{"gene":"PAXIP1","run_date":"2026-06-10T05:19:53","timeline":{"discoveries":[{"year":2000,"finding":"PTIP (PAXIP1) was identified as a novel protein that directly binds to the activation domain of PAX2 (and other Pax proteins) in vitro, in yeast two-hybrid assays, and in tissue culture cells. The octapeptide repression domain of Pax2 inhibits this binding. PTIP contains five BRCT domains and co-localizes with Pax2 in the nucleus at actively expressed chromatin and the nuclear matrix fraction.","method":"Yeast two-hybrid, in vitro binding, co-immunoprecipitation in tissue culture, nuclear fractionation, co-localization","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Y2H, in vitro binding, co-IP, co-localization) in a single study establishing the founding interaction","pmids":["10908331"],"is_preprint":false},{"year":2003,"finding":"PTIP is essential for progression through mitosis. PTIP-null mouse embryos show reduced mitosis, widespread cell death, DNA damage preceding nuclear condensation, and defective phospho-histone H3 expression. Neither embryonic fibroblasts nor embryonic stem cells from PTIP mutants proliferate in culture. Trophoblast cells are more sensitive to DNA-damaging agents.","method":"Constitutive null allele generation in mice, immunostaining for mitotic markers (phospho-H3), DNA damage markers, cell culture proliferation assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with multiple cellular readouts (mitosis, DNA damage, proliferation) across multiple cell types","pmids":["12588986"],"is_preprint":false},{"year":2004,"finding":"Human PTIP (hPTIP) contains 1069 amino acids and six BRCT domains. It shows increased association with 53BP1 in response to ionizing radiation (IR), and this IR-induced association requires ATM. PTIP is required for ATM-mediated phosphorylation of p53 at Ser15 and for IR-induced up-regulation of p21. PTIP depletion increases cellular sensitivity to IR.","method":"Co-immunoprecipitation, deletion analysis, siRNA knockdown, Western blot for p53-Ser15 phosphorylation and p21, cell survival assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, domain mapping, siRNA with multiple functional readouts in single rigorous study","pmids":["15456759"],"is_preprint":false},{"year":2007,"finding":"Endogenous PTIP and a novel protein PA1 are components of a Set1-like histone H3K4 methyltransferase (HMT) complex containing ASH2L, RBBP5, WDR5, hDPY-30, NCOA6, MLL3, MLL4, and UTX. The PTIP complex carries HMT activity specifically methylating H3K4. PA1 binds PTIP directly and requires PTIP for interaction with the rest of the complex. hDPY-30 binds ASH2L directly.","method":"Co-purification, mass spectrometry, co-immunoprecipitation, in vitro HMT assay, direct binding assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — complex purification with MS identification, in vitro enzymatic assay, and direct binding assays; multiple orthogonal methods","pmids":["17500065"],"is_preprint":false},{"year":2007,"finding":"PTIP bridges the DNA-binding protein PAX2 to the ALR/MLL3/MLL4 H3K4 methyltransferase complex. PAX2 promotes assembly of this complex and H3K4 methylation at a PAX2-binding DNA element through PTIP. Without PTIP, PAX2 binds DNA but fails to assemble the ALR complex. PTIP-null and conditional mutants show reduced H3K4 methylation levels.","method":"Co-purification, conditional and constitutive knockout mice, chromatin immunoprecipitation (ChIP), H3K4 methylation assays","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — co-purification, genetic knockout with multiple alleles, ChIP; independently corroborates PMID 17500065","pmids":["17925232"],"is_preprint":false},{"year":2008,"finding":"PTIP/Swift is required for efficient PCNA ubiquitination and recruitment of TLS polymerase eta to chromatin in response to DNA damage. Immunodepletion of PTIP/Swift from Xenopus egg extracts prevented PCNA ubiquitination and polymerase eta recruitment during replicative stress. PTIP depletion in mammalian cells by RNAi reduced PCNA ubiquitination and decreased recruitment of polymerase eta and Rad51 to chromatin.","method":"Xenopus egg extract immunodepletion, siRNA knockdown in mammalian cells, chromatin fractionation assays","journal":"DNA repair","confidence":"High","confidence_rationale":"Tier 2 / Strong — immunodepletion in Xenopus extracts plus RNAi in mammalian cells with consistent results across two systems","pmids":["18353733"],"is_preprint":false},{"year":2009,"finding":"Recruitment of PTIP to damaged chromatin depends on the DNA damage signaling pathway γH2AX→MDC1→RNF8, which in turn facilitates sustained localization of PA1 to DNA break sites. The N-terminal PA1-binding domain and C-terminal focus-localization domain of PTIP are critical for its DNA damage repair function, which is likely independent of the MLL complexes.","method":"Co-immunoprecipitation, siRNA knockdown, immunofluorescence for DNA damage foci, domain deletion analysis, cell viability after ionizing radiation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP, domain mapping, foci analysis; multiple methods in one study","pmids":["19124460"],"is_preprint":false},{"year":2009,"finding":"PTIP is required for PPARγ and C/EBPα expression during adipogenesis. PTIP deletion in mouse embryonic fibroblasts markedly decreases PPARγ expression and impairs H3K4 trimethylation and RNA Pol II occupancy at PPARγ and C/EBPα promoters. Rescue of the adipogenesis defect in PTIP-/- MEFs requires co-expression of both PPARγ and C/EBPα.","method":"Conditional knockout mice, ChIP for H3K4me3 and RNA Pol II, rescue experiments with PPARγ/C/EBPα co-expression, adipogenesis assays","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO, ChIP, and genetic rescue with defined transcription factors; multiple orthogonal methods","pmids":["19583951"],"is_preprint":false},{"year":2009,"finding":"RNF8 controls DNA damage-induced nuclear foci formation of PTIP, which in turn regulates 53BP1 localization to DNA damage sites. PTIP is also required for ATM-dependent SMC1 phosphorylation at damage sites. PTIP acts downstream of RNF8 and upstream of 53BP1 in the DNA damage response pathway.","method":"siRNA knockdown, immunofluorescence for nuclear foci, Western blot for SMC1 phosphorylation, epistasis analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via siRNA depletion with multiple readouts (foci, phosphorylation), pathway ordering established","pmids":["19414588"],"is_preprint":false},{"year":2009,"finding":"Drosophila PTIP ortholog is essential for anterior/posterior patterning and segmentation. Loss of Drosophila ptip decreases global H3K4 methylation and increases H3K27 methylation. Drosophila PTIP is required to activate homeotic gene expression in response to derepression of Polycomb group genes, and binds to promoter sequences coincident with increased H3K4 trimethylation.","method":"Genetic null alleles in Drosophila, global histone methylation analysis, cell culture reporter assays, ChIP at homeotic gene promoters","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — ortholog in Drosophila with genetic loss-of-function, ChIP, and global histone modification analysis; consistent with mammalian data","pmids":["19429789"],"is_preprint":false},{"year":2009,"finding":"PTIP is required to maintain H3K4 methylation in embryonic stem cells. PTIP deletion in ES cells leads to spontaneous differentiation to trophectoderm, loss of pluripotency, reduced Oct4 expression, reduced H3K4 methylation, and impaired differentiation along all three germ layers in embryoid bodies.","method":"Conditional PTIP knockout in ES cells using Cre recombinase, flow cytometry, immunostaining, ChIP for H3K4 methylation","journal":"Stem cells (Dayton, Ohio)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with multiple cellular and molecular readouts, single lab","pmids":["19544464"],"is_preprint":false},{"year":2010,"finding":"PTIP promotes DNA double-strand break repair through homologous recombination (HR). PTIP-deficient chicken DT40 cells show increased spontaneous DNA lesions, sensitivity to IR and camptothecin, and reduced HR efficiency as measured by artificial recombination substrates. PTIP-depleted HeLa cells also show reduced HR efficiency.","method":"Gene disruption in DT40 cells, HR efficiency assay with recombination substrates, sensitivity assays (IR, camptothecin), siRNA in HeLa cells","journal":"Genes to cells : devoted to molecular & cellular mechanisms","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout plus siRNA depletion in two cell systems with direct HR efficiency measurement","pmids":["20088963"],"is_preprint":false},{"year":2010,"finding":"PTIP promotes H3K4me3 and transcription initiation at downstream switch regions of the immunoglobulin heavy-chain (Igh) locus in activated B cells. PTIP-deficient B cells show impaired H3K4me3 and transcription at Igh switch regions, leading to defective class switch recombination (CSR). PTIP accumulation at DSBs also contributes to CSR and genome stability independently of Igh switch transcription.","method":"Conditional B-cell-specific PTIP knockout, ChIP-seq, RNA-seq, class switch recombination assays, flow cytometry","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with ChIP-seq, transcriptomics, and functional CSR assay; multiple orthogonal methods","pmids":["20671152"],"is_preprint":false},{"year":2011,"finding":"PTIP is required for long-range chromatin interactions between the 3' regulatory region enhancer and germline transcript promoters at the immunoglobulin heavy chain locus. Loss of PTIP in mature B cells inhibits CSR by suppressing H3K4 methylation at germline transcript promoters, reduces Pax5 binding, and abolishes chromatin looping detected by chromosome conformation capture.","method":"CD19-Cre conditional PTIP knockout, ChIP, chromosome conformation capture (3C), class switch recombination assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO, ChIP, 3C with multiple functional readouts; establishes PTIP role in 3D chromatin organization","pmids":["21282469"],"is_preprint":false},{"year":2011,"finding":"The tandem BRCT5-BRCT6 domain of human PTIP directly recognizes the γH2AX tail, and this interaction depends on phosphorylation of H2AX Ser139. Crystal structure at 2.15 Å resolution of the hPTIP BRCT5/6-γH2AX complex was determined, and mutation analysis confirmed the molecular basis for the interaction.","method":"X-ray crystallography (2.15 Å resolution), mutagenesis, binding assays","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with mutagenesis validation; directly establishes molecular mechanism of γH2AX recognition","pmids":["22064073"],"is_preprint":false},{"year":2012,"finding":"PAXIP1/PTIP regulates RAG-mediated cleavage and repair during V(D)J recombination in DP thymocytes. Loss of PAXIP1 diminishes Jα H3K4me3 and germline transcription, suppresses DSB formation at 3' Jα segments, and results in accumulation of unresolved Tcra breaks. PAXIP1 is also essential for S1PR1-mediated mature thymocyte egress from the thymus through transcriptional activation of S1pr1.","method":"Conditional knockout in thymocytes, ChIP for H3K4me3, DSB detection assays (LMPCR), flow cytometry, gene expression analysis","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with ChIP, direct DSB measurement, and functional lymphocyte trafficking readout; multiple methods","pmids":["23159437"],"is_preprint":false},{"year":2012,"finding":"The mutant androgen receptor (AR) with poly-glutamine expansion (associated with SBMA) specifically interacts with PTIP and sequesters PTIP away from radiation-induced nuclear foci. This results in increased sensitivity to DNA-damaging agents and chromosomal instabilities. In a mouse model of SBMA, DNA damage is detected in muscle cells and muscular atrophy is accelerated when one copy of PTIP is removed.","method":"Co-immunoprecipitation, immunofluorescence for nuclear foci, DNA damage assays, mouse genetic model (PTIP heterozygosity in SBMA model)","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and foci analysis plus in vivo genetic model; single lab, consistent across methods","pmids":["22736030"],"is_preprint":false},{"year":2014,"finding":"PTIP binds to Artemis nuclease as a PTIP-binding protein. Loss of Artemis restores PARP inhibitor resistance in BRCA1-deficient cells, demonstrating Artemis is a major downstream effector of the 53BP1-PTIP pathway that prevents end resection and promotes NHEJ, directly competing with homologous recombination repair.","method":"Co-immunoprecipitation, genetic epistasis (double knockout cell lines), PARP inhibitor sensitivity assays, end resection assays","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP identifying novel binding partner, genetic epistasis with functional PARP inhibitor sensitivity readout","pmids":["25512557"],"is_preprint":false},{"year":2014,"finding":"PITX2 associates with the PTIP-containing MLL4/KMT2D histone H3K4 methyltransferase complex. This association is dependent on PITX2's homeodomain. The PITX2 protein complex possesses H3K4 HMT activity, and ChIP shows co-occupancy of PITX2 and PTIP on PITX2 transcriptional target promoters.","method":"Co-immunoprecipitation, in vitro HMT assay, chromatin immunoprecipitation (ChIP), domain deletion analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, in vitro enzymatic assay, and ChIP; single lab with multiple methods","pmids":["24486544"],"is_preprint":false},{"year":2015,"finding":"The phosphatase PPM1B can dephosphorylate the Pax2 activation domain and displace PTIP, thereby inhibiting H3K4 methylation and gene activation. PPM1B is an essential component of the Groucho4 repressor complex recruited by Pax2. Loss of PPM1B prevents Groucho-mediated gene repression, demonstrating that phosphorylation state of Pax2 controls the switch between PTIP-mediated activation and PPM1B/Groucho-mediated repression.","method":"Co-immunoprecipitation, phosphatase assays, ChIP, reporter gene assays, siRNA knockdown","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, biochemical phosphatase assay, and ChIP; single lab, multiple methods","pmids":["25631048"],"is_preprint":false},{"year":2016,"finding":"A PTIP-PA1 subcomplex functions independently from the MLL3/MLL4 complex to mediate transcription and class switch recombination. Using quantitative proteomics in primary lymphocytes, a tandem BRCT domain of PTIP was identified as sufficient for CSR, with PA1 as its main functional partner. PTIP promotes CSR separately from its association with the MLL3/MLL4 complex and from its localization to sites of DNA damage.","method":"Quantitative proteomics, domain mapping by mutagenesis, B-cell conditional knockout, class switch recombination assays","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — quantitative proteomics plus genetic domain dissection and functional CSR assay; multiple orthogonal methods","pmids":["26744420"],"is_preprint":false},{"year":2016,"finding":"PAXIP1 BRCT domains interact with WEE1 kinase and regulate WEE1-mediated phosphorylation of CDK1. Ectopic expression of PAXIP1 promotes enhanced caspase-3-mediated apoptosis in cells treated with WEE1 inhibitor AZD1775 and cisplatin.","method":"Co-immunoprecipitation (BRCT-mediated interaction network), pharmacologic screen, ectopic expression, caspase-3 activity assays","journal":"Molecular cancer therapeutics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP for interaction, functional readout with ectopic expression; single lab but multiple cell-based assays","pmids":["27196765"],"is_preprint":false},{"year":2021,"finding":"DACH1 interacts with PTIP and is recruited by DACH1 to its promoter-binding sites. DACH1-PTIP recruitment represses transcription and reduces promoter H3K4Me3 levels. DACH1 knockdown in podocytes combined with hyperglycemia triggers target gene upregulation and increased promoter H3K4Me3, revealing that DACH1 uses PTIP-H3K4Me3 activity for transcriptional repression at DACH1 target loci.","method":"Co-immunoprecipitation, ChIP for H3K4me3, RNA sequencing, conditional knockout mice, siRNA knockdown","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus ChIP with KO and KD; single lab, two orthogonal methods","pmids":["33998601"],"is_preprint":false},{"year":2022,"finding":"PTIP governs NAD+ metabolism in macrophages by regulating CD38 expression. PTIP cooperates with acetyltransferase p300 to establish an active intronic enhancer of CD38 with enriched H3K27ac. PTIP deletion impairs proinflammatory response, promotes metabolic switch from glycolysis to oxidative phosphorylation, and alters NAD+ metabolism via downregulating CD38.","method":"Conditional knockout in macrophages, ChIP for H3K27ac, metabolic profiling (NAD+ measurement), cytokine assays, enhancer identification by ChIP-seq","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO, ChIP-seq, and metabolic assays; single lab with multiple orthogonal methods","pmids":["35354042"],"is_preprint":false},{"year":2022,"finding":"PTIP is essential for proper chromosome segregation during mitosis in HeLa cells. PTIP inactivation results in prolonged mitotic time, inefficient chromosome alignment, and increased cell death during mitotic exit. PTIP localizes to the mitotic centrosome via its C-terminal BRCT domains.","method":"siRNA knockdown, live-cell imaging, immunofluorescence for centrosome localization, BRCT domain deletion analysis","journal":"Cell division","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization with domain mapping and functional loss-of-function with mitotic phenotype readout; single lab","pmids":["36153541"],"is_preprint":false},{"year":2023,"finding":"PAXIP1 and STAG2 converge to maintain 3D genome architecture and facilitiate promoter-enhancer contacts for glucocorticoid receptor (GR)-dependent transcription. PAXIP1 is required for stability of cohesin on chromatin, cohesin localization to GR-occupied sites, and maintenance of enhancer-promoter interactions. PAXIP1 and STAG2 depletion alter the GR transcriptome without altering the GR cistrome.","method":"CRISPR genome-wide screen, ChIP-seq for cohesin, ATAC-seq, Hi-C, co-immunoprecipitation, conditional knockdown","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR screen, ChIP-seq, Hi-C, and functional transcriptional assays; multiple orthogonal methods establishing mechanism","pmids":["37070193"],"is_preprint":false},{"year":2023,"finding":"PAXIP1 (with binding partner PAGR1) promotes global chromatin association of cohesin independently of DNA replication, transcription, or DNA repair. Depletion of PAXIP1 severely aggravates cohesion defects in ESCO2 mutant cells leading to mitotic cell death. Cohesin regulation by PAXIP1 requires PAGR1 and a conserved FDF motif in PAGR1. PAXIP1 co-localizes with cohesin on active gene promoters and enhancers.","method":"CRISPR synthetic lethality screens, ChIP-seq for cohesin, co-immunoprecipitation, domain mutagenesis (FDF motif), cohesion assays, live-cell imaging","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR screen, ChIP-seq, co-IP, domain mutagenesis, multiple functional assays; rigorous single-study evidence","pmids":["37702151"],"is_preprint":false},{"year":2024,"finding":"PTIP undergoes UFMylation in response to replication stress (detected by denaturing co-immunoprecipitation). This post-translational modification promotes end resection and degradation of nascent DNA at stalled replication forks in BRCA1-deficient cells. PTIP-depleted and UFL1-depleted BRCA1 knockdown cells are less sensitive to PARP inhibitors.","method":"Denaturing co-immunoprecipitation, DNA fiber assays for fork degradation, cell viability assay with PARP inhibitors, siRNA knockdown","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — denaturing co-IP establishing UFMylation, functional fork degradation assay, PARP inhibitor sensitivity; single lab","pmids":["38657865"],"is_preprint":false},{"year":2024,"finding":"PTIP is required for H3K4me3 upregulation in an intermediate phase after ionizing radiation and promotes cell cycle arrest by epigenetically inducing PRDM1. PTIP is a component of the MLL histone methyltransferase complex required for this radiation-induced H3K4me3 increase and downstream PRDM1 expression.","method":"Conditional knockout in hematopoietic cells, ChIP for H3K4me3, gene expression analysis, cell cycle assays after IR","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with ChIP and cell cycle readout; single lab, two orthogonal methods","pmids":["39097652"],"is_preprint":false},{"year":2024,"finding":"PAXIP1 and PAGR1 are epistatic to STAG2 in oncogenic KRAS-driven lung tumorigenesis in vivo. Gene expression and chromatin accessibility profiles in STAG2- and PAXIP1-deficient neoplastic cells are similar, functionally linking STAG2-cohesin to the PAXIP1/PAGR1 heterodimeric complex as a tumor-suppressive axis.","method":"Somatic CRISPR-Cas9 in autochthonous mouse lung cancer model, tumor barcoding, RNA-seq, ATAC-seq, genetic epistasis in vivo","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic epistasis with CRISPR, supported by RNA-seq and ATAC-seq; preprint and peer-reviewed publication available","pmids":["39652422","39345539"],"is_preprint":false},{"year":2025,"finding":"A fraction of PTIP is actively transported from the nucleus to mitochondria, causing mitochondrial aggregation, cytochrome c release into the cytoplasm, and cellular apoptosis. Deletion of an N-terminal glutamine-rich region, mutation of a conserved threonine within BRCT3, and truncation of the C-terminal BRCT5 domain each significantly reduced apoptosis.","method":"Subcellular fractionation, immunofluorescence for mitochondrial localization, cytochrome c release assay, domain deletion/mutagenesis, apoptosis assays","journal":"Journal of cellular signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct localization with functional consequence and domain mutagenesis; single lab, novel finding without independent replication","pmids":["41608385"],"is_preprint":false}],"current_model":"PAXIP1/PTIP is a multi-BRCT-domain nuclear scaffold protein that functions in two major contexts: (1) as an integral component of the MLL3/MLL4-containing Set1-like histone H3K4 methyltransferase complex, where it bridges sequence-specific DNA-binding factors (PAX2, PITX2, DACH1) to chromatin-modifying machinery to establish active H3K4me3 marks at developmentally regulated genes and immunoglobulin loci, and also cooperates with PAGR1/PA1 as a subcomplex that can act independently of MLL3/MLL4 to promote transcription; and (2) in the DNA damage response, where it is recruited to break sites via a γH2AX→MDC1→RNF8 pathway through direct BRCT5/6 recognition of phospho-γH2AX, acts upstream of 53BP1 to regulate its localization, promotes NHEJ via recruitment of Artemis, and facilitates homologous recombination and PCNA ubiquitination for translesion synthesis. PTIP also promotes global cohesin chromatin association through its PAGR1 partner (requiring the PAGR1 FDF motif), maintains 3D enhancer-promoter contacts, undergoes UFMylation to regulate replication fork stability in BRCA1-deficient cells, and a fraction localizes to mitochondria to trigger apoptosis via cytochrome c release."},"narrative":{"mechanistic_narrative":"PAXIP1 (PTIP) is a multi-BRCT-domain nuclear scaffold that couples sequence-specific DNA-binding factors to histone H3K4 methylation machinery and functions in parallel in the DNA damage response [PMID:10908331, PMID:17500065, PMID:19124460]. As an integral component of a Set1-like MLL3/MLL4 (KMT2C/KMT2D) H3K4 methyltransferase complex containing ASH2L, RBBP5, WDR5, hDPY-30, NCOA6, UTX, and the PTIP-binding protein PA1/PAGR1, it carries H3K4-specific HMT activity [PMID:17500065]. Through its BRCT modules PTIP bridges DNA-binding transcription factors—PAX2, PITX2, and DACH1—to this complex, assembling it at target elements to deposit H3K4 methylation and activate (or, in the DACH1 context, repress) developmentally and metabolically regulated genes [PMID:10908331, PMID:17925232, PMID:24486544, PMID:33998601]. This activity underlies its requirement for H3K4me3, pluripotency-gene expression, and lineage differentiation in embryonic stem cells, for adipogenic induction of PPARγ and C/EBPα, and for H3K4me3 and germline transcription that license immunoglobulin class switch recombination and Tcra V(D)J recombination [PMID:19583951, PMID:19544464, PMID:20671152, PMID:23159437]; a PTIP-PA1 subcomplex can mediate transcription and class switch recombination independently of MLL3/MLL4 [PMID:26744420]. PTIP also organizes 3D chromatin, maintaining long-range enhancer-promoter contacts at the Igh locus and, together with its PAGR1 partner, promoting global cohesin association with chromatin to support cohesin-dependent enhancer-promoter looping and tumor suppression downstream of STAG2 [PMID:21282469, PMID:37070193, PMID:37702151, PMID:39652422, PMID:39345539]. In the DNA damage response, PTIP is recruited to break sites through direct BRCT5/6 recognition of phospho-γH2AX downstream of the γH2AX→MDC1→RNF8 axis, acts upstream of 53BP1 and ATM-dependent SMC1 phosphorylation, and promotes NHEJ via the Artemis nuclease while also facilitating homologous recombination and PCNA-ubiquitination-dependent translesion synthesis [PMID:18353733, PMID:19124460, PMID:19414588, PMID:20088963, PMID:22064073, PMID:25512557]. PTIP is essential for mitotic progression and chromosome segregation, localizing to the mitotic centrosome via its C-terminal BRCT domains [PMID:12588986, PMID:36153541].","teleology":[{"year":2000,"claim":"Established PAXIP1's founding identity as a five-BRCT nuclear protein that directly binds the PAX2 activation domain, defining it as a transcription-factor-associated chromatin protein.","evidence":"Yeast two-hybrid, in vitro binding, co-IP and nuclear co-localization in cultured cells","pmids":["10908331"],"confidence":"High","gaps":["Did not identify the chromatin-modifying activity downstream of PAX2 binding","Functional consequence of the interaction unresolved"]},{"year":2003,"claim":"Demonstrated PTIP is genetically essential for mitotic progression and genome integrity, the first in vivo evidence of a core proliferative role.","evidence":"Constitutive null mouse embryos with mitotic, DNA-damage, and proliferation readouts","pmids":["12588986"],"confidence":"High","gaps":["Molecular basis linking PTIP loss to DNA damage and mitotic failure not defined","Could not separate transcriptional from DNA-repair contributions"]},{"year":2004,"claim":"Connected PTIP to the ATM-dependent DNA damage response by showing IR-induced, ATM-requiring association with 53BP1 and a requirement for p53-Ser15 phosphorylation.","evidence":"Co-IP, deletion mapping, siRNA, phospho-Western, survival assays in human cells","pmids":["15456759"],"confidence":"High","gaps":["Direct recruitment mechanism to damage sites unknown","Whether PTIP acts upstream or downstream of 53BP1 unresolved"]},{"year":2007,"claim":"Defined PTIP as an integral subunit of a Set1-like MLL3/MLL4 H3K4 methyltransferase complex and identified PA1 as its direct partner, establishing the molecular basis of its transcriptional activity.","evidence":"Complex co-purification with mass spectrometry, in vitro HMT assay, direct binding assays","pmids":["17500065","17925232"],"confidence":"High","gaps":["Whether all functions require the full MLL3/MLL4 complex unresolved","Range of recruiting DNA-binding factors not yet enumerated"]},{"year":2008,"claim":"Extended PTIP's repair role to replication stress, showing it is required for PCNA ubiquitination and recruitment of translesion polymerase eta and Rad51.","evidence":"Xenopus egg extract immunodepletion plus mammalian RNAi with chromatin fractionation","pmids":["18353733"],"confidence":"High","gaps":["Direct versus indirect contribution to PCNA ubiquitination not separated","Mechanism connecting PTIP to the ubiquitination machinery undefined"]},{"year":2009,"claim":"Ordered PTIP within the DNA damage signaling cascade — recruited via γH2AX→MDC1→RNF8, acting downstream of RNF8 and upstream of 53BP1 — and established its requirement for ATM-dependent SMC1 phosphorylation and for HR.","evidence":"siRNA epistasis, foci imaging, phospho-Western, DT40 gene disruption and HR substrate assays","pmids":["19124460","19414588","20088963"],"confidence":"High","gaps":["Direct phospho-mark recognized by PTIP not yet structurally defined","How PTIP regulates 53BP1 localization mechanistically unresolved"]},{"year":2009,"claim":"Generalized PTIP's MLL-complex function to developmental and lineage transcription programs, showing it maintains H3K4 methylation required for pluripotency, adipogenesis, and homeotic patterning.","evidence":"Conditional/constitutive knockouts in mouse ES cells and MEFs and Drosophila null alleles with ChIP and rescue","pmids":["19583951","19544464","19429789"],"confidence":"High","gaps":["Locus selectivity of PTIP-dependent H3K4 methylation not fully explained","Direct versus indirect transcriptional targets not all defined"]},{"year":2010,"claim":"Showed PTIP licenses immunoglobulin class switch recombination by driving H3K4me3 and germline transcription at switch regions while separately contributing at DSBs.","evidence":"B-cell conditional knockout with ChIP-seq, RNA-seq, and CSR assays","pmids":["20671152"],"confidence":"High","gaps":["Relative contribution of transcription versus DSB function to CSR not quantified","Mechanism of switch-region targeting unresolved"]},{"year":2011,"claim":"Revealed PTIP organizes 3D chromatin, being required for enhancer-promoter looping at the Igh locus, linking H3K4 methylation to higher-order genome architecture.","evidence":"Conditional knockout with ChIP and chromosome conformation capture","pmids":["21282469"],"confidence":"High","gaps":["Whether looping defect is cause or consequence of lost H3K4 methylation unresolved","Generality beyond the Igh locus not yet tested"]},{"year":2011,"claim":"Provided the structural basis for damage-site recruitment by solving the PTIP BRCT5/6–γH2AX complex, demonstrating direct phospho-Ser139 recognition.","evidence":"2.15 Å X-ray crystallography with mutagenesis and binding assays","pmids":["22064073"],"confidence":"High","gaps":["Does not address how recruitment is coordinated with the RNF8 pathway","Affinity contributions of other BRCT pairs not defined"]},{"year":2012,"claim":"Demonstrated PTIP couples H3K4me3-dependent germline transcription to programmed DSB resolution during V(D)J recombination and to thymocyte egress, broadening its lymphocyte developmental role.","evidence":"Thymocyte conditional knockout with ChIP, LMPCR DSB detection, and trafficking assays","pmids":["23159437"],"confidence":"High","gaps":["Direct mechanistic link between H3K4me3 and RAG cleavage not fully resolved","Whether S1pr1 regulation is direct unresolved"]},{"year":2012,"claim":"Linked PTIP to disease by showing poly-glutamine-expanded androgen receptor sequesters PTIP from damage foci, sensitizing cells and worsening SBMA muscle pathology.","evidence":"Co-IP, foci imaging, DNA damage assays, and PTIP-heterozygous SBMA mouse model","pmids":["22736030"],"confidence":"Medium","gaps":["Single-lab finding without independent replication","Whether sequestration fully accounts for the phenotype unresolved"]},{"year":2014,"claim":"Identified Artemis as a PTIP-binding effector downstream of the 53BP1-PTIP axis that promotes NHEJ by blocking end resection, explaining PTIP's role in repair pathway choice and PARP-inhibitor response.","evidence":"Co-IP, double-knockout epistasis, end-resection and PARP-inhibitor sensitivity assays","pmids":["25512557"],"confidence":"High","gaps":["Structural basis of the PTIP-Artemis interaction undefined","How Artemis recruitment is regulated temporally unresolved"]},{"year":2014,"claim":"Showed PTIP-MLL4 activity is recruited by the homeodomain factor PITX2, extending the TF-bridging paradigm to additional developmental regulators.","evidence":"Co-IP, in vitro HMT assay, ChIP, and domain mapping","pmids":["24486544"],"confidence":"Medium","gaps":["Single-lab finding","In vivo significance of PITX2-PTIP cooperation not tested"]},{"year":2015,"claim":"Established a phosphorylation-controlled activation/repression switch in which PPM1B dephosphorylates the PAX2 activation domain to displace PTIP and recruit Groucho repressors.","evidence":"Co-IP, phosphatase assays, ChIP, reporter assays, and siRNA","pmids":["25631048"],"confidence":"Medium","gaps":["Single-lab finding","Genome-wide scope of the switch not defined"]},{"year":2016,"claim":"Dissected PTIP function by showing a PTIP-PA1 BRCT subcomplex mediates transcription and class switch recombination independently of MLL3/MLL4 and of damage-site localization.","evidence":"Quantitative proteomics, domain mutagenesis, B-cell knockout, and CSR assays","pmids":["26744420"],"confidence":"High","gaps":["Identity of additional PA1-subcomplex effectors unresolved","Mechanism of MLL-independent transcriptional activation undefined"]},{"year":2016,"claim":"Connected PTIP BRCT domains to cell-cycle and apoptotic control through interaction with WEE1 kinase and modulation of CDK1 phosphorylation and chemosensitivity.","evidence":"Co-IP interaction network, pharmacologic screen, ectopic expression, caspase-3 assays","pmids":["27196765"],"confidence":"Medium","gaps":["Single-lab finding with correlative functional readout","Whether WEE1 regulation is direct unresolved"]},{"year":2021,"claim":"Revealed PTIP can be used for transcriptional repression, recruited by DACH1 to reduce promoter H3K4me3, demonstrating context-dependent outcomes of PTIP-H3K4me3 activity.","evidence":"Co-IP, ChIP for H3K4me3, RNA-seq, conditional knockout, and siRNA in podocytes","pmids":["33998601"],"confidence":"Medium","gaps":["Single-lab finding","Mechanism by which DACH1-PTIP reduces rather than deposits H3K4me3 unresolved"]},{"year":2022,"claim":"Extended PTIP enhancer function to macrophage metabolism, showing it cooperates with p300 to establish an H3K27ac-marked CD38 enhancer governing NAD+ metabolism and inflammation.","evidence":"Macrophage conditional knockout, ChIP-seq, metabolic profiling, cytokine assays","pmids":["35354042"],"confidence":"Medium","gaps":["Single-lab finding","Direct versus indirect role at the CD38 enhancer not separated"]},{"year":2022,"claim":"Demonstrated PTIP is required for proper chromosome segregation and localizes to the mitotic centrosome via its C-terminal BRCT domains, providing a molecular handle on its mitotic role.","evidence":"siRNA, live-cell imaging, immunofluorescence, and BRCT domain mapping in HeLa cells","pmids":["36153541"],"confidence":"Medium","gaps":["Single-lab finding","Centrosomal binding partners undefined"]},{"year":2023,"claim":"Established that PAXIP1, with PAGR1, promotes global cohesin chromatin association and cohesin-dependent enhancer-promoter contacts, linking it to STAG2-cohesin biology and a tumor-suppressive axis.","evidence":"CRISPR screens, ChIP-seq for cohesin, Hi-C, ATAC-seq, co-IP, FDF-motif mutagenesis, and in vivo lung tumor epistasis","pmids":["37070193","37702151","39652422","39345539"],"confidence":"High","gaps":["Mechanism by which PAXIP1/PAGR1 loads or stabilizes cohesin undefined","Whether cohesin role is separable from H3K4 methylation function unresolved"]},{"year":2024,"claim":"Identified UFMylation of PTIP under replication stress as a regulator of nascent-DNA degradation at stalled forks in BRCA1-deficient cells, adding a post-translational layer to its fork-protection role.","evidence":"Denaturing co-IP, DNA fiber assays, and PARP-inhibitor sensitivity with siRNA","pmids":["38657865"],"confidence":"Medium","gaps":["Single-lab finding","UFMylation site and how it alters PTIP activity undefined"]},{"year":2024,"claim":"Showed PTIP drives an intermediate post-irradiation H3K4me3 increase that epigenetically induces PRDM1 to promote cell-cycle arrest, tying its MLL-complex function to the damage response output.","evidence":"Hematopoietic conditional knockout, ChIP for H3K4me3, expression and cell-cycle assays after IR","pmids":["39097652"],"confidence":"Medium","gaps":["Single-lab finding","Directness of PRDM1 regulation not fully established"]},{"year":2025,"claim":"Reported a non-canonical mitochondrial pool of PTIP that triggers cytochrome c release and apoptosis, dependent on its N-terminal glutamine-rich region and specific BRCT residues.","evidence":"Subcellular fractionation, immunofluorescence, cytochrome c release and apoptosis assays, domain mutagenesis","pmids":["41608385"],"confidence":"Medium","gaps":["Single-lab finding without independent replication","Trigger and transport machinery for nuclear-to-mitochondrial relocation undefined"]},{"year":null,"claim":"How PTIP partitions among its distinct roles — MLL-dependent transcription, MLL-independent PA1 transcription, cohesin loading, DNA repair, and mitochondrial apoptosis — and how each is selectively engaged at given loci or conditions remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model assigning PTIP molecules to specific functions","Regulation of context-specific recruitment (TF identity, post-translational modification, subcomplex composition) undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,4,18,22]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,4,3,6]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[14]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,2]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[6,14,8]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[24]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[30]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[3,4,13]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[4,7,12,25]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[6,8,11,17]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[12,15,20]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1,24]}],"complexes":["MLL3/MLL4 (KMT2C/KMT2D) Set1-like H3K4 methyltransferase complex","PTIP-PA1/PAGR1 subcomplex","cohesin (STAG2)"],"partners":["PAX2","PAGR1","53BP1","PITX2","DACH1","ARTEMIS","WEE1","STAG2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6ZW49","full_name":"PAX-interacting protein 1","aliases":["PAX transactivation activation domain-interacting protein"],"length_aa":1069,"mass_kda":121.3,"function":"Involved in DNA damage response and in transcriptional regulation through histone methyltransferase (HMT) complexes. Plays a role in early development. In DNA damage response is required for cell survival after ionizing radiation. In vitro shown to be involved in the homologous recombination mechanism for the repair of double-strand breaks (DSBs). Its localization to DNA damage foci requires RNF8 and UBE2N. Recruits TP53BP1 to DNA damage foci and, at least in particular repair processes, effective DNA damage response appears to require the association with TP53BP1 phosphorylated by ATM at 'Ser-25'. Together with TP53BP1 regulates ATM association. Proposed to recruit PAGR1 to sites of DNA damage and the PAGR1:PAXIP1 complex is required for cell survival in response to DNA damage; the function is probably independent of MLL-containing histone methyltransferase (HMT) complexes. However, this function has been questioned (By similarity). Promotes ubiquitination of PCNA following UV irradiation and may regulate recruitment of polymerase eta and RAD51 to chromatin after DNA damage. Proposed to be involved in transcriptional regulation by linking MLL-containing histone methyltransferase (HMT) complexes to gene promoters by interacting with promoter-bound transcription factors such as PAX2. Associates with gene promoters that are known to be regulated by KMT2D/MLL2. During immunoglobulin class switching in activated B-cells is involved in trimethylation of histone H3 at 'Lys-4' and in transcription initiation of downstream switch regions at the immunoglobulin heavy-chain (Igh) locus; this function appears to involve the recruitment of MLL-containing HMT complexes. Conflictingly, its function in transcriptional regulation during immunoglobulin class switching is reported to be independent of the MLL2/MLL3 complex (By similarity)","subcellular_location":"Nucleus matrix; Chromosome","url":"https://www.uniprot.org/uniprotkb/Q6ZW49/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PAXIP1","classification":"Not Classified","n_dependent_lines":309,"n_total_lines":1208,"dependency_fraction":0.25579470198675497},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PAXIP1","total_profiled":1310},"omim":[{"mim_id":"612033","title":"PAXIP1-ASSOCIATED GLUTAMATE-RICH PROTEIN 1; PAGR1","url":"https://www.omim.org/entry/612033"},{"mim_id":"612032","title":"DPY30 HISTONE METHYLTRANSFERASE COMPLEX REGULATORY SUBUNIT; DPY30","url":"https://www.omim.org/entry/612032"},{"mim_id":"609636","title":"ALZHEIMER DISEASE 10","url":"https://www.omim.org/entry/609636"},{"mim_id":"608254","title":"PAX TRANSCRIPTION ACTIVATION DOMAIN-INTERACTING PROTEIN 1; PAXIP1","url":"https://www.omim.org/entry/608254"},{"mim_id":"607281","title":"LSM1 HOMOLOG, mRNA DEGRADATION-ASSOCIATED; LSM1","url":"https://www.omim.org/entry/607281"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":24.8}],"url":"https://www.proteinatlas.org/search/PAXIP1"},"hgnc":{"alias_symbol":["CAGF29","CAGF28","TNRC2","PTIP"],"prev_symbol":["PAXIP1L"]},"alphafold":{"accession":"Q6ZW49","domains":[{"cath_id":"3.40.50.10190","chopping":"2-96","consensus_level":"medium","plddt":80.2021,"start":2,"end":96},{"cath_id":"3.40.50.10190","chopping":"98-186","consensus_level":"medium","plddt":89.3445,"start":98,"end":186},{"cath_id":"3.40.50.10190","chopping":"611-696_818-825","consensus_level":"medium","plddt":89.5664,"start":611,"end":825},{"cath_id":"3.40.50.10190","chopping":"711-802","consensus_level":"medium","plddt":92.7362,"start":711,"end":802},{"cath_id":"3.40.50.10190","chopping":"856-967","consensus_level":"medium","plddt":91.3483,"start":856,"end":967},{"cath_id":"3.40.50.10190","chopping":"971-1069","consensus_level":"medium","plddt":90.0115,"start":971,"end":1069}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6ZW49","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6ZW49-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6ZW49-F1-predicted_aligned_error_v6.png","plddt_mean":69.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PAXIP1","jax_strain_url":"https://www.jax.org/strain/search?query=PAXIP1"},"sequence":{"accession":"Q6ZW49","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6ZW49.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6ZW49/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6ZW49"}},"corpus_meta":[{"pmid":"17500065","id":"PMC_17500065","title":"PTIP 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Regulation of PAXIP1-AS1 by SMC3/CEBPB at rs112651172 in Psychiatric Disorders Drives Synaptic and Behavioral Dysfunctions in Mice.","date":"2025","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/40911142","citation_count":4,"is_preprint":false},{"pmid":"30831521","id":"PMC_30831521","title":"Establishment of TUSMi008-A, an induced pluripotent stem cell (iPSC) line from a 76-year old Alzheimer's disease (AD) patient with PAXIP1 gene mutation.","date":"2019","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/30831521","citation_count":4,"is_preprint":false},{"pmid":"33993864","id":"PMC_33993864","title":"PTIP Deficiency in B Lymphocytes Reduces Subcutaneous Fat Deposition in Mice.","date":"2021","source":"Biochemistry. Biokhimiia","url":"https://pubmed.ncbi.nlm.nih.gov/33993864","citation_count":3,"is_preprint":false},{"pmid":"39652422","id":"PMC_39652422","title":"A STAG2-PAXIP1/PAGR1 axis suppresses lung tumorigenesis.","date":"2024","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/39652422","citation_count":2,"is_preprint":false},{"pmid":"35655387","id":"PMC_35655387","title":"An essential role for PTIP in mediating Hox gene regulation along PcG and trxG pathways.","date":"2022","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/35655387","citation_count":2,"is_preprint":false},{"pmid":"36648392","id":"PMC_36648392","title":"Ptip is essential for tooth development via regulating Wnt pathway.","date":"2023","source":"Oral diseases","url":"https://pubmed.ncbi.nlm.nih.gov/36648392","citation_count":2,"is_preprint":false},{"pmid":"37272101","id":"PMC_37272101","title":"PTIP Deficiency in B Lymphocytes Ameliorates Dextran Sulfate Sodium-Induced Ulcerative Colitis in Mice.","date":"2023","source":"Discovery medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37272101","citation_count":2,"is_preprint":false},{"pmid":"36153541","id":"PMC_36153541","title":"The genomic stability regulator PTIP is required for proper chromosome segregation in mitosis.","date":"2022","source":"Cell division","url":"https://pubmed.ncbi.nlm.nih.gov/36153541","citation_count":2,"is_preprint":false},{"pmid":"39345539","id":"PMC_39345539","title":"A STAG2-PAXIP1/PAGR1 axis suppresses lung tumorigenesis.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/39345539","citation_count":1,"is_preprint":false},{"pmid":"41608385","id":"PMC_41608385","title":"PAX-Interacting Protein 1 (PTIP) Promotes Apoptosis.","date":"2025","source":"Journal of cellular signaling","url":"https://pubmed.ncbi.nlm.nih.gov/41608385","citation_count":1,"is_preprint":false},{"pmid":"40869273","id":"PMC_40869273","title":"Ptip and the Trr-COMPASS-like Complex Regulate Cardiac Progenitor Cell Division in the Drosophila Embryonic Heart Tube.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40869273","citation_count":1,"is_preprint":false},{"pmid":"41812975","id":"PMC_41812975","title":"Chromatin regulator PTIP: A critical safeguard against B cell apoptosis and exhaustion in TLR-4-driven inflammation.","date":"2026","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/41812975","citation_count":0,"is_preprint":false},{"pmid":"41514145","id":"PMC_41514145","title":"PTIP inhibits proliferation, migration, and angiogenesis of retinal microvascular endothelial cells in a high-glucose environment.","date":"2026","source":"In vitro cellular & developmental biology. Animal","url":"https://pubmed.ncbi.nlm.nih.gov/41514145","citation_count":0,"is_preprint":false},{"pmid":"41623573","id":"PMC_41623573","title":"A Newly Characterized, Two BRCT Domain-Containing Isoform of PAX-Interacting Protein (PTIP) Generated via Frame Shift and Alternative Pre-mRNA Splicing.","date":"2025","source":"Journal of cellular signaling","url":"https://pubmed.ncbi.nlm.nih.gov/41623573","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":28400,"output_tokens":8016,"usd":0.10272,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":17714,"output_tokens":6959,"usd":0.131272,"stage2_stop_reason":"end_turn"},"total_usd":0.233992,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"PTIP (PAXIP1) was identified as a novel protein that directly binds to the activation domain of PAX2 (and other Pax proteins) in vitro, in yeast two-hybrid assays, and in tissue culture cells. The octapeptide repression domain of Pax2 inhibits this binding. PTIP contains five BRCT domains and co-localizes with Pax2 in the nucleus at actively expressed chromatin and the nuclear matrix fraction.\",\n      \"method\": \"Yeast two-hybrid, in vitro binding, co-immunoprecipitation in tissue culture, nuclear fractionation, co-localization\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Y2H, in vitro binding, co-IP, co-localization) in a single study establishing the founding interaction\",\n      \"pmids\": [\"10908331\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"PTIP is essential for progression through mitosis. PTIP-null mouse embryos show reduced mitosis, widespread cell death, DNA damage preceding nuclear condensation, and defective phospho-histone H3 expression. Neither embryonic fibroblasts nor embryonic stem cells from PTIP mutants proliferate in culture. Trophoblast cells are more sensitive to DNA-damaging agents.\",\n      \"method\": \"Constitutive null allele generation in mice, immunostaining for mitotic markers (phospho-H3), DNA damage markers, cell culture proliferation assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with multiple cellular readouts (mitosis, DNA damage, proliferation) across multiple cell types\",\n      \"pmids\": [\"12588986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Human PTIP (hPTIP) contains 1069 amino acids and six BRCT domains. It shows increased association with 53BP1 in response to ionizing radiation (IR), and this IR-induced association requires ATM. PTIP is required for ATM-mediated phosphorylation of p53 at Ser15 and for IR-induced up-regulation of p21. PTIP depletion increases cellular sensitivity to IR.\",\n      \"method\": \"Co-immunoprecipitation, deletion analysis, siRNA knockdown, Western blot for p53-Ser15 phosphorylation and p21, cell survival assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, domain mapping, siRNA with multiple functional readouts in single rigorous study\",\n      \"pmids\": [\"15456759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Endogenous PTIP and a novel protein PA1 are components of a Set1-like histone H3K4 methyltransferase (HMT) complex containing ASH2L, RBBP5, WDR5, hDPY-30, NCOA6, MLL3, MLL4, and UTX. The PTIP complex carries HMT activity specifically methylating H3K4. PA1 binds PTIP directly and requires PTIP for interaction with the rest of the complex. hDPY-30 binds ASH2L directly.\",\n      \"method\": \"Co-purification, mass spectrometry, co-immunoprecipitation, in vitro HMT assay, direct binding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — complex purification with MS identification, in vitro enzymatic assay, and direct binding assays; multiple orthogonal methods\",\n      \"pmids\": [\"17500065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PTIP bridges the DNA-binding protein PAX2 to the ALR/MLL3/MLL4 H3K4 methyltransferase complex. PAX2 promotes assembly of this complex and H3K4 methylation at a PAX2-binding DNA element through PTIP. Without PTIP, PAX2 binds DNA but fails to assemble the ALR complex. PTIP-null and conditional mutants show reduced H3K4 methylation levels.\",\n      \"method\": \"Co-purification, conditional and constitutive knockout mice, chromatin immunoprecipitation (ChIP), H3K4 methylation assays\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — co-purification, genetic knockout with multiple alleles, ChIP; independently corroborates PMID 17500065\",\n      \"pmids\": [\"17925232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"PTIP/Swift is required for efficient PCNA ubiquitination and recruitment of TLS polymerase eta to chromatin in response to DNA damage. Immunodepletion of PTIP/Swift from Xenopus egg extracts prevented PCNA ubiquitination and polymerase eta recruitment during replicative stress. PTIP depletion in mammalian cells by RNAi reduced PCNA ubiquitination and decreased recruitment of polymerase eta and Rad51 to chromatin.\",\n      \"method\": \"Xenopus egg extract immunodepletion, siRNA knockdown in mammalian cells, chromatin fractionation assays\",\n      \"journal\": \"DNA repair\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — immunodepletion in Xenopus extracts plus RNAi in mammalian cells with consistent results across two systems\",\n      \"pmids\": [\"18353733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Recruitment of PTIP to damaged chromatin depends on the DNA damage signaling pathway γH2AX→MDC1→RNF8, which in turn facilitates sustained localization of PA1 to DNA break sites. The N-terminal PA1-binding domain and C-terminal focus-localization domain of PTIP are critical for its DNA damage repair function, which is likely independent of the MLL complexes.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, immunofluorescence for DNA damage foci, domain deletion analysis, cell viability after ionizing radiation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP, domain mapping, foci analysis; multiple methods in one study\",\n      \"pmids\": [\"19124460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PTIP is required for PPARγ and C/EBPα expression during adipogenesis. PTIP deletion in mouse embryonic fibroblasts markedly decreases PPARγ expression and impairs H3K4 trimethylation and RNA Pol II occupancy at PPARγ and C/EBPα promoters. Rescue of the adipogenesis defect in PTIP-/- MEFs requires co-expression of both PPARγ and C/EBPα.\",\n      \"method\": \"Conditional knockout mice, ChIP for H3K4me3 and RNA Pol II, rescue experiments with PPARγ/C/EBPα co-expression, adipogenesis assays\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO, ChIP, and genetic rescue with defined transcription factors; multiple orthogonal methods\",\n      \"pmids\": [\"19583951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"RNF8 controls DNA damage-induced nuclear foci formation of PTIP, which in turn regulates 53BP1 localization to DNA damage sites. PTIP is also required for ATM-dependent SMC1 phosphorylation at damage sites. PTIP acts downstream of RNF8 and upstream of 53BP1 in the DNA damage response pathway.\",\n      \"method\": \"siRNA knockdown, immunofluorescence for nuclear foci, Western blot for SMC1 phosphorylation, epistasis analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via siRNA depletion with multiple readouts (foci, phosphorylation), pathway ordering established\",\n      \"pmids\": [\"19414588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Drosophila PTIP ortholog is essential for anterior/posterior patterning and segmentation. Loss of Drosophila ptip decreases global H3K4 methylation and increases H3K27 methylation. Drosophila PTIP is required to activate homeotic gene expression in response to derepression of Polycomb group genes, and binds to promoter sequences coincident with increased H3K4 trimethylation.\",\n      \"method\": \"Genetic null alleles in Drosophila, global histone methylation analysis, cell culture reporter assays, ChIP at homeotic gene promoters\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ortholog in Drosophila with genetic loss-of-function, ChIP, and global histone modification analysis; consistent with mammalian data\",\n      \"pmids\": [\"19429789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"PTIP is required to maintain H3K4 methylation in embryonic stem cells. PTIP deletion in ES cells leads to spontaneous differentiation to trophectoderm, loss of pluripotency, reduced Oct4 expression, reduced H3K4 methylation, and impaired differentiation along all three germ layers in embryoid bodies.\",\n      \"method\": \"Conditional PTIP knockout in ES cells using Cre recombinase, flow cytometry, immunostaining, ChIP for H3K4 methylation\",\n      \"journal\": \"Stem cells (Dayton, Ohio)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with multiple cellular and molecular readouts, single lab\",\n      \"pmids\": [\"19544464\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PTIP promotes DNA double-strand break repair through homologous recombination (HR). PTIP-deficient chicken DT40 cells show increased spontaneous DNA lesions, sensitivity to IR and camptothecin, and reduced HR efficiency as measured by artificial recombination substrates. PTIP-depleted HeLa cells also show reduced HR efficiency.\",\n      \"method\": \"Gene disruption in DT40 cells, HR efficiency assay with recombination substrates, sensitivity assays (IR, camptothecin), siRNA in HeLa cells\",\n      \"journal\": \"Genes to cells : devoted to molecular & cellular mechanisms\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout plus siRNA depletion in two cell systems with direct HR efficiency measurement\",\n      \"pmids\": [\"20088963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PTIP promotes H3K4me3 and transcription initiation at downstream switch regions of the immunoglobulin heavy-chain (Igh) locus in activated B cells. PTIP-deficient B cells show impaired H3K4me3 and transcription at Igh switch regions, leading to defective class switch recombination (CSR). PTIP accumulation at DSBs also contributes to CSR and genome stability independently of Igh switch transcription.\",\n      \"method\": \"Conditional B-cell-specific PTIP knockout, ChIP-seq, RNA-seq, class switch recombination assays, flow cytometry\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with ChIP-seq, transcriptomics, and functional CSR assay; multiple orthogonal methods\",\n      \"pmids\": [\"20671152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PTIP is required for long-range chromatin interactions between the 3' regulatory region enhancer and germline transcript promoters at the immunoglobulin heavy chain locus. Loss of PTIP in mature B cells inhibits CSR by suppressing H3K4 methylation at germline transcript promoters, reduces Pax5 binding, and abolishes chromatin looping detected by chromosome conformation capture.\",\n      \"method\": \"CD19-Cre conditional PTIP knockout, ChIP, chromosome conformation capture (3C), class switch recombination assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO, ChIP, 3C with multiple functional readouts; establishes PTIP role in 3D chromatin organization\",\n      \"pmids\": [\"21282469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The tandem BRCT5-BRCT6 domain of human PTIP directly recognizes the γH2AX tail, and this interaction depends on phosphorylation of H2AX Ser139. Crystal structure at 2.15 Å resolution of the hPTIP BRCT5/6-γH2AX complex was determined, and mutation analysis confirmed the molecular basis for the interaction.\",\n      \"method\": \"X-ray crystallography (2.15 Å resolution), mutagenesis, binding assays\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with mutagenesis validation; directly establishes molecular mechanism of γH2AX recognition\",\n      \"pmids\": [\"22064073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PAXIP1/PTIP regulates RAG-mediated cleavage and repair during V(D)J recombination in DP thymocytes. Loss of PAXIP1 diminishes Jα H3K4me3 and germline transcription, suppresses DSB formation at 3' Jα segments, and results in accumulation of unresolved Tcra breaks. PAXIP1 is also essential for S1PR1-mediated mature thymocyte egress from the thymus through transcriptional activation of S1pr1.\",\n      \"method\": \"Conditional knockout in thymocytes, ChIP for H3K4me3, DSB detection assays (LMPCR), flow cytometry, gene expression analysis\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with ChIP, direct DSB measurement, and functional lymphocyte trafficking readout; multiple methods\",\n      \"pmids\": [\"23159437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The mutant androgen receptor (AR) with poly-glutamine expansion (associated with SBMA) specifically interacts with PTIP and sequesters PTIP away from radiation-induced nuclear foci. This results in increased sensitivity to DNA-damaging agents and chromosomal instabilities. In a mouse model of SBMA, DNA damage is detected in muscle cells and muscular atrophy is accelerated when one copy of PTIP is removed.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence for nuclear foci, DNA damage assays, mouse genetic model (PTIP heterozygosity in SBMA model)\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and foci analysis plus in vivo genetic model; single lab, consistent across methods\",\n      \"pmids\": [\"22736030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PTIP binds to Artemis nuclease as a PTIP-binding protein. Loss of Artemis restores PARP inhibitor resistance in BRCA1-deficient cells, demonstrating Artemis is a major downstream effector of the 53BP1-PTIP pathway that prevents end resection and promotes NHEJ, directly competing with homologous recombination repair.\",\n      \"method\": \"Co-immunoprecipitation, genetic epistasis (double knockout cell lines), PARP inhibitor sensitivity assays, end resection assays\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP identifying novel binding partner, genetic epistasis with functional PARP inhibitor sensitivity readout\",\n      \"pmids\": [\"25512557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PITX2 associates with the PTIP-containing MLL4/KMT2D histone H3K4 methyltransferase complex. This association is dependent on PITX2's homeodomain. The PITX2 protein complex possesses H3K4 HMT activity, and ChIP shows co-occupancy of PITX2 and PTIP on PITX2 transcriptional target promoters.\",\n      \"method\": \"Co-immunoprecipitation, in vitro HMT assay, chromatin immunoprecipitation (ChIP), domain deletion analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, in vitro enzymatic assay, and ChIP; single lab with multiple methods\",\n      \"pmids\": [\"24486544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The phosphatase PPM1B can dephosphorylate the Pax2 activation domain and displace PTIP, thereby inhibiting H3K4 methylation and gene activation. PPM1B is an essential component of the Groucho4 repressor complex recruited by Pax2. Loss of PPM1B prevents Groucho-mediated gene repression, demonstrating that phosphorylation state of Pax2 controls the switch between PTIP-mediated activation and PPM1B/Groucho-mediated repression.\",\n      \"method\": \"Co-immunoprecipitation, phosphatase assays, ChIP, reporter gene assays, siRNA knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, biochemical phosphatase assay, and ChIP; single lab, multiple methods\",\n      \"pmids\": [\"25631048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A PTIP-PA1 subcomplex functions independently from the MLL3/MLL4 complex to mediate transcription and class switch recombination. Using quantitative proteomics in primary lymphocytes, a tandem BRCT domain of PTIP was identified as sufficient for CSR, with PA1 as its main functional partner. PTIP promotes CSR separately from its association with the MLL3/MLL4 complex and from its localization to sites of DNA damage.\",\n      \"method\": \"Quantitative proteomics, domain mapping by mutagenesis, B-cell conditional knockout, class switch recombination assays\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — quantitative proteomics plus genetic domain dissection and functional CSR assay; multiple orthogonal methods\",\n      \"pmids\": [\"26744420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PAXIP1 BRCT domains interact with WEE1 kinase and regulate WEE1-mediated phosphorylation of CDK1. Ectopic expression of PAXIP1 promotes enhanced caspase-3-mediated apoptosis in cells treated with WEE1 inhibitor AZD1775 and cisplatin.\",\n      \"method\": \"Co-immunoprecipitation (BRCT-mediated interaction network), pharmacologic screen, ectopic expression, caspase-3 activity assays\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP for interaction, functional readout with ectopic expression; single lab but multiple cell-based assays\",\n      \"pmids\": [\"27196765\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DACH1 interacts with PTIP and is recruited by DACH1 to its promoter-binding sites. DACH1-PTIP recruitment represses transcription and reduces promoter H3K4Me3 levels. DACH1 knockdown in podocytes combined with hyperglycemia triggers target gene upregulation and increased promoter H3K4Me3, revealing that DACH1 uses PTIP-H3K4Me3 activity for transcriptional repression at DACH1 target loci.\",\n      \"method\": \"Co-immunoprecipitation, ChIP for H3K4me3, RNA sequencing, conditional knockout mice, siRNA knockdown\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus ChIP with KO and KD; single lab, two orthogonal methods\",\n      \"pmids\": [\"33998601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PTIP governs NAD+ metabolism in macrophages by regulating CD38 expression. PTIP cooperates with acetyltransferase p300 to establish an active intronic enhancer of CD38 with enriched H3K27ac. PTIP deletion impairs proinflammatory response, promotes metabolic switch from glycolysis to oxidative phosphorylation, and alters NAD+ metabolism via downregulating CD38.\",\n      \"method\": \"Conditional knockout in macrophages, ChIP for H3K27ac, metabolic profiling (NAD+ measurement), cytokine assays, enhancer identification by ChIP-seq\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO, ChIP-seq, and metabolic assays; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"35354042\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PTIP is essential for proper chromosome segregation during mitosis in HeLa cells. PTIP inactivation results in prolonged mitotic time, inefficient chromosome alignment, and increased cell death during mitotic exit. PTIP localizes to the mitotic centrosome via its C-terminal BRCT domains.\",\n      \"method\": \"siRNA knockdown, live-cell imaging, immunofluorescence for centrosome localization, BRCT domain deletion analysis\",\n      \"journal\": \"Cell division\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization with domain mapping and functional loss-of-function with mitotic phenotype readout; single lab\",\n      \"pmids\": [\"36153541\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PAXIP1 and STAG2 converge to maintain 3D genome architecture and facilitiate promoter-enhancer contacts for glucocorticoid receptor (GR)-dependent transcription. PAXIP1 is required for stability of cohesin on chromatin, cohesin localization to GR-occupied sites, and maintenance of enhancer-promoter interactions. PAXIP1 and STAG2 depletion alter the GR transcriptome without altering the GR cistrome.\",\n      \"method\": \"CRISPR genome-wide screen, ChIP-seq for cohesin, ATAC-seq, Hi-C, co-immunoprecipitation, conditional knockdown\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR screen, ChIP-seq, Hi-C, and functional transcriptional assays; multiple orthogonal methods establishing mechanism\",\n      \"pmids\": [\"37070193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PAXIP1 (with binding partner PAGR1) promotes global chromatin association of cohesin independently of DNA replication, transcription, or DNA repair. Depletion of PAXIP1 severely aggravates cohesion defects in ESCO2 mutant cells leading to mitotic cell death. Cohesin regulation by PAXIP1 requires PAGR1 and a conserved FDF motif in PAGR1. PAXIP1 co-localizes with cohesin on active gene promoters and enhancers.\",\n      \"method\": \"CRISPR synthetic lethality screens, ChIP-seq for cohesin, co-immunoprecipitation, domain mutagenesis (FDF motif), cohesion assays, live-cell imaging\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR screen, ChIP-seq, co-IP, domain mutagenesis, multiple functional assays; rigorous single-study evidence\",\n      \"pmids\": [\"37702151\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PTIP undergoes UFMylation in response to replication stress (detected by denaturing co-immunoprecipitation). This post-translational modification promotes end resection and degradation of nascent DNA at stalled replication forks in BRCA1-deficient cells. PTIP-depleted and UFL1-depleted BRCA1 knockdown cells are less sensitive to PARP inhibitors.\",\n      \"method\": \"Denaturing co-immunoprecipitation, DNA fiber assays for fork degradation, cell viability assay with PARP inhibitors, siRNA knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — denaturing co-IP establishing UFMylation, functional fork degradation assay, PARP inhibitor sensitivity; single lab\",\n      \"pmids\": [\"38657865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PTIP is required for H3K4me3 upregulation in an intermediate phase after ionizing radiation and promotes cell cycle arrest by epigenetically inducing PRDM1. PTIP is a component of the MLL histone methyltransferase complex required for this radiation-induced H3K4me3 increase and downstream PRDM1 expression.\",\n      \"method\": \"Conditional knockout in hematopoietic cells, ChIP for H3K4me3, gene expression analysis, cell cycle assays after IR\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with ChIP and cell cycle readout; single lab, two orthogonal methods\",\n      \"pmids\": [\"39097652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PAXIP1 and PAGR1 are epistatic to STAG2 in oncogenic KRAS-driven lung tumorigenesis in vivo. Gene expression and chromatin accessibility profiles in STAG2- and PAXIP1-deficient neoplastic cells are similar, functionally linking STAG2-cohesin to the PAXIP1/PAGR1 heterodimeric complex as a tumor-suppressive axis.\",\n      \"method\": \"Somatic CRISPR-Cas9 in autochthonous mouse lung cancer model, tumor barcoding, RNA-seq, ATAC-seq, genetic epistasis in vivo\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic epistasis with CRISPR, supported by RNA-seq and ATAC-seq; preprint and peer-reviewed publication available\",\n      \"pmids\": [\"39652422\", \"39345539\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A fraction of PTIP is actively transported from the nucleus to mitochondria, causing mitochondrial aggregation, cytochrome c release into the cytoplasm, and cellular apoptosis. Deletion of an N-terminal glutamine-rich region, mutation of a conserved threonine within BRCT3, and truncation of the C-terminal BRCT5 domain each significantly reduced apoptosis.\",\n      \"method\": \"Subcellular fractionation, immunofluorescence for mitochondrial localization, cytochrome c release assay, domain deletion/mutagenesis, apoptosis assays\",\n      \"journal\": \"Journal of cellular signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct localization with functional consequence and domain mutagenesis; single lab, novel finding without independent replication\",\n      \"pmids\": [\"41608385\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PAXIP1/PTIP is a multi-BRCT-domain nuclear scaffold protein that functions in two major contexts: (1) as an integral component of the MLL3/MLL4-containing Set1-like histone H3K4 methyltransferase complex, where it bridges sequence-specific DNA-binding factors (PAX2, PITX2, DACH1) to chromatin-modifying machinery to establish active H3K4me3 marks at developmentally regulated genes and immunoglobulin loci, and also cooperates with PAGR1/PA1 as a subcomplex that can act independently of MLL3/MLL4 to promote transcription; and (2) in the DNA damage response, where it is recruited to break sites via a γH2AX→MDC1→RNF8 pathway through direct BRCT5/6 recognition of phospho-γH2AX, acts upstream of 53BP1 to regulate its localization, promotes NHEJ via recruitment of Artemis, and facilitates homologous recombination and PCNA ubiquitination for translesion synthesis. PTIP also promotes global cohesin chromatin association through its PAGR1 partner (requiring the PAGR1 FDF motif), maintains 3D enhancer-promoter contacts, undergoes UFMylation to regulate replication fork stability in BRCA1-deficient cells, and a fraction localizes to mitochondria to trigger apoptosis via cytochrome c release.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PAXIP1 (PTIP) is a multi-BRCT-domain nuclear scaffold that couples sequence-specific DNA-binding factors to histone H3K4 methylation machinery and functions in parallel in the DNA damage response [#0, #3, #6]. As an integral component of a Set1-like MLL3/MLL4 (KMT2C/KMT2D) H3K4 methyltransferase complex containing ASH2L, RBBP5, WDR5, hDPY-30, NCOA6, UTX, and the PTIP-binding protein PA1/PAGR1, it carries H3K4-specific HMT activity [#3]. Through its BRCT modules PTIP bridges DNA-binding transcription factors—PAX2, PITX2, and DACH1—to this complex, assembling it at target elements to deposit H3K4 methylation and activate (or, in the DACH1 context, repress) developmentally and metabolically regulated genes [#0, #4, #18, #22]. This activity underlies its requirement for H3K4me3, pluripotency-gene expression, and lineage differentiation in embryonic stem cells, for adipogenic induction of PPARγ and C/EBPα, and for H3K4me3 and germline transcription that license immunoglobulin class switch recombination and Tcra V(D)J recombination [#7, #10, #12, #15]; a PTIP-PA1 subcomplex can mediate transcription and class switch recombination independently of MLL3/MLL4 [#20]. PTIP also organizes 3D chromatin, maintaining long-range enhancer-promoter contacts at the Igh locus and, together with its PAGR1 partner, promoting global cohesin association with chromatin to support cohesin-dependent enhancer-promoter looping and tumor suppression downstream of STAG2 [#13, #25, #26, #29]. In the DNA damage response, PTIP is recruited to break sites through direct BRCT5/6 recognition of phospho-γH2AX downstream of the γH2AX→MDC1→RNF8 axis, acts upstream of 53BP1 and ATM-dependent SMC1 phosphorylation, and promotes NHEJ via the Artemis nuclease while also facilitating homologous recombination and PCNA-ubiquitination-dependent translesion synthesis [#5, #6, #8, #11, #14, #17]. PTIP is essential for mitotic progression and chromosome segregation, localizing to the mitotic centrosome via its C-terminal BRCT domains [#1, #24].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established PAXIP1's founding identity as a five-BRCT nuclear protein that directly binds the PAX2 activation domain, defining it as a transcription-factor-associated chromatin protein.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro binding, co-IP and nuclear co-localization in cultured cells\",\n      \"pmids\": [\"10908331\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the chromatin-modifying activity downstream of PAX2 binding\", \"Functional consequence of the interaction unresolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Demonstrated PTIP is genetically essential for mitotic progression and genome integrity, the first in vivo evidence of a core proliferative role.\",\n      \"evidence\": \"Constitutive null mouse embryos with mitotic, DNA-damage, and proliferation readouts\",\n      \"pmids\": [\"12588986\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis linking PTIP loss to DNA damage and mitotic failure not defined\", \"Could not separate transcriptional from DNA-repair contributions\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Connected PTIP to the ATM-dependent DNA damage response by showing IR-induced, ATM-requiring association with 53BP1 and a requirement for p53-Ser15 phosphorylation.\",\n      \"evidence\": \"Co-IP, deletion mapping, siRNA, phospho-Western, survival assays in human cells\",\n      \"pmids\": [\"15456759\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct recruitment mechanism to damage sites unknown\", \"Whether PTIP acts upstream or downstream of 53BP1 unresolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined PTIP as an integral subunit of a Set1-like MLL3/MLL4 H3K4 methyltransferase complex and identified PA1 as its direct partner, establishing the molecular basis of its transcriptional activity.\",\n      \"evidence\": \"Complex co-purification with mass spectrometry, in vitro HMT assay, direct binding assays\",\n      \"pmids\": [\"17500065\", \"17925232\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether all functions require the full MLL3/MLL4 complex unresolved\", \"Range of recruiting DNA-binding factors not yet enumerated\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Extended PTIP's repair role to replication stress, showing it is required for PCNA ubiquitination and recruitment of translesion polymerase eta and Rad51.\",\n      \"evidence\": \"Xenopus egg extract immunodepletion plus mammalian RNAi with chromatin fractionation\",\n      \"pmids\": [\"18353733\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct versus indirect contribution to PCNA ubiquitination not separated\", \"Mechanism connecting PTIP to the ubiquitination machinery undefined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Ordered PTIP within the DNA damage signaling cascade — recruited via γH2AX→MDC1→RNF8, acting downstream of RNF8 and upstream of 53BP1 — and established its requirement for ATM-dependent SMC1 phosphorylation and for HR.\",\n      \"evidence\": \"siRNA epistasis, foci imaging, phospho-Western, DT40 gene disruption and HR substrate assays\",\n      \"pmids\": [\"19124460\", \"19414588\", \"20088963\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct phospho-mark recognized by PTIP not yet structurally defined\", \"How PTIP regulates 53BP1 localization mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Generalized PTIP's MLL-complex function to developmental and lineage transcription programs, showing it maintains H3K4 methylation required for pluripotency, adipogenesis, and homeotic patterning.\",\n      \"evidence\": \"Conditional/constitutive knockouts in mouse ES cells and MEFs and Drosophila null alleles with ChIP and rescue\",\n      \"pmids\": [\"19583951\", \"19544464\", \"19429789\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Locus selectivity of PTIP-dependent H3K4 methylation not fully explained\", \"Direct versus indirect transcriptional targets not all defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed PTIP licenses immunoglobulin class switch recombination by driving H3K4me3 and germline transcription at switch regions while separately contributing at DSBs.\",\n      \"evidence\": \"B-cell conditional knockout with ChIP-seq, RNA-seq, and CSR assays\",\n      \"pmids\": [\"20671152\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of transcription versus DSB function to CSR not quantified\", \"Mechanism of switch-region targeting unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Revealed PTIP organizes 3D chromatin, being required for enhancer-promoter looping at the Igh locus, linking H3K4 methylation to higher-order genome architecture.\",\n      \"evidence\": \"Conditional knockout with ChIP and chromosome conformation capture\",\n      \"pmids\": [\"21282469\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether looping defect is cause or consequence of lost H3K4 methylation unresolved\", \"Generality beyond the Igh locus not yet tested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Provided the structural basis for damage-site recruitment by solving the PTIP BRCT5/6–γH2AX complex, demonstrating direct phospho-Ser139 recognition.\",\n      \"evidence\": \"2.15 Å X-ray crystallography with mutagenesis and binding assays\",\n      \"pmids\": [\"22064073\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address how recruitment is coordinated with the RNF8 pathway\", \"Affinity contributions of other BRCT pairs not defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrated PTIP couples H3K4me3-dependent germline transcription to programmed DSB resolution during V(D)J recombination and to thymocyte egress, broadening its lymphocyte developmental role.\",\n      \"evidence\": \"Thymocyte conditional knockout with ChIP, LMPCR DSB detection, and trafficking assays\",\n      \"pmids\": [\"23159437\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct mechanistic link between H3K4me3 and RAG cleavage not fully resolved\", \"Whether S1pr1 regulation is direct unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Linked PTIP to disease by showing poly-glutamine-expanded androgen receptor sequesters PTIP from damage foci, sensitizing cells and worsening SBMA muscle pathology.\",\n      \"evidence\": \"Co-IP, foci imaging, DNA damage assays, and PTIP-heterozygous SBMA mouse model\",\n      \"pmids\": [\"22736030\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab finding without independent replication\", \"Whether sequestration fully accounts for the phenotype unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified Artemis as a PTIP-binding effector downstream of the 53BP1-PTIP axis that promotes NHEJ by blocking end resection, explaining PTIP's role in repair pathway choice and PARP-inhibitor response.\",\n      \"evidence\": \"Co-IP, double-knockout epistasis, end-resection and PARP-inhibitor sensitivity assays\",\n      \"pmids\": [\"25512557\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the PTIP-Artemis interaction undefined\", \"How Artemis recruitment is regulated temporally unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed PTIP-MLL4 activity is recruited by the homeodomain factor PITX2, extending the TF-bridging paradigm to additional developmental regulators.\",\n      \"evidence\": \"Co-IP, in vitro HMT assay, ChIP, and domain mapping\",\n      \"pmids\": [\"24486544\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab finding\", \"In vivo significance of PITX2-PTIP cooperation not tested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Established a phosphorylation-controlled activation/repression switch in which PPM1B dephosphorylates the PAX2 activation domain to displace PTIP and recruit Groucho repressors.\",\n      \"evidence\": \"Co-IP, phosphatase assays, ChIP, reporter assays, and siRNA\",\n      \"pmids\": [\"25631048\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab finding\", \"Genome-wide scope of the switch not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Dissected PTIP function by showing a PTIP-PA1 BRCT subcomplex mediates transcription and class switch recombination independently of MLL3/MLL4 and of damage-site localization.\",\n      \"evidence\": \"Quantitative proteomics, domain mutagenesis, B-cell knockout, and CSR assays\",\n      \"pmids\": [\"26744420\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of additional PA1-subcomplex effectors unresolved\", \"Mechanism of MLL-independent transcriptional activation undefined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected PTIP BRCT domains to cell-cycle and apoptotic control through interaction with WEE1 kinase and modulation of CDK1 phosphorylation and chemosensitivity.\",\n      \"evidence\": \"Co-IP interaction network, pharmacologic screen, ectopic expression, caspase-3 assays\",\n      \"pmids\": [\"27196765\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab finding with correlative functional readout\", \"Whether WEE1 regulation is direct unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed PTIP can be used for transcriptional repression, recruited by DACH1 to reduce promoter H3K4me3, demonstrating context-dependent outcomes of PTIP-H3K4me3 activity.\",\n      \"evidence\": \"Co-IP, ChIP for H3K4me3, RNA-seq, conditional knockout, and siRNA in podocytes\",\n      \"pmids\": [\"33998601\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab finding\", \"Mechanism by which DACH1-PTIP reduces rather than deposits H3K4me3 unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended PTIP enhancer function to macrophage metabolism, showing it cooperates with p300 to establish an H3K27ac-marked CD38 enhancer governing NAD+ metabolism and inflammation.\",\n      \"evidence\": \"Macrophage conditional knockout, ChIP-seq, metabolic profiling, cytokine assays\",\n      \"pmids\": [\"35354042\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab finding\", \"Direct versus indirect role at the CD38 enhancer not separated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated PTIP is required for proper chromosome segregation and localizes to the mitotic centrosome via its C-terminal BRCT domains, providing a molecular handle on its mitotic role.\",\n      \"evidence\": \"siRNA, live-cell imaging, immunofluorescence, and BRCT domain mapping in HeLa cells\",\n      \"pmids\": [\"36153541\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab finding\", \"Centrosomal binding partners undefined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established that PAXIP1, with PAGR1, promotes global cohesin chromatin association and cohesin-dependent enhancer-promoter contacts, linking it to STAG2-cohesin biology and a tumor-suppressive axis.\",\n      \"evidence\": \"CRISPR screens, ChIP-seq for cohesin, Hi-C, ATAC-seq, co-IP, FDF-motif mutagenesis, and in vivo lung tumor epistasis\",\n      \"pmids\": [\"37070193\", \"37702151\", \"39652422\", \"39345539\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which PAXIP1/PAGR1 loads or stabilizes cohesin undefined\", \"Whether cohesin role is separable from H3K4 methylation function unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified UFMylation of PTIP under replication stress as a regulator of nascent-DNA degradation at stalled forks in BRCA1-deficient cells, adding a post-translational layer to its fork-protection role.\",\n      \"evidence\": \"Denaturing co-IP, DNA fiber assays, and PARP-inhibitor sensitivity with siRNA\",\n      \"pmids\": [\"38657865\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab finding\", \"UFMylation site and how it alters PTIP activity undefined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed PTIP drives an intermediate post-irradiation H3K4me3 increase that epigenetically induces PRDM1 to promote cell-cycle arrest, tying its MLL-complex function to the damage response output.\",\n      \"evidence\": \"Hematopoietic conditional knockout, ChIP for H3K4me3, expression and cell-cycle assays after IR\",\n      \"pmids\": [\"39097652\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab finding\", \"Directness of PRDM1 regulation not fully established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Reported a non-canonical mitochondrial pool of PTIP that triggers cytochrome c release and apoptosis, dependent on its N-terminal glutamine-rich region and specific BRCT residues.\",\n      \"evidence\": \"Subcellular fractionation, immunofluorescence, cytochrome c release and apoptosis assays, domain mutagenesis\",\n      \"pmids\": [\"41608385\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab finding without independent replication\", \"Trigger and transport machinery for nuclear-to-mitochondrial relocation undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PTIP partitions among its distinct roles — MLL-dependent transcription, MLL-independent PA1 transcription, cohesin loading, DNA repair, and mitochondrial apoptosis — and how each is selectively engaged at given loci or conditions remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model assigning PTIP molecules to specific functions\", \"Regulation of context-specific recruitment (TF identity, post-translational modification, subcomplex composition) undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 4, 18, 22]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 4, 3, 6]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [6, 14, 8]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [24]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [30]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [3, 4, 13]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [4, 7, 12, 25]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [6, 8, 11, 17]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [12, 15, 20]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1, 24]}\n    ],\n    \"complexes\": [\n      \"MLL3/MLL4 (KMT2C/KMT2D) Set1-like H3K4 methyltransferase complex\",\n      \"PTIP-PA1/PAGR1 subcomplex\",\n      \"cohesin (STAG2)\"\n    ],\n    \"partners\": [\n      \"PAX2\",\n      \"PAGR1\",\n      \"53BP1\",\n      \"PITX2\",\n      \"DACH1\",\n      \"Artemis\",\n      \"WEE1\",\n      \"STAG2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}