and directionality in human brain not established"]},{"year":2016,"claim":"Defined the genetic and cellular basis of CDCA7L overexpression in multiple myeloma, linking an IRF4-bound enhancer risk allele to increased expression and a pro-proliferative, anti-apoptotic role.","evidence":"Chromatin conformation capture, IRF4 ChIP, reporter assays, and siRNA knockdown with proliferation/apoptosis readouts","pmids":["27882933"],"confidence":"High","gaps":["Downstream effectors of CDCA7L driving myeloma proliferation not identified","Whether the Myc or LEDGF/p75 axis mediates the myeloma phenotype untested"]},{"year":2016,"claim":"Extended the JPO2:LEDGF/p75 complex to a metastatic function, showing CDCA7L drives medulloblastoma metastasis via feed-forward PI3K/AKT circuits.","evidence":"In vivo medulloblastoma metastasis model with overexpression, complex identification, and PI3K/AKT pathway readouts","pmids":["27013196"],"confidence":"Medium","gaps":["Pathway circuit details from a single lab with limited orthogonal validation","Direct molecular link between CDCA7L and AKT activation not resolved"]},{"year":null,"claim":"How CDCA7L's transcriptional repressor activity, its c-Myc cofactor function, and its LEDGF/p75-dependent chromatin tethering are mechanistically integrated into a single coherent activity remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of CDCA7L or its complexes","Genome-wide direct target set not defined","Whether MAO repression and oncogenic cofactor roles share a common molecular surface unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,6]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,6]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,2]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1,3,4]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,6,7]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[2,7]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[7,8]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[8]}],"complexes":["JPO2:LEDGF/p75 complex"],"partners":["PSIP1","MYC","SP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96GN5","full_name":"Cell division cycle-associated 7-like protein","aliases":["Protein JPO2","Transcription factor RAM2"],"length_aa":454,"mass_kda":52.2,"function":"Plays a role in transcriptional regulation as a repressor that inhibits monoamine oxidase A (MAOA) activity and gene expression by binding to the promoter. Plays an important oncogenic role in mediating the full transforming effect of MYC in medulloblastoma cells. Involved in apoptotic signaling pathways; May act downstream of P38-kinase and BCL-2, but upstream of CASP3/caspase-3 as well as CCND1/cyclin D1 and E2F1","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q96GN5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CDCA7L","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"HIST2H2BE","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CDCA7L","total_profiled":1310},"omim":[{"mim_id":"615203","title":"RHOMBOID DOMAIN-CONTAINING PROTEIN 2; RHBDD2","url":"https://www.omim.org/entry/615203"},{"mim_id":"609685","title":"CELL DIVISION CYCLE-ASSOCIATED PROTEIN 7-LIKE; CDCA7L","url":"https://www.omim.org/entry/609685"},{"mim_id":"309850","title":"MONOAMINE OXIDASE A; MAOA","url":"https://www.omim.org/entry/309850"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nucleoli","reliability":"Supported"},{"location":"Nucleoli fibrillar center","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"bone marrow","ntpm":48.8}],"url":"https://www.proteinatlas.org/search/CDCA7L"},"hgnc":{"alias_symbol":["RAM2","R1","JPO2"],"prev_symbol":[]},"alphafold":{"accession":"Q96GN5","domains":[{"cath_id":"-","chopping":"329-452","consensus_level":"medium","plddt":92.2588,"start":329,"end":452}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96GN5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96GN5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96GN5-F1-predicted_aligned_error_v6.png","plddt_mean":66.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CDCA7L","jax_strain_url":"https://www.jax.org/strain/search?query=CDCA7L"},"sequence":{"accession":"Q96GN5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96GN5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96GN5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96GN5"}},"corpus_meta":[{"pmid":"12040173","id":"PMC_12040173","title":"TNF-R1 signaling: a beautiful 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microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/7694035","citation_count":22,"is_preprint":false},{"pmid":"29742458","id":"PMC_29742458","title":"Interferons type II and their receptors R1 and R2 in fish species: Evolution, structure, and function.","date":"2018","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/29742458","citation_count":22,"is_preprint":false},{"pmid":"10684288","id":"PMC_10684288","title":"Activation of lymphocyte signaling by the R1 protein of rhesus monkey rhadinovirus.","date":"2000","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/10684288","citation_count":22,"is_preprint":false},{"pmid":"27013196","id":"PMC_27013196","title":"JPO2/CDCA7L and LEDGF/p75 Are Novel Mediators of PI3K/AKT Signaling and Aggressive Phenotypes in Medulloblastoma.","date":"2016","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/27013196","citation_count":21,"is_preprint":false},{"pmid":"19132322","id":"PMC_19132322","title":"Impact of TNF-R1 and CD95 internalization on apoptotic and antiapoptotic signaling.","date":"2009","source":"Results and problems in cell differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/19132322","citation_count":21,"is_preprint":false},{"pmid":"19643596","id":"PMC_19643596","title":"TRAIL-R1 polymorphisms and cancer susceptibility: an evidence-based meta-analysis.","date":"2009","source":"European journal of cancer (Oxford, England : 1990)","url":"https://pubmed.ncbi.nlm.nih.gov/19643596","citation_count":21,"is_preprint":false},{"pmid":"12182940","id":"PMC_12182940","title":"Cloning and characterization of rhesus monkey MCH-R1 and MCH-R2.","date":"2002","source":"Peptides","url":"https://pubmed.ncbi.nlm.nih.gov/12182940","citation_count":21,"is_preprint":false},{"pmid":"26138346","id":"PMC_26138346","title":"TRAIL-receptor preferences in pancreatic cancer cells revisited: Both TRAIL-R1 and TRAIL-R2 have a licence to kill.","date":"2015","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/26138346","citation_count":21,"is_preprint":false},{"pmid":"16426839","id":"PMC_16426839","title":"Functional expression of TRAIL receptors TRAIL-R1 and TRAIL-R2 in esophageal adenocarcinoma.","date":"2006","source":"European journal of cancer (Oxford, England : 1990)","url":"https://pubmed.ncbi.nlm.nih.gov/16426839","citation_count":20,"is_preprint":false},{"pmid":"17454214","id":"PMC_17454214","title":"Maternal and umbilical sTNF-R1 in preeclamptic pregnancies with intrauterine normal and growth retarded fetus.","date":"2007","source":"Hypertension in pregnancy","url":"https://pubmed.ncbi.nlm.nih.gov/17454214","citation_count":20,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50883,"output_tokens":3858,"usd":0.10526,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10887,"output_tokens":3554,"usd":0.071642,"stage2_stop_reason":"end_turn"},"total_usd":0.176902,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"Looking through the abstracts for papers about the canonical human/mammalian protein CDCA7L (also known as RAM2, R1, JPO2), I need to carefully distinguish this gene from the many other genes that share these alias symbols (ribonucleotide reductase R1, plasmid R1, TRAIL-R1, GABA-B R1, NMDA R1, etc.).\n\nRelevant papers for CDCA7L/JPO2/RAM2/R1 (the transcription factor/Myc-interacting protein):\n- PMID:15654081 (Chen et al. 2005) - R1 as MAO A repressor\n- PMID:16728402 (Ou et al. 2006) - glucocorticoid regulation of MAO A via R1\n- PMID:16829576 (Ou et al. 2006) - MAO A and R1 in apoptosis\n- PMID:16735438 (Maertens et al. 2006) - JPO2 binds p75/LEDGF\n- PMID:15994933 (Huang et al. 2005) - JPO2 as c-Myc interactor\n- PMID:17669426 (Bartholomeeusen et al. 2007) - JPO2 and LEDGF/p75 interaction\n- PMID:21654740 (Johnson et al. 2011) - R1 in MDD\n- PMID:20980443 (Chen et al. 2010) - EAPP and R1 regulate MAO B\n- PMID:27882933 (Li et al. 2016) - CDCA7L in multiple myeloma\n- PMID:27013196 (Chan et al. 2016) - JPO2/CDCA7L in medulloblastoma\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"CDCA7L (R1/RAM2) was identified as a novel transcriptional repressor of the MAO A gene. It was cloned by yeast one-hybrid screening using Sp1-binding sites in the MAO A core promoter. Transfection of R1 in neuroblastoma cells inhibited MAO A promoter and enzymatic activity in a dose-dependent manner. Gel-shift assay showed endogenous R1 protein interacted with the R1 binding sequence, and ChIP confirmed direct binding to the natural MAO A promoter in vivo. Immunocytochemical analysis showed R1 is expressed in both cytosol and nucleus.\",\n      \"method\": \"Yeast one-hybrid screen, luciferase reporter assay, gel-shift/EMSA, chromatin immunoprecipitation (ChIP), immunocytochemistry, transfection overexpression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (yeast one-hybrid, EMSA, ChIP, reporter assay) in a single focused study establishing direct DNA binding and transcriptional repression\",\n      \"pmids\": [\"15654081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Glucocorticoid (dexamethasone) induces time-dependent translocation of CDCA7L (R1) from the cytosol to the nucleus in neuroblastoma and glioblastoma cells, but not in R1 knockdown cells. R1 interacts with Sp1-binding sites in the MAO A promoter and represses MAO A gene expression. Glucocorticoid receptor interacts indirectly with the MAO A promoter via Sp1 or R1. Androgen receptor interacts with Sp1 but not R1 on Sp1 sites, revealing differential regulation.\",\n      \"method\": \"Luciferase reporter assay, gel-shift/EMSA, shRNA knockdown, immunofluorescence/immunocytochemistry for subcellular localization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal knockdown validation, EMSA, reporter assays, and direct localization experiment with functional consequence in a single focused study\",\n      \"pmids\": [\"16728402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"In serum starvation-induced apoptosis, R1 (CDCA7L/JPO2) protein levels are reduced while MAO A and caspase-3 are increased. Using p38 kinase inhibitor, R1 overexpression, and MAO A inhibitor, R1 and MAO A were positioned downstream of p38 kinase and Bcl-2 but upstream of caspase-3 in the apoptotic signaling pathway. Immunoprecipitation and immunohistochemistry demonstrated that c-Myc co-localizes with R1 and induces R1 gene expression. R1 and MAO A were shown to act upstream of cyclin D1 and E2F1 in c-Myc-induced proliferative signaling.\",\n      \"method\": \"Pharmacological inhibition (p38 inhibitor, MAO A inhibitor), overexpression, siRNA knockdown, co-immunoprecipitation, immunohistochemistry, western blot\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis established by multiple orthogonal interventions (inhibitors, overexpression, siRNA), co-IP for c-Myc/R1 interaction, in a single focused study\",\n      \"pmids\": [\"16829576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CDCA7L (JPO2) associates with transcriptional co-activator p75 (LEDGF/p75) both in vitro and in vivo. The PHAT domain of p75, which mediates its interaction with HIV-1 integrase, also mediates interaction with JPO2. Recombinant integrase competes with JPO2 for binding to p75 in vitro (mutually competitive). JPO2 binds p75 through a 61-residue region (amino acids 58–119) distinct from its Myc-interacting domain. In cells, JPO2 and p75 co-localize throughout the cell cycle and concentrate on condensed chromosomes during mitosis. JPO2 association with chromatin strictly depends upon p75, and p75 stabilizes intracellular steady-state levels of JPO2.\",\n      \"method\": \"In vitro binding assay, co-immunoprecipitation, competitive binding with recombinant proteins, domain mapping, live-cell co-localization (fluorescence microscopy), protein stability assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal in vitro and in vivo binding confirmed, competition assay, domain mapping, and live-cell co-localization with functional consequence (chromatin tethering, protein stability)\",\n      \"pmids\": [\"16735438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CDCA7L (JPO2) was identified as a novel c-Myc NH2-terminal domain (MycNTD) binding protein by two-hybrid screening of a medulloblastoma cDNA library. JPO2 shows nuclear co-localization with c-Myc and interacts with c-Myc both in vitro and in mammalian cells. In Rat1a transformation assays, JPO2 potentiates c-Myc transforming activity and can complement a transformation-defective Myc mutant. RNAi-mediated JPO2 knockdown impairs colony formation in medulloblastoma cells.\",\n      \"method\": \"Yeast two-hybrid screen, in vitro binding, co-immunoprecipitation, immunofluorescence co-localization, Rat1a transformation assay, RNAi knockdown/colony formation assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — interaction confirmed by yeast two-hybrid, in vitro binding, and co-IP; functional role confirmed by transformation assay and RNAi loss-of-function with specific phenotypic readout\",\n      \"pmids\": [\"15994933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"JPO2 (CDCA7L) was identified as a binding partner of the C-terminal integrase-binding domain (IBD) of LEDGF/p75 by yeast two-hybrid screening. Specific interaction was verified by pull-down, AlphaScreen, and co-immunoprecipitation. Competition assays using recombinant proteins showed mutually exclusive binding of either JPO2 or HIV-1 integrase to LEDGF/p75. Notably, JPO2 retains binding to certain LEDGF/p75 mutants (I365A, D366A, F406A) that are totally defective for HIV-1 integrase interaction, indicating different binding mechanisms. JPO2 overexpression caused modest but reproducible inhibition of HIV-1 replication, consistent with competition for LEDGF/p75. JPO2 overexpression also activated transcription from the HIV-1 LTR.\",\n      \"method\": \"Yeast two-hybrid screen, pull-down, AlphaScreen, co-immunoprecipitation, competition assay with recombinant proteins, site-directed mutagenesis of LEDGF/p75, HIV-1 replication assay, LTR-driven reporter assay\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — interaction confirmed by three independent methods (pull-down, AlphaScreen, co-IP), mutagenesis mapping, and functional consequence in viral replication assay\",\n      \"pmids\": [\"17669426\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CDCA7L (R1/RAM2/JPO2) was identified as a novel transcriptional repressor of MAO B using Sp1-binding motifs as bait in a yeast one-hybrid screen. EMSA demonstrated that R1 competed with Sp1 for binding to the Sp1 site in the MAO B promoter in vitro. R1 reduced Sp1-activated glucocorticoid activation of MAO B promoter activity. ChIP analysis showed lower occupancy by R1 at the MAO B core promoter in response to dexamethasone.\",\n      \"method\": \"Yeast one-hybrid screen, EMSA, luciferase reporter assay, chromatin immunoprecipitation (ChIP)\",\n      \"journal\": \"Molecular pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (yeast one-hybrid, EMSA, ChIP, reporter assay) establishing direct DNA binding and competition with Sp1 at the MAO B promoter\",\n      \"pmids\": [\"20980443\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A multiple myeloma risk SNP (rs4487645 G>T) resides in an enhancer element 47 kb upstream of CDCA7L. The G-risk allele increases IRF4 binding at the enhancer, which interacts with the CDCA7L promoter by chromatin looping. The G allele is associated with increased CDCA7L expression. Suppression of CDCA7L limits myeloma cell proliferation through apoptosis.\",\n      \"method\": \"Genetic association + functional characterization: chromatin conformation capture (enhancer-promoter interaction), IRF4 ChIP, reporter assay, siRNA knockdown with proliferation/apoptosis readout\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — enhancer-promoter interaction confirmed by chromatin conformation capture, IRF4 binding by ChIP, and loss-of-function knockdown with specific apoptosis readout\",\n      \"pmids\": [\"27882933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"JPO2 (CDCA7L) and its partner LEDGF/p75 are critical modulators of PI3K/AKT signaling and metastasis in medulloblastoma. JPO2 overexpression induced metastatic medulloblastoma in vivo. Two synergistic feed-forward regulatory circuits involving LEDGF/p75 and AKT were identified as promoting metastatic phenotypes downstream of JPO2.\",\n      \"method\": \"In vivo medulloblastoma metastasis model, overexpression, identification of JPO2:LEDGF/p75 protein complex, pathway analysis (PI3K/AKT signaling readouts)\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo model with defined phenotype and protein complex identified, but pathway circuit details rely on single lab with limited orthogonal validation in abstract\",\n      \"pmids\": [\"27013196\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"R1 (CDCA7L/JPO2) protein levels are significantly reduced by ~37.5% in postmortem prefrontal cortex of untreated MDD subjects compared to controls, and this reduction is significantly correlated with an approximately 40% increase in MAO A protein levels and MAO A catalytic activity within the same MDD groups. This supports an in vivo regulatory relationship between R1 and MAO A.\",\n      \"method\": \"Western blot quantification of postmortem human brain tissue, MAO A catalytic activity assay, correlation analysis\",\n      \"journal\": \"Neuropsychopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct protein quantification in human postmortem tissue with correlated MAO A activity, but purely correlative/observational rather than interventional\",\n      \"pmids\": [\"21654740\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CDCA7L (JPO2/RAM2/R1) is a nuclear transcriptional repressor that binds Sp1 sites in the MAO A and MAO B promoters to suppress their expression; it interacts directly with c-Myc (via the MycNTD) to potentiate oncogenic transformation; it is tethered to chromatin and stabilized by LEDGF/p75 through its PHAT domain in a manner that competes with HIV-1 integrase binding; it participates in apoptotic and proliferative signaling downstream of p38/Bcl-2 and upstream of caspase-3/cyclin D1; its expression is regulated by an IRF4-bound enhancer element whose risk allele drives increased CDCA7L expression in multiple myeloma; and in medulloblastoma, the JPO2:LEDGF/p75 complex promotes metastasis by modulating PI3K/AKT signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CDCA7L (also called R1/RAM2/JPO2) is a nuclear transcriptional repressor and c-Myc cofactor that links transcriptional control of monoamine oxidase genes to oncogenic proliferation and survival signaling [#0, #4]. It was cloned through Sp1-binding sites in the MAO A core promoter and represses MAO A transcription by binding the promoter directly, competing with Sp1; the same Sp1-competition mechanism represses MAO B, and glucocorticoid signaling drives its cytosol-to-nucleus translocation to modulate this repression [#0, #6, #1]. Independently identified as a binding partner of the c-Myc NH2-terminal domain, CDCA7L co-localizes with and binds c-Myc, potentiates c-Myc transforming activity, and complements a transformation-defective Myc mutant, with its loss impairing colony formation in medulloblastoma cells [#4]. Within apoptotic and proliferative circuits, CDCA7L acts downstream of p38 kinase and Bcl-2 but upstream of caspase-3, and upstream of cyclin D1 and E2F1 in c-Myc-induced proliferation [#2]. CDCA7L is tethered to chromatin and stabilized by the transcriptional co-activator LEDGF/p75, binding the same PHAT/integrase-binding domain that engages HIV-1 integrase such that the two compete for LEDGF/p75; this association is required for CDCA7L chromatin loading and underlies a JPO2:LEDGF/p75 complex that promotes PI3K/AKT-driven metastasis in medulloblastoma [#3, #5, #8]. Its expression is elevated by a multiple myeloma risk allele at an upstream IRF4-bound enhancer, and CDCA7L supports myeloma cell proliferation and suppresses apoptosis [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established CDCA7L's two foundational activities — that it is a sequence-specific transcriptional repressor of MAO A and an independent c-Myc cofactor — defining it as both a DNA-binding regulator and an oncogenic partner.\",\n      \"evidence\": \"Yeast one-hybrid via Sp1 sites with EMSA/ChIP/reporter for MAO A repression; yeast two-hybrid against MycNTD with transformation and RNAi assays for the Myc link\",\n      \"pmids\": [\"15654081\", \"15994933\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct DNA-binding domain of CDCA7L not mapped\", \"Mechanism by which it potentiates Myc transformation (cofactor recruitment vs. target gene effects) unresolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Connected CDCA7L's MAO A repression to upstream glucocorticoid signaling through ligand-induced nuclear translocation, showing its repressor activity is regulated rather than constitutive.\",\n      \"evidence\": \"Reporter assays, EMSA, shRNA knockdown, and immunofluorescence localization in neuroblastoma/glioblastoma cells\",\n      \"pmids\": [\"16728402\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signal transducing the dexamethasone cue to CDCA7L translocation not identified\", \"Whether translocation involves post-translational modification unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Positioned CDCA7L within apoptotic and proliferative pathways by epistasis, placing it downstream of p38/Bcl-2 and upstream of caspase-3, cyclin D1, and E2F1, and confirming c-Myc induces its expression.\",\n      \"evidence\": \"Pharmacological inhibition, overexpression, siRNA, co-IP, and IHC in apoptosis and proliferation models\",\n      \"pmids\": [\"16829576\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular targets mediating caspase-3 and cyclin D1 effects not defined\", \"Whether the apoptotic role is dependent on MAO A activity vs. independent transcriptional targets unresolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identified LEDGF/p75 as the factor that tethers CDCA7L to chromatin and stabilizes it, revealing how a repressor lacking strong autonomous chromatin retention is loaded onto chromosomes.\",\n      \"evidence\": \"In vitro and in vivo binding, domain mapping (aa 58–119), competition with recombinant integrase, live-cell co-localization, and protein stability assays\",\n      \"pmids\": [\"16735438\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of chromatin tethering for specific target genes not tested\", \"Genomic loci co-occupied by CDCA7L and LEDGF/p75 not mapped\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Refined the CDCA7L–LEDGF/p75 interface and demonstrated functional competition with HIV-1 integrase, showing CDCA7L can interfere with viral replication and activate the HIV-1 LTR.\",\n      \"evidence\": \"Yeast two-hybrid, pull-down, AlphaScreen, co-IP, LEDGF/p75 mutagenesis, HIV-1 replication and LTR reporter assays\",\n      \"pmids\": [\"17669426\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological relevance of LTR activation by CDCA7L unclear\", \"Distinct binding determinants on LEDGF/p75 for CDCA7L vs. integrase only partially mapped\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Generalized the Sp1-competition repressor mechanism beyond MAO A to MAO B, establishing CDCA7L as a coordinated regulator of monoamine oxidase gene expression.\",\n      \"evidence\": \"Yeast one-hybrid, EMSA Sp1-competition, ChIP, and reporter assays on the MAO B promoter\",\n      \"pmids\": [\"20980443\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether additional Sp1-driven promoters are targets not surveyed\", \"Stoichiometry of CDCA7L vs. Sp1 occupancy in vivo not quantified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Provided in vivo human evidence for the CDCA7L–MAO A regulatory axis by correlating reduced CDCA7L with elevated MAO A in depressive disorder brain tissue.\",\n      \"evidence\": \"Western blot quantification and MAO A activity assay in postmortem prefrontal cortex with correlation analysis\",\n      \"pmids\": [\"21654740\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Correlative/observational, not interventional\", \"Causality and directionality in human brain not established\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined the genetic and cellular basis of CDCA7L overexpression in multiple myeloma, linking an IRF4-bound enhancer risk allele to increased expression and a pro-proliferative, anti-apoptotic role.\",\n      \"evidence\": \"Chromatin conformation capture, IRF4 ChIP, reporter assays, and siRNA knockdown with proliferation/apoptosis readouts\",\n      \"pmids\": [\"27882933\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream effectors of CDCA7L driving myeloma proliferation not identified\", \"Whether the Myc or LEDGF/p75 axis mediates the myeloma phenotype untested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Extended the JPO2:LEDGF/p75 complex to a metastatic function, showing CDCA7L drives medulloblastoma metastasis via feed-forward PI3K/AKT circuits.\",\n      \"evidence\": \"In vivo medulloblastoma metastasis model with overexpression, complex identification, and PI3K/AKT pathway readouts\",\n      \"pmids\": [\"27013196\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Pathway circuit details from a single lab with limited orthogonal validation\", \"Direct molecular link between CDCA7L and AKT activation not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CDCA7L's transcriptional repressor activity, its c-Myc cofactor function, and its LEDGF/p75-dependent chromatin tethering are mechanistically integrated into a single coherent activity remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of CDCA7L or its complexes\", \"Genome-wide direct target set not defined\", \"Whether MAO repression and oncogenic cofactor roles share a common molecular surface unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 6]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1, 3, 4]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 6, 7]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [2, 7]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [7, 8]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"complexes\": [\"JPO2:LEDGF/p75 complex\"],\n    \"partners\": [\"PSIP1\", \"MYC\", \"SP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}