{"gene":"MYSM1","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2011,"finding":"MYSM1 functions as a histone H2A deubiquitinase (H2A-DUB) that removes monoubiquitin from H2A-K119, and its loss in mice causes defects in hematopoiesis including lymphopenia, anemia, and impaired HSC function associated with elevated ROS, γH2AX DNA damage marker, and p53 protein in hematopoietic progenitors.","method":"Mysm1(tm1a/tm1a) targeted mouse line characterization; bone marrow transplantation to establish cell-intrinsic requirement","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function mouse model with multiple orthogonal phenotypic readouts, replicated across multiple labs","pmids":["22184403"],"is_preprint":false},{"year":2011,"finding":"MYSM1 derepresses EBF1 transcription in B cell progenitors by orchestrating histone modifications and transcription factor recruitment to the EBF1 locus, establishing an essential intrinsic role in early B cell commitment.","method":"Mysm1-deficient mice; chromatin immunoprecipitation (ChIP) at EBF1 locus; rescue experiments","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP demonstrating direct locus association, loss-of-function mouse model with specific molecular readout, replicated by multiple labs","pmids":["22169041"],"is_preprint":false},{"year":2013,"finding":"MYSM1 directly associates with the Gfi1 enhancer element in HSCs and promotes Gfi1 transcription by modulating histone modifications and directing recruitment of transcription factors Gata2 and Runx1 to the Gfi1 locus; loss of Mysm1 drives HSCs from quiescence into rapid cycling and increases apoptotic rate.","method":"Mysm1(-/-) mice; ChIP at Gfi1 locus; transcription factor recruitment assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP plus loss-of-function with defined molecular mechanism, single lab with two orthogonal methods","pmids":["24014243"],"is_preprint":false},{"year":2013,"finding":"MYSM1 interacts with transcription factor NFIL3/E4BP4 and its recruitment to the ID2 locus is dependent on MYSM1; MYSM1 maintains active chromatin at the ID2 locus to promote NK cell maturation.","method":"Mysm1(-/-) mice; co-immunoprecipitation; ChIP at ID2 locus","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus ChIP in single lab","pmids":["24062447"],"is_preprint":false},{"year":2014,"finding":"MYSM1 derepresses transcription of the Flt3 gene by directing histone modifications at the Flt3 promoter and enabling PU.1 recruitment specifically at the Flt3 locus (but not at GM-CSF-α or M-CSFR loci), thereby controlling dendritic cell development from common myeloid progenitors.","method":"Mysm1(-/-) mice; ChIP at Flt3 promoter; in vitro DC differentiation assays with Flt3L or GM-CSF","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus loss-of-function with specific molecular readout, single lab","pmids":["25217698"],"is_preprint":false},{"year":2015,"finding":"MYSM1 deficiency results in p53 protein elevation in hematopoietic cells; genetic double-knockout (Mysm1(-/-)p53(-/-)) fully rescues all developmental and hematopoietic defects including lymphopoiesis and HSC numbers/function, establishing p53 activation as the driving mechanism for hematopoietic abnormalities in Mysm1 deficiency.","method":"Mysm1(-/-)p53(-/-) double-knockout mice; bone marrow transplantation; flow cytometric analysis of hematopoietic progenitors","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis by double-knockout, replicated independently by two labs (Belle et al. and Gatzka et al.)","pmids":["25710881","25613381"],"is_preprint":false},{"year":2015,"finding":"A homozygous MYSM1 missense mutation affecting the catalytic site within the JAMM/MPN deubiquitinase domain causes human immunodeficiency with absent B lymphocytes and T-cell lymphopenia; in vivo genetic reversion of the mutation in a hematopoietic stem cell restored normal immunohematopoietic phenotype.","method":"Whole-exome sequencing; genome-wide homozygosity mapping; Sanger sequencing; immunophenotyping","journal":"The Journal of allergy and clinical immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human genetic evidence with natural reversion experiment confirming causality, single case","pmids":["26220525"],"is_preprint":false},{"year":2015,"finding":"MYSM1 protein associates with p53 and co-localizes to promoters of p53-target genes Bbc3/PUMA and Cdkn1a/p21, antagonizing their p53-driven expression by modulating H3K27ac and H3K4me3 histone modifications and reducing p53 recruitment; PUMA (but not p21) is the essential non-redundant effector of p53-induced MPP apoptosis in Mysm1 deficiency.","method":"Co-IP of MYSM1 with p53; ChIP at PUMA and p21 promoters; Mysm1(-/-)Puma(-/-) double-knockout mice; transcriptome analysis","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — Co-IP, ChIP, and genetic double-knockout epistasis with defined molecular outcome, multiple orthogonal methods in one study","pmids":["26768662"],"is_preprint":false},{"year":2015,"finding":"MYSM1 accumulates in the cytoplasm in response to microbial stimuli where it interacts with TRAF3 and TRAF6 via its SWIRM domain and removes K63-linked polyubiquitin chains via its metalloproteinase/MPN domain to inactivate these complexes and terminate PRR-driven pro-inflammatory and type I interferon responses.","method":"Co-immunoprecipitation of MYSM1 with TRAF3/TRAF6; domain mutagenesis (SWIRM and MPN domain mutants); Mysm1-deficient mice challenged with microbial stimuli; cytokine/IFN quantification","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — Co-IP with domain mutagenesis establishing two distinct functional motifs, loss-of-function in vivo with defined signaling readout","pmids":["26474655"],"is_preprint":false},{"year":2015,"finding":"MYSM1 is a transcriptional activator of Pax5 (a repressor of plasma cell differentiation) by facilitating key transcription factor recruitment and coordinating histone modifications at the Pax5 loci, thereby intrinsically repressing plasma cell differentiation and antibody production.","method":"Mysm1-deficient mice; ChIP at Pax5 locus; B cell differentiation assays; antibody quantification","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus loss-of-function with specific molecular readout, single lab","pmids":["26348977"],"is_preprint":false},{"year":2016,"finding":"MYSM1 is required for expression of IRF2 and IRF8 in HSCs; lower IRF2/IRF8 levels in Mysm1(-/-) HSCs lead to enhanced p53 transcription, contributing to HSC quiescence defects; Mysm1 enhances function of the IRF2 and IRF8 promoters.","method":"Mysm1(-/-) mice; promoter reporter assays for IRF2 and IRF8; gene expression analysis","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter assays plus loss-of-function, single lab with two orthogonal methods","pmids":["27277682"],"is_preprint":false},{"year":2016,"finding":"MYSM1 recruits c-Myc to the promoter of miR-150 and stimulates its transcription; miR-150 in turn decreases FLT3 expression in B1a cells, defining a MYSM1/miR-150/FLT3 pathway that inhibits B1a cell proliferation.","method":"ChIP demonstrating c-Myc recruitment to miR-150 promoter in MYSM1-dependent manner; Mysm1-deficient mice; miR-150/FLT3 expression analysis","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus loss-of-function genetic model, single lab","pmids":["27590507"],"is_preprint":false},{"year":2016,"finding":"MYSM1 expression in the bone marrow niche (non-hematopoietic cells) is dispensable for HSC maintenance and hematopoietic homeostasis; selective deletion of Mysm1 in non-hematopoietic cells did not affect HSC number, viability, or hematopoietic output.","method":"Bone marrow chimeras with wild-type donor into Mysm1fl/flTg.CreERT2 recipients; tamoxifen-induced Mysm1 ablation in non-hematopoietic cells; flow cytometric analysis","journal":"Experimental hematology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — negative finding from conditional genetic model with rigorous controls, single lab","pmids":["27833034"],"is_preprint":false},{"year":2017,"finding":"MYSM1 loss in CD8+ T cells leads to a hyperactivated CD8+ T-cell state with increased apoptosis and preferential p53 upregulation, resulting in reduced CD8+ T-cell numbers and impaired CD8+ T-cell-dependent pathology in experimental cerebral malaria.","method":"Conditional Mysm1 knockout in T cells (Mysm1fl/flTg.CD8-cre model); flow cytometry; cytokine production assays; cerebral malaria model","journal":"Immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional knockout with defined cellular and molecular phenotype, single lab","pmids":["28066899"],"is_preprint":false},{"year":2019,"finding":"MYSM1 physically binds the androgen receptor (AR) without increasing AR expression, and MYSM1 knockdown results in activation of Akt/c-Raf/GSK-3β signaling in castration-resistant prostate cancer cells.","method":"Co-immunoprecipitation assay of MYSM1 with AR; MYSM1 knockdown; western blot for Akt/c-Raf/GSK-3β pathway activation","journal":"Aging","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP without mutagenesis or reconstitution, single lab","pmids":["31761786"],"is_preprint":false},{"year":2020,"finding":"MYSM1 interacts with STING and cleaves STING K63-linked ubiquitination to suppress cGAS-STING signaling; MYSM1 expression is induced upon DNA virus infection and intracellular DNA stimulation.","method":"Co-immunoprecipitation of MYSM1 with STING; ubiquitination assay showing removal of K63-linked ubiquitin from STING; Mysm1-deficient mice challenged with DNA virus","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus in-cell ubiquitination assay with loss-of-function in vivo, single lab","pmids":["33086059"],"is_preprint":false},{"year":2020,"finding":"MYSM1 colocalizes with γH2AX foci upon DNA double-strand break induction, and mass spectrometry-based proteomics identified an interacting network of DNA damage and replication proteins (enriched after etoposide treatment) as MYSM1 binding partners.","method":"Co-localization of MYSM1 with γH2AX by immunofluorescence; affinity pulldown followed by mass spectrometry in 293T cells treated with etoposide","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — co-localization plus MS interactome without functional validation, single lab","pmids":["32466590"],"is_preprint":false},{"year":2021,"finding":"MYSM1 directly binds the promoter region of miR-200/CDH1 in colorectal cancer cells, impairs repressive H2AK119ub1 enrichment at this locus, and epigenetically activates miR-200/CDH1 expression; MYSM1 loss activates PI3K/AKT signaling.","method":"ChIP at miR-200/CDH1 promoter; H2AK119ub1 ChIP; gain- and loss-of-function in CRC cell lines; in vivo xenograft models","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus functional rescue assays, single lab with multiple orthogonal methods","pmids":["34706761"],"is_preprint":false},{"year":2021,"finding":"MYSM1 loss represses ribosomal protein gene expression and protein synthesis in cMYC-driven B cell lymphoma, strongly inhibiting cMYC oncogenic activity and protecting against B cell lymphoma onset and progression.","method":"cMYC-driven B cell lymphoma mouse models crossed with Mysm1-deficient mice; ribosomal protein gene expression analysis; protein synthesis measurement","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in lymphoma model, single lab with defined molecular readout","pmids":["34114734"],"is_preprint":false},{"year":2022,"finding":"MYSM1 induces apoptosis in TNBC cells and sensitizes them to cisplatin; MYSM1 overexpression increases cisplatin-induced apoptosis via RSK3 inactivation and consequent decreased phosphorylation of BAD at Ser112.","method":"MYSM1 overexpression and knockdown in TNBC cell lines; apoptosis assays; western blot for RSK3 and phospho-BAD(Ser112)","journal":"Cell death discovery","confidence":"Low","confidence_rationale":"Tier 3 / Weak — cell-line gain/loss-of-function with downstream signaling readout, no direct interaction demonstrated, single lab","pmids":["35217648"],"is_preprint":false},{"year":2023,"finding":"MYSM1 loss-of-function (patient splice variant causing absent protein) results in persistent DNA damage foci and prolonged DNA damage response signaling after DSBs from immunoglobulin recombination and ionizing radiation, without altering DSB generation or repair itself; MYSM1 specifically regulates termination of DNA damage responses.","method":"MYSM1-deficient pre-B cells and U2OS cells; γH2AX focus assays; irradiation-induced DSB repair kinetics; patient cells with constitutive γH2AX","journal":"The Journal of allergy and clinical immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function in patient-derived and cell-line models with specific molecular readout, single lab","pmids":["38065233"],"is_preprint":false},{"year":2023,"finding":"MYSM1 acts as a co-activator of ERα in breast cancer, maintaining ERα stability via direct ERα deubiquitination and regulating histone modifications on cis-regulatory elements of ERα-target genes to facilitate chromatin decondensation; small molecule Imatinib was identified to interact with the MPN catalytic domain of MYSM1.","method":"Co-immunoprecipitation of MYSM1 with ERα; ubiquitination assays; ChIP; xenograft models; virtual screening/docking for Imatinib-MPN interaction","journal":"EMBO molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus ubiquitination assay and ChIP, single lab with multiple orthogonal methods","pmids":["38177530"],"is_preprint":false},{"year":2023,"finding":"MYSM1 DUB catalytic activity (tested via D660N point mutation that renders protein catalytically inactive) is universally required for its functions in hematopoiesis, leukocyte development, and other aspects of mammalian physiology; Mysm1DN/DN mice phenocopy Mysm1-knockout mice.","method":"CRISPR-generated Mysm1D660N (catalytic dead) knock-in mouse; Mysm1fl/DN CreERT2 inducible model; full hematopoietic and immune cell characterization","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — active-site mutagenesis in vivo with comprehensive phenotypic analysis showing catalytic activity is required, single lab but rigorous","pmids":["36611064"],"is_preprint":false},{"year":2024,"finding":"MYSM1 epigenetically regulates Id4 transcription by modifying histone marks at the Id4 promoter (H2AK119ub1 removal); loss of MYSM1 in neural stem cells (via Nestin-Cre) causes microcephaly with hyperproliferation, increased apoptosis, and skewed differentiation toward neurogenesis over astrogliogenesis; Id4 re-expression rescues these defects.","method":"Nestin-Cre Mysm1 conditional knockout mice; RNA sequencing; genome-wide CUT&Tag for histone modifications; Id4 rescue experiments","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with genome-wide epigenomic profiling, rescue experiment, multiple orthogonal methods in one study","pmids":["38342917"],"is_preprint":false},{"year":2024,"finding":"MYSM1 directly interacts with TRIM21 via its MPN domain and regulates TRIM21 deubiquitination and protein stability; MYSM1 exacerbates doxorubicin-induced cardiotoxicity by enhancing ferroptosis through the MYSM1-TRIM21 axis.","method":"Co-IP combined with LC-MS/MS identifying TRIM21 as MYSM1 substrate; MPN domain requirement established; AAV9-mediated cardiomyocyte-specific MYSM1 knockdown in mice","journal":"Cell communication and signaling : CCS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP/MS plus domain requirement and in vivo cardiomyocyte-specific KD, single lab","pmids":["39695708"],"is_preprint":false},{"year":2024,"finding":"MYSM1 expression and DUB catalytic activity in mature dendritic cells are dispensable for DC maintenance in vivo or DC activation by microbial stimuli; instead, MYSM1 acts via its DUB catalytic activity specifically in haematopoietic progenitors to support normal DC lineage development and functional programming.","method":"Mysm1flCreERT2, Mysm1flCD11c-cre, and Mysm1DN conditional mouse models; flow cytometry; transcriptional profiling of DCs","journal":"Immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple conditional genetic models with cell-type specific deletion and catalytic dead allele, single lab","pmids":["38316548"],"is_preprint":false},{"year":2025,"finding":"MYSM1 deubiquitinates RIPK2 and recruits PP2A to dephosphorylate RIPK2 at S176, thereby inhibiting NF-κB and MAPK signaling pathways and attenuating osteoarthritis progression.","method":"Co-IP of MYSM1 with RIPK2 and PP2A; ubiquitination and phosphorylation assays; Ripk2S176D and Ripk2S176A mutation rescue experiments; MYSM1 knockout and overexpression in OA mouse models","journal":"Bone research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus mutagenesis rescue experiments in vivo, single lab with multiple orthogonal methods","pmids":["39746943"],"is_preprint":false},{"year":2025,"finding":"MYSM1 mediates K63-linked deubiquitination and stabilization of STAT1 at K379 via its MPN metalloprotease domain, promoting STAT1 transcription factor function and necroptosis-related gene expression in myocardial ischemia/reperfusion injury.","method":"Proteome-wide quantitative analysis identifying STAT1 as MYSM1 substrate; Co-IP; ubiquitination assays with site-specific K379 mutation; AAV9 cardiomyocyte-specific MYSM1 knockdown in I/R mouse model","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, site-specific ubiquitination assay, and in vivo model, single lab","pmids":["39897566"],"is_preprint":false},{"year":2025,"finding":"MYSM1 deubiquitinates and stabilizes PARP1 in an MPN domain-dependent manner, mediating PARP1-dependent cardiomyocyte parthanatos and cardiac hypertrophy.","method":"Co-IP combined with LC-MS identifying PARP1 as MYSM1 substrate; MPN domain mutagenesis; AAV9 cardiomyocyte-specific MYSM1 knockdown in angiotensin II and TAC cardiac hypertrophy mouse models","journal":"Hypertension","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP/MS plus domain mutagenesis and in vivo model, single lab","pmids":["39907013"],"is_preprint":false},{"year":2025,"finding":"MYSM1 interacts with TRAF2 and TRAF3 via its SWIRM domain and removes K63-linked polyubiquitin chains to decrease TRAF2-TRAF3 complex stability, thereby impairing NIK degradation and sustaining non-canonical NF-κB activation while also promoting MAPK (p38, JNK) signaling in lung adenocarcinoma.","method":"Co-IP of MYSM1 with TRAF2/TRAF3; K63-ubiquitin chain removal assays; domain mapping; rescue experiments with TRAF2/TRAF3 inhibition; in vitro and in vivo functional assays","journal":"NPJ precision oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mapping plus rescue experiments, single lab","pmids":["41162619"],"is_preprint":false},{"year":2026,"finding":"Mysm1 mutations (meander tail alleles) in mice cause anterior-selective cerebellar malformation through cell-autonomous effects on granule cell precursors; multimodal single-nucleus assays show Mysm1 affects gene expression in several lineages and granule cell precursor proportions by E14.5, identifying a developmental role in cerebellar compartment specification.","method":"Positional cloning/complementation of meander tail mutations to Mysm1; single-nucleus multimodal genomics; non-complementing endonuclease-generated Mysm1 alleles","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic complementation plus single-nucleus multiomics, preprint, single lab","pmids":["42124724"],"is_preprint":true}],"current_model":"MYSM1 is a metalloprotease-family deubiquitinase with a catalytically essential MPN/JAMM domain plus SWIRM and SANT domains; in the nucleus it removes monoubiquitin from histone H2A-K119 to activate gene expression at specific loci (EBF1, Gfi1, Flt3, Id4, Pax5, miR-200, and others) by remodeling histone marks and recruiting transcription factors, thereby controlling hematopoietic stem cell quiescence, lymphocyte and myeloid lineage development, and neural stem cell homeostasis through p53-dependent and p53-independent mechanisms; in the cytoplasm, MYSM1 accumulates upon innate immune stimulation and removes K63-linked polyubiquitin chains from TRAF3, TRAF6, and STING to terminate PRR-driven pro-inflammatory and type I interferon signaling; beyond these established functions, MYSM1 also deubiquitinates non-histone substrates including ERα, STAT1, PARP1, TRIM21, and RIPK2, regulating their stability and activity in cancer and cardiac contexts, and localizes to DNA double-strand break sites where it promotes termination of the DNA damage response without affecting break repair itself."},"narrative":{"mechanistic_narrative":"MYSM1 is a JAMM/MPN-domain metalloprotease deubiquitinase whose catalytic activity is universally required for its roles across hematopoiesis, immune cell development, and broader mammalian physiology, as a catalytically dead D660N knock-in fully phenocopies the null [PMID:36611064]. In the nucleus, MYSM1 removes monoubiquitin from histone H2A-K119 to derepress lineage-specifying loci, coordinating histone modifications and recruiting transcription factors to activate EBF1, Gfi1, Flt3, Pax5, and Id4 expression, thereby driving B-cell commitment, HSC quiescence, dendritic-cell and NK-cell development, and neural stem cell homeostasis [PMID:22184403, PMID:22169041, PMID:24014243, PMID:25217698, PMID:26348977, PMID:38342917]. A central consequence of MYSM1 loss is aberrant p53 activation: MYSM1 associates with p53 and restrains transcription of its proapoptotic target PUMA, and genetic ablation of p53 fully rescues the hematopoietic defects of Mysm1 deficiency, identifying p53/PUMA-driven apoptosis as the principal cause of those phenotypes [PMID:25710881, PMID:25613381, PMID:26768662]. In the cytoplasm, MYSM1 accumulates upon microbial or DNA-virus stimulation and uses its SWIRM domain to engage TRAF3/TRAF6 and STING and its MPN domain to strip K63-linked polyubiquitin chains, terminating PRR-driven pro-inflammatory and type I interferon signaling [PMID:26474655, PMID:33086059]. Beyond histones, MYSM1 deubiquitinates and regulates the stability or activity of non-histone substrates including STAT1, PARP1, TRIM21, and RIPK2 in cancer, cardiac, and inflammatory contexts [PMID:38177530, PMID:39695708, PMID:39746943, PMID:39897566, PMID:39907013]. A homozygous catalytic-site mutation causes human immunodeficiency with absent B cells and T-cell lymphopenia, and loss-of-function additionally produces prolonged DNA damage response signaling without affecting break repair [PMID:26220525, PMID:38065233].","teleology":[{"year":2011,"claim":"Established MYSM1's core biochemical identity as an H2A-K119 deubiquitinase and its physiological requirement in hematopoiesis, answering what enzymatic activity MYSM1 carries and why its loss matters.","evidence":"Targeted Mysm1 mouse line with bone marrow transplantation showing cell-intrinsic HSC and lineage defects, elevated ROS, γH2AX, and p53","pmids":["22184403"],"confidence":"High","gaps":["Did not resolve whether H2A-DUB activity or non-histone activity drives each phenotype","Mechanism linking DUB loss to p53 elevation undefined"]},{"year":2011,"claim":"Defined how MYSM1 controls lineage commitment at the molecular level by showing it derepresses a specific gene through chromatin remodeling and transcription factor recruitment.","evidence":"Mysm1-deficient mice with ChIP at the EBF1 locus and rescue experiments","pmids":["22169041"],"confidence":"High","gaps":["Did not map which histone marks are direct substrates versus secondary","Generality of the locus-specific recruitment mechanism untested at this stage"]},{"year":2013,"claim":"Generalized the locus-specific activator model to HSC quiescence and NK maturation, showing MYSM1 directs transcription factor recruitment (Gata2/Runx1, NFIL3) at defined enhancers.","evidence":"Mysm1(-/-) mice with ChIP at Gfi1 and ID2 loci plus co-immunoprecipitation","pmids":["24014243","24062447"],"confidence":"Medium","gaps":["Whether TF recruitment is a direct consequence of H2A deubiquitination not established","Single-lab Co-IP for NFIL3 interaction"]},{"year":2014,"claim":"Extended the chromatin-activator role to myeloid/dendritic lineage by showing MYSM1 enables PU.1 recruitment selectively at Flt3.","evidence":"Mysm1(-/-) mice with ChIP at Flt3 promoter and in vitro DC differentiation assays","pmids":["25217698"],"confidence":"Medium","gaps":["Basis for locus selectivity (Flt3 but not GM-CSF-α/M-CSFR) unexplained","Single lab"]},{"year":2015,"claim":"Identified p53 as the central downstream effector of MYSM1 loss and PUMA as the non-redundant apoptotic mediator, explaining why diverse hematopoietic defects share one cause.","evidence":"Mysm1(-/-)p53(-/-) and Mysm1(-/-)Puma(-/-) double-knockout mice with Co-IP and ChIP at PUMA/p21 promoters","pmids":["25710881","25613381","26768662"],"confidence":"High","gaps":["Mechanism by which MYSM1 loss elevates p53 protein not fully resolved","Whether MYSM1-p53 promoter antagonism requires DUB activity at this stage untested"]},{"year":2015,"claim":"Confirmed disease causality in humans, linking a catalytic-site mutation to immunodeficiency and validating the catalytic domain's requirement via natural reversion.","evidence":"Whole-exome sequencing and immunophenotyping of a patient with in vivo HSC reversion","pmids":["26220525"],"confidence":"Medium","gaps":["Single case","Molecular consequence of the missense allele on substrate spectrum not characterized"]},{"year":2015,"claim":"Revealed a distinct cytoplasmic, immune-regulatory function in which MYSM1 uses separable domains to engage and inactivate innate signaling adaptors, broadening MYSM1 beyond a nuclear histone enzyme.","evidence":"Co-IP of MYSM1 with TRAF3/TRAF6, SWIRM and MPN domain mutagenesis, and Mysm1-deficient mice challenged with microbial stimuli","pmids":["26474655"],"confidence":"High","gaps":["What triggers cytoplasmic relocalization on stimulation not defined","K63-chain editing specificity versus other DUBs unaddressed"]},{"year":2015,"claim":"Added further hematopoietic loci (Pax5) and an IRF2/IRF8→p53 regulatory link, sharpening the locus-specific activator network upstream of the p53 axis.","evidence":"Mysm1-deficient mice with ChIP at Pax5 and promoter reporter assays for IRF2/IRF8","pmids":["26348977","27277682"],"confidence":"Medium","gaps":["Direct versus indirect regulation of IRF promoters unresolved","Single lab"]},{"year":2016,"claim":"Distinguished the cell-intrinsic source of MYSM1 function, establishing that hematopoietic-progenitor MYSM1, not niche expression, drives HSC maintenance.","evidence":"Bone marrow chimeras with non-hematopoietic Mysm1 ablation; MYSM1/miR-150/FLT3 axis defined by ChIP","pmids":["27833034","27590507"],"confidence":"Medium","gaps":["Negative niche result does not exclude subtle non-hematopoietic roles","Single lab"]},{"year":2020,"claim":"Extended cytoplasmic immune regulation to the cGAS-STING axis and localized MYSM1 to DNA damage sites, hinting at a DDR role.","evidence":"Co-IP and K63-ubiquitination assays for STING; γH2AX co-localization and MS interactome after etoposide","pmids":["33086059","32466590"],"confidence":"Medium","gaps":["DDR interactome lacks functional validation (Low confidence)","Whether STING editing uses the same domains as TRAF editing not tested directly"]},{"year":2021,"claim":"Showed MYSM1 acts as an epigenetic regulator in cancer via H2AK119ub1 removal and links its loss to oncogenic signaling and cMYC-driven translation.","evidence":"ChIP/H2AK119ub1 ChIP at miR-200/CDH1 in CRC and cMYC lymphoma genetic models with ribosomal gene/protein synthesis readouts","pmids":["34706761","34114734"],"confidence":"Medium","gaps":["Context-dependent tumor-suppressor versus oncogenic roles not unified","Single lab per finding"]},{"year":2023,"claim":"Demonstrated that DUB catalytic activity is required for essentially all MYSM1 functions in vivo, unifying histone and non-histone activities under a single enzymatic requirement.","evidence":"CRISPR Mysm1 D660N catalytic-dead knock-in and inducible Mysm1fl/DN mice with comprehensive hematopoietic/immune profiling","pmids":["36611064"],"confidence":"High","gaps":["Does not separate which substrates are rate-limiting for which phenotype","Single lab"]},{"year":2023,"claim":"Established non-histone deubiquitination as a bona fide MYSM1 activity by showing direct ERα deubiquitination/stabilization and a DDR-termination function, plus a druggable MPN active site.","evidence":"Co-IP, ubiquitination assays, ChIP, and Imatinib docking for ERα; patient and U2OS cells with γH2AX kinetics for DDR termination","pmids":["38177530","38065233"],"confidence":"Medium","gaps":["DDR-termination substrate(s) not identified","Imatinib-MPN interaction in vivo relevance untested"]},{"year":2024,"claim":"Refined the developmental requirement to progenitor stages and extended epigenetic control to neural stem cells via Id4, while broadening cardiac non-histone substrates (TRIM21).","evidence":"Conditional DC models with Mysm1DN; Nestin-Cre KO with CUT&Tag and Id4 rescue; Co-IP/MS for TRIM21 with MPN domain mapping","pmids":["38316548","38342917","39695708"],"confidence":"Medium","gaps":["Substrate hierarchy across tissues unresolved","Single lab per substrate"]},{"year":2025,"claim":"Expanded the non-histone substrate repertoire (STAT1, PARP1, RIPK2, TRAF2/3) defining tissue-specific deubiquitination outcomes in cardiac, inflammatory, and oncogenic settings.","evidence":"Co-IP/MS, site-specific ubiquitination assays, MPN/SWIRM domain mapping, and AAV9 or KO in vivo disease models","pmids":["39897566","39907013","39746943","41162619"],"confidence":"Medium","gaps":["Determinants of substrate selectivity across contexts unknown","Each substrate validated in a single lab/disease model"]},{"year":null,"claim":"How MYSM1 achieves locus- and substrate-selectivity—choosing among histone H2A, innate-immune adaptors, and diverse non-histone proteins in a context-dependent manner—remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural basis for substrate discrimination defined","No unifying model for nuclear versus cytoplasmic partitioning","DDR-termination substrate uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[8,15,21,22,24,26,27,28,29]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,8,22]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,2,4,9,17,23]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[0,17,23]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1,2,23]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[8,15]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[16,20]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,2,4,9,23]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[8,15,29]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[0,17,23]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[5,7]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[20]}],"complexes":[],"partners":["TRAF3","TRAF6","STING","TP53","STAT1","PARP1","TRIM21","RIPK2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q5VVJ2","full_name":"Deubiquitinase MYSM1","aliases":["Myb-like, SWIRM and MPN domain-containing protein 1"],"length_aa":828,"mass_kda":95.0,"function":"Metalloprotease with deubiquitinase activity that plays important regulator roles in hematopoietic stem cell function, blood cell production and immune response (PubMed:24062447, PubMed:26220525, PubMed:28115216). Participates in the normal programming of B-cell responses to antigen after the maturation process (By similarity). Within the cytoplasm, plays critical roles in the repression of innate immunity and autoimmunity (PubMed:33086059). Removes 'Lys-63'-linked polyubiquitins from TRAF3 and TRAF6 complexes (By similarity). Attenuates NOD2-mediated inflammation and tissue injury by promoting 'Lys-63'-linked deubiquitination of RIPK2 component (By similarity). Suppresses the CGAS-STING1 signaling pathway by cleaving STING1 'Lys-63'-linked ubiquitin chains (PubMed:33086059). In the nucleus, acts as a hematopoietic transcription regulator derepressing a range of genes essential for normal stem cell differentiation including EBF1 and PAX5 in B-cells, ID2 in NK-cell progenitor or FLT3 in dendritic cell precursors (PubMed:24062447). Deubiquitinates monoubiquitinated histone H2A, a specific tag for epigenetic transcriptional repression, leading to dissociation of histone H1 from the nucleosome (PubMed:17707232)","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q5VVJ2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MYSM1","classification":"Not Classified","n_dependent_lines":30,"n_total_lines":1208,"dependency_fraction":0.024834437086092714},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MYSM1","total_profiled":1310},"omim":[{"mim_id":"618116","title":"BONE MARROW FAILURE SYNDROME 4; BMFS4","url":"https://www.omim.org/entry/618116"},{"mim_id":"614675","title":"BONE MARROW FAILURE SYNDROME 1; BMFS1","url":"https://www.omim.org/entry/614675"},{"mim_id":"612176","title":"MYB-LIKE, SWIRM, AND MPN DOMAINS-CONTAINING PROTEIN 1; MYSM1","url":"https://www.omim.org/entry/612176"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nucleoli","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MYSM1"},"hgnc":{"alias_symbol":["KIAA1915"],"prev_symbol":[]},"alphafold":{"accession":"Q5VVJ2","domains":[{"cath_id":"1.10.10.10","chopping":"389-457","consensus_level":"high","plddt":85.1746,"start":389,"end":457},{"cath_id":"3.40.140.10","chopping":"566-809","consensus_level":"high","plddt":89.4482,"start":566,"end":809}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5VVJ2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5VVJ2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5VVJ2-F1-predicted_aligned_error_v6.png","plddt_mean":64.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MYSM1","jax_strain_url":"https://www.jax.org/strain/search?query=MYSM1"},"sequence":{"accession":"Q5VVJ2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5VVJ2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5VVJ2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5VVJ2"}},"corpus_meta":[{"pmid":"22184403","id":"PMC_22184403","title":"The 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stimulation.","date":"2024","source":"Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/38316548","citation_count":1,"is_preprint":false},{"pmid":"31607324","id":"PMC_31607324","title":"[Deubiquitinase MYSM1 Regulates Differentiation of Human B Cells to Plasma Cells].","date":"2019","source":"Zhongguo shi yan xue ye xue za zhi","url":"https://pubmed.ncbi.nlm.nih.gov/31607324","citation_count":1,"is_preprint":false},{"pmid":"40344568","id":"PMC_40344568","title":"MiR-129-5p alleviates depression and anxiety by increasing astrocyte ATP production partly through targeting deubiquitinase Mysm1.","date":"2025","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/40344568","citation_count":1,"is_preprint":false},{"pmid":"41162619","id":"PMC_41162619","title":"MYSM1 promotes lung adenocarcinoma progression via TRAF2/3-mediated activation of MAPK and non-canonical NF-κB pathways.","date":"2025","source":"NPJ precision oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41162619","citation_count":0,"is_preprint":false},{"pmid":"33858043","id":"PMC_33858043","title":"[A novel compound heterozygous mutation in MYSM1 gene in a 1-month-old girl: a bone marrow failure syndrome 4 family survey and literature review].","date":"2021","source":"Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi","url":"https://pubmed.ncbi.nlm.nih.gov/33858043","citation_count":0,"is_preprint":false},{"pmid":"42124724","id":"PMC_42124724","title":"Mysm1 mutations in meander tail mice cause anterior-selective cerebellum malformation.","date":"2026","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/42124724","citation_count":0,"is_preprint":false},{"pmid":"41414839","id":"PMC_41414839","title":"MYSM1 regulates the proliferation and differentiation of bovine skeletal muscle satellite cells via BRG1-mediated activation of the AKT/mTOR/NF-κB signaling pathway.","date":"2025","source":"Animal bioscience","url":"https://pubmed.ncbi.nlm.nih.gov/41414839","citation_count":0,"is_preprint":false},{"pmid":"41917542","id":"PMC_41917542","title":"MYSM1 expression in monocytes is negatively correlated to disease activity in Rheumatoid Arthritis, which may be related to the inhibitory effect on inflammatory aging.","date":"2026","source":"Clinical rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/41917542","citation_count":0,"is_preprint":false},{"pmid":"28446309","id":"PMC_28446309","title":"[Establishment of mouse stably knockout of MYSM1 in MSC cell line C3H10T1/2 and its effect on the immune regulation in vitro].","date":"2017","source":"Zhongguo shi yan xue ye xue za zhi","url":"https://pubmed.ncbi.nlm.nih.gov/28446309","citation_count":0,"is_preprint":false},{"pmid":"40535318","id":"PMC_40535318","title":"Genetic and Clinical Progression of MYSM1 Related Bone Marrow Failure into Myeloid Malignancies: Case Series and Review of Literature.","date":"2025","source":"Clinical hematology international","url":"https://pubmed.ncbi.nlm.nih.gov/40535318","citation_count":0,"is_preprint":false},{"pmid":"29020094","id":"PMC_29020094","title":"Correction: Expression of MYSM1 is associated with tumor progression in colorectal cancer.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/29020094","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":30094,"output_tokens":7421,"usd":0.100798,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":16667,"output_tokens":5011,"usd":0.104305,"stage2_stop_reason":"end_turn"},"total_usd":0.205103,"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\": 2011,\n      \"finding\": \"MYSM1 functions as a histone H2A deubiquitinase (H2A-DUB) that removes monoubiquitin from H2A-K119, and its loss in mice causes defects in hematopoiesis including lymphopenia, anemia, and impaired HSC function associated with elevated ROS, γH2AX DNA damage marker, and p53 protein in hematopoietic progenitors.\",\n      \"method\": \"Mysm1(tm1a/tm1a) targeted mouse line characterization; bone marrow transplantation to establish cell-intrinsic requirement\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function mouse model with multiple orthogonal phenotypic readouts, replicated across multiple labs\",\n      \"pmids\": [\"22184403\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MYSM1 derepresses EBF1 transcription in B cell progenitors by orchestrating histone modifications and transcription factor recruitment to the EBF1 locus, establishing an essential intrinsic role in early B cell commitment.\",\n      \"method\": \"Mysm1-deficient mice; chromatin immunoprecipitation (ChIP) at EBF1 locus; rescue experiments\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP demonstrating direct locus association, loss-of-function mouse model with specific molecular readout, replicated by multiple labs\",\n      \"pmids\": [\"22169041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MYSM1 directly associates with the Gfi1 enhancer element in HSCs and promotes Gfi1 transcription by modulating histone modifications and directing recruitment of transcription factors Gata2 and Runx1 to the Gfi1 locus; loss of Mysm1 drives HSCs from quiescence into rapid cycling and increases apoptotic rate.\",\n      \"method\": \"Mysm1(-/-) mice; ChIP at Gfi1 locus; transcription factor recruitment assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus loss-of-function with defined molecular mechanism, single lab with two orthogonal methods\",\n      \"pmids\": [\"24014243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MYSM1 interacts with transcription factor NFIL3/E4BP4 and its recruitment to the ID2 locus is dependent on MYSM1; MYSM1 maintains active chromatin at the ID2 locus to promote NK cell maturation.\",\n      \"method\": \"Mysm1(-/-) mice; co-immunoprecipitation; ChIP at ID2 locus\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus ChIP in single lab\",\n      \"pmids\": [\"24062447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MYSM1 derepresses transcription of the Flt3 gene by directing histone modifications at the Flt3 promoter and enabling PU.1 recruitment specifically at the Flt3 locus (but not at GM-CSF-α or M-CSFR loci), thereby controlling dendritic cell development from common myeloid progenitors.\",\n      \"method\": \"Mysm1(-/-) mice; ChIP at Flt3 promoter; in vitro DC differentiation assays with Flt3L or GM-CSF\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus loss-of-function with specific molecular readout, single lab\",\n      \"pmids\": [\"25217698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MYSM1 deficiency results in p53 protein elevation in hematopoietic cells; genetic double-knockout (Mysm1(-/-)p53(-/-)) fully rescues all developmental and hematopoietic defects including lymphopoiesis and HSC numbers/function, establishing p53 activation as the driving mechanism for hematopoietic abnormalities in Mysm1 deficiency.\",\n      \"method\": \"Mysm1(-/-)p53(-/-) double-knockout mice; bone marrow transplantation; flow cytometric analysis of hematopoietic progenitors\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis by double-knockout, replicated independently by two labs (Belle et al. and Gatzka et al.)\",\n      \"pmids\": [\"25710881\", \"25613381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"A homozygous MYSM1 missense mutation affecting the catalytic site within the JAMM/MPN deubiquitinase domain causes human immunodeficiency with absent B lymphocytes and T-cell lymphopenia; in vivo genetic reversion of the mutation in a hematopoietic stem cell restored normal immunohematopoietic phenotype.\",\n      \"method\": \"Whole-exome sequencing; genome-wide homozygosity mapping; Sanger sequencing; immunophenotyping\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human genetic evidence with natural reversion experiment confirming causality, single case\",\n      \"pmids\": [\"26220525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MYSM1 protein associates with p53 and co-localizes to promoters of p53-target genes Bbc3/PUMA and Cdkn1a/p21, antagonizing their p53-driven expression by modulating H3K27ac and H3K4me3 histone modifications and reducing p53 recruitment; PUMA (but not p21) is the essential non-redundant effector of p53-induced MPP apoptosis in Mysm1 deficiency.\",\n      \"method\": \"Co-IP of MYSM1 with p53; ChIP at PUMA and p21 promoters; Mysm1(-/-)Puma(-/-) double-knockout mice; transcriptome analysis\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — Co-IP, ChIP, and genetic double-knockout epistasis with defined molecular outcome, multiple orthogonal methods in one study\",\n      \"pmids\": [\"26768662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MYSM1 accumulates in the cytoplasm in response to microbial stimuli where it interacts with TRAF3 and TRAF6 via its SWIRM domain and removes K63-linked polyubiquitin chains via its metalloproteinase/MPN domain to inactivate these complexes and terminate PRR-driven pro-inflammatory and type I interferon responses.\",\n      \"method\": \"Co-immunoprecipitation of MYSM1 with TRAF3/TRAF6; domain mutagenesis (SWIRM and MPN domain mutants); Mysm1-deficient mice challenged with microbial stimuli; cytokine/IFN quantification\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — Co-IP with domain mutagenesis establishing two distinct functional motifs, loss-of-function in vivo with defined signaling readout\",\n      \"pmids\": [\"26474655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MYSM1 is a transcriptional activator of Pax5 (a repressor of plasma cell differentiation) by facilitating key transcription factor recruitment and coordinating histone modifications at the Pax5 loci, thereby intrinsically repressing plasma cell differentiation and antibody production.\",\n      \"method\": \"Mysm1-deficient mice; ChIP at Pax5 locus; B cell differentiation assays; antibody quantification\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus loss-of-function with specific molecular readout, single lab\",\n      \"pmids\": [\"26348977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MYSM1 is required for expression of IRF2 and IRF8 in HSCs; lower IRF2/IRF8 levels in Mysm1(-/-) HSCs lead to enhanced p53 transcription, contributing to HSC quiescence defects; Mysm1 enhances function of the IRF2 and IRF8 promoters.\",\n      \"method\": \"Mysm1(-/-) mice; promoter reporter assays for IRF2 and IRF8; gene expression analysis\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter assays plus loss-of-function, single lab with two orthogonal methods\",\n      \"pmids\": [\"27277682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MYSM1 recruits c-Myc to the promoter of miR-150 and stimulates its transcription; miR-150 in turn decreases FLT3 expression in B1a cells, defining a MYSM1/miR-150/FLT3 pathway that inhibits B1a cell proliferation.\",\n      \"method\": \"ChIP demonstrating c-Myc recruitment to miR-150 promoter in MYSM1-dependent manner; Mysm1-deficient mice; miR-150/FLT3 expression analysis\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus loss-of-function genetic model, single lab\",\n      \"pmids\": [\"27590507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MYSM1 expression in the bone marrow niche (non-hematopoietic cells) is dispensable for HSC maintenance and hematopoietic homeostasis; selective deletion of Mysm1 in non-hematopoietic cells did not affect HSC number, viability, or hematopoietic output.\",\n      \"method\": \"Bone marrow chimeras with wild-type donor into Mysm1fl/flTg.CreERT2 recipients; tamoxifen-induced Mysm1 ablation in non-hematopoietic cells; flow cytometric analysis\",\n      \"journal\": \"Experimental hematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — negative finding from conditional genetic model with rigorous controls, single lab\",\n      \"pmids\": [\"27833034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MYSM1 loss in CD8+ T cells leads to a hyperactivated CD8+ T-cell state with increased apoptosis and preferential p53 upregulation, resulting in reduced CD8+ T-cell numbers and impaired CD8+ T-cell-dependent pathology in experimental cerebral malaria.\",\n      \"method\": \"Conditional Mysm1 knockout in T cells (Mysm1fl/flTg.CD8-cre model); flow cytometry; cytokine production assays; cerebral malaria model\",\n      \"journal\": \"Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional knockout with defined cellular and molecular phenotype, single lab\",\n      \"pmids\": [\"28066899\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MYSM1 physically binds the androgen receptor (AR) without increasing AR expression, and MYSM1 knockdown results in activation of Akt/c-Raf/GSK-3β signaling in castration-resistant prostate cancer cells.\",\n      \"method\": \"Co-immunoprecipitation assay of MYSM1 with AR; MYSM1 knockdown; western blot for Akt/c-Raf/GSK-3β pathway activation\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP without mutagenesis or reconstitution, single lab\",\n      \"pmids\": [\"31761786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MYSM1 interacts with STING and cleaves STING K63-linked ubiquitination to suppress cGAS-STING signaling; MYSM1 expression is induced upon DNA virus infection and intracellular DNA stimulation.\",\n      \"method\": \"Co-immunoprecipitation of MYSM1 with STING; ubiquitination assay showing removal of K63-linked ubiquitin from STING; Mysm1-deficient mice challenged with DNA virus\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus in-cell ubiquitination assay with loss-of-function in vivo, single lab\",\n      \"pmids\": [\"33086059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MYSM1 colocalizes with γH2AX foci upon DNA double-strand break induction, and mass spectrometry-based proteomics identified an interacting network of DNA damage and replication proteins (enriched after etoposide treatment) as MYSM1 binding partners.\",\n      \"method\": \"Co-localization of MYSM1 with γH2AX by immunofluorescence; affinity pulldown followed by mass spectrometry in 293T cells treated with etoposide\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — co-localization plus MS interactome without functional validation, single lab\",\n      \"pmids\": [\"32466590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MYSM1 directly binds the promoter region of miR-200/CDH1 in colorectal cancer cells, impairs repressive H2AK119ub1 enrichment at this locus, and epigenetically activates miR-200/CDH1 expression; MYSM1 loss activates PI3K/AKT signaling.\",\n      \"method\": \"ChIP at miR-200/CDH1 promoter; H2AK119ub1 ChIP; gain- and loss-of-function in CRC cell lines; in vivo xenograft models\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus functional rescue assays, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"34706761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MYSM1 loss represses ribosomal protein gene expression and protein synthesis in cMYC-driven B cell lymphoma, strongly inhibiting cMYC oncogenic activity and protecting against B cell lymphoma onset and progression.\",\n      \"method\": \"cMYC-driven B cell lymphoma mouse models crossed with Mysm1-deficient mice; ribosomal protein gene expression analysis; protein synthesis measurement\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in lymphoma model, single lab with defined molecular readout\",\n      \"pmids\": [\"34114734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MYSM1 induces apoptosis in TNBC cells and sensitizes them to cisplatin; MYSM1 overexpression increases cisplatin-induced apoptosis via RSK3 inactivation and consequent decreased phosphorylation of BAD at Ser112.\",\n      \"method\": \"MYSM1 overexpression and knockdown in TNBC cell lines; apoptosis assays; western blot for RSK3 and phospho-BAD(Ser112)\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — cell-line gain/loss-of-function with downstream signaling readout, no direct interaction demonstrated, single lab\",\n      \"pmids\": [\"35217648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MYSM1 loss-of-function (patient splice variant causing absent protein) results in persistent DNA damage foci and prolonged DNA damage response signaling after DSBs from immunoglobulin recombination and ionizing radiation, without altering DSB generation or repair itself; MYSM1 specifically regulates termination of DNA damage responses.\",\n      \"method\": \"MYSM1-deficient pre-B cells and U2OS cells; γH2AX focus assays; irradiation-induced DSB repair kinetics; patient cells with constitutive γH2AX\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function in patient-derived and cell-line models with specific molecular readout, single lab\",\n      \"pmids\": [\"38065233\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MYSM1 acts as a co-activator of ERα in breast cancer, maintaining ERα stability via direct ERα deubiquitination and regulating histone modifications on cis-regulatory elements of ERα-target genes to facilitate chromatin decondensation; small molecule Imatinib was identified to interact with the MPN catalytic domain of MYSM1.\",\n      \"method\": \"Co-immunoprecipitation of MYSM1 with ERα; ubiquitination assays; ChIP; xenograft models; virtual screening/docking for Imatinib-MPN interaction\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus ubiquitination assay and ChIP, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"38177530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MYSM1 DUB catalytic activity (tested via D660N point mutation that renders protein catalytically inactive) is universally required for its functions in hematopoiesis, leukocyte development, and other aspects of mammalian physiology; Mysm1DN/DN mice phenocopy Mysm1-knockout mice.\",\n      \"method\": \"CRISPR-generated Mysm1D660N (catalytic dead) knock-in mouse; Mysm1fl/DN CreERT2 inducible model; full hematopoietic and immune cell characterization\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — active-site mutagenesis in vivo with comprehensive phenotypic analysis showing catalytic activity is required, single lab but rigorous\",\n      \"pmids\": [\"36611064\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MYSM1 epigenetically regulates Id4 transcription by modifying histone marks at the Id4 promoter (H2AK119ub1 removal); loss of MYSM1 in neural stem cells (via Nestin-Cre) causes microcephaly with hyperproliferation, increased apoptosis, and skewed differentiation toward neurogenesis over astrogliogenesis; Id4 re-expression rescues these defects.\",\n      \"method\": \"Nestin-Cre Mysm1 conditional knockout mice; RNA sequencing; genome-wide CUT&Tag for histone modifications; Id4 rescue experiments\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with genome-wide epigenomic profiling, rescue experiment, multiple orthogonal methods in one study\",\n      \"pmids\": [\"38342917\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MYSM1 directly interacts with TRIM21 via its MPN domain and regulates TRIM21 deubiquitination and protein stability; MYSM1 exacerbates doxorubicin-induced cardiotoxicity by enhancing ferroptosis through the MYSM1-TRIM21 axis.\",\n      \"method\": \"Co-IP combined with LC-MS/MS identifying TRIM21 as MYSM1 substrate; MPN domain requirement established; AAV9-mediated cardiomyocyte-specific MYSM1 knockdown in mice\",\n      \"journal\": \"Cell communication and signaling : CCS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP/MS plus domain requirement and in vivo cardiomyocyte-specific KD, single lab\",\n      \"pmids\": [\"39695708\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MYSM1 expression and DUB catalytic activity in mature dendritic cells are dispensable for DC maintenance in vivo or DC activation by microbial stimuli; instead, MYSM1 acts via its DUB catalytic activity specifically in haematopoietic progenitors to support normal DC lineage development and functional programming.\",\n      \"method\": \"Mysm1flCreERT2, Mysm1flCD11c-cre, and Mysm1DN conditional mouse models; flow cytometry; transcriptional profiling of DCs\",\n      \"journal\": \"Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple conditional genetic models with cell-type specific deletion and catalytic dead allele, single lab\",\n      \"pmids\": [\"38316548\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MYSM1 deubiquitinates RIPK2 and recruits PP2A to dephosphorylate RIPK2 at S176, thereby inhibiting NF-κB and MAPK signaling pathways and attenuating osteoarthritis progression.\",\n      \"method\": \"Co-IP of MYSM1 with RIPK2 and PP2A; ubiquitination and phosphorylation assays; Ripk2S176D and Ripk2S176A mutation rescue experiments; MYSM1 knockout and overexpression in OA mouse models\",\n      \"journal\": \"Bone research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus mutagenesis rescue experiments in vivo, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"39746943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MYSM1 mediates K63-linked deubiquitination and stabilization of STAT1 at K379 via its MPN metalloprotease domain, promoting STAT1 transcription factor function and necroptosis-related gene expression in myocardial ischemia/reperfusion injury.\",\n      \"method\": \"Proteome-wide quantitative analysis identifying STAT1 as MYSM1 substrate; Co-IP; ubiquitination assays with site-specific K379 mutation; AAV9 cardiomyocyte-specific MYSM1 knockdown in I/R mouse model\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, site-specific ubiquitination assay, and in vivo model, single lab\",\n      \"pmids\": [\"39897566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MYSM1 deubiquitinates and stabilizes PARP1 in an MPN domain-dependent manner, mediating PARP1-dependent cardiomyocyte parthanatos and cardiac hypertrophy.\",\n      \"method\": \"Co-IP combined with LC-MS identifying PARP1 as MYSM1 substrate; MPN domain mutagenesis; AAV9 cardiomyocyte-specific MYSM1 knockdown in angiotensin II and TAC cardiac hypertrophy mouse models\",\n      \"journal\": \"Hypertension\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP/MS plus domain mutagenesis and in vivo model, single lab\",\n      \"pmids\": [\"39907013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MYSM1 interacts with TRAF2 and TRAF3 via its SWIRM domain and removes K63-linked polyubiquitin chains to decrease TRAF2-TRAF3 complex stability, thereby impairing NIK degradation and sustaining non-canonical NF-κB activation while also promoting MAPK (p38, JNK) signaling in lung adenocarcinoma.\",\n      \"method\": \"Co-IP of MYSM1 with TRAF2/TRAF3; K63-ubiquitin chain removal assays; domain mapping; rescue experiments with TRAF2/TRAF3 inhibition; in vitro and in vivo functional assays\",\n      \"journal\": \"NPJ precision oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mapping plus rescue experiments, single lab\",\n      \"pmids\": [\"41162619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Mysm1 mutations (meander tail alleles) in mice cause anterior-selective cerebellar malformation through cell-autonomous effects on granule cell precursors; multimodal single-nucleus assays show Mysm1 affects gene expression in several lineages and granule cell precursor proportions by E14.5, identifying a developmental role in cerebellar compartment specification.\",\n      \"method\": \"Positional cloning/complementation of meander tail mutations to Mysm1; single-nucleus multimodal genomics; non-complementing endonuclease-generated Mysm1 alleles\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic complementation plus single-nucleus multiomics, preprint, single lab\",\n      \"pmids\": [\"42124724\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"MYSM1 is a metalloprotease-family deubiquitinase with a catalytically essential MPN/JAMM domain plus SWIRM and SANT domains; in the nucleus it removes monoubiquitin from histone H2A-K119 to activate gene expression at specific loci (EBF1, Gfi1, Flt3, Id4, Pax5, miR-200, and others) by remodeling histone marks and recruiting transcription factors, thereby controlling hematopoietic stem cell quiescence, lymphocyte and myeloid lineage development, and neural stem cell homeostasis through p53-dependent and p53-independent mechanisms; in the cytoplasm, MYSM1 accumulates upon innate immune stimulation and removes K63-linked polyubiquitin chains from TRAF3, TRAF6, and STING to terminate PRR-driven pro-inflammatory and type I interferon signaling; beyond these established functions, MYSM1 also deubiquitinates non-histone substrates including ERα, STAT1, PARP1, TRIM21, and RIPK2, regulating their stability and activity in cancer and cardiac contexts, and localizes to DNA double-strand break sites where it promotes termination of the DNA damage response without affecting break repair itself.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MYSM1 is a JAMM/MPN-domain metalloprotease deubiquitinase whose catalytic activity is universally required for its roles across hematopoiesis, immune cell development, and broader mammalian physiology, as a catalytically dead D660N knock-in fully phenocopies the null [#22]. In the nucleus, MYSM1 removes monoubiquitin from histone H2A-K119 to derepress lineage-specifying loci, coordinating histone modifications and recruiting transcription factors to activate EBF1, Gfi1, Flt3, Pax5, and Id4 expression, thereby driving B-cell commitment, HSC quiescence, dendritic-cell and NK-cell development, and neural stem cell homeostasis [#0, #1, #2, #4, #9, #23]. A central consequence of MYSM1 loss is aberrant p53 activation: MYSM1 associates with p53 and restrains transcription of its proapoptotic target PUMA, and genetic ablation of p53 fully rescues the hematopoietic defects of Mysm1 deficiency, identifying p53/PUMA-driven apoptosis as the principal cause of those phenotypes [#5, #7]. In the cytoplasm, MYSM1 accumulates upon microbial or DNA-virus stimulation and uses its SWIRM domain to engage TRAF3/TRAF6 and STING and its MPN domain to strip K63-linked polyubiquitin chains, terminating PRR-driven pro-inflammatory and type I interferon signaling [#8, #15]. Beyond histones, MYSM1 deubiquitinates and regulates the stability or activity of non-histone substrates including STAT1, PARP1, TRIM21, and RIPK2 in cancer, cardiac, and inflammatory contexts [#21, #24, #26, #27, #28]. A homozygous catalytic-site mutation causes human immunodeficiency with absent B cells and T-cell lymphopenia, and loss-of-function additionally produces prolonged DNA damage response signaling without affecting break repair [#6, #20].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Established MYSM1's core biochemical identity as an H2A-K119 deubiquitinase and its physiological requirement in hematopoiesis, answering what enzymatic activity MYSM1 carries and why its loss matters.\",\n      \"evidence\": \"Targeted Mysm1 mouse line with bone marrow transplantation showing cell-intrinsic HSC and lineage defects, elevated ROS, \\u03b3H2AX, and p53\",\n      \"pmids\": [\"22184403\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve whether H2A-DUB activity or non-histone activity drives each phenotype\", \"Mechanism linking DUB loss to p53 elevation undefined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined how MYSM1 controls lineage commitment at the molecular level by showing it derepresses a specific gene through chromatin remodeling and transcription factor recruitment.\",\n      \"evidence\": \"Mysm1-deficient mice with ChIP at the EBF1 locus and rescue experiments\",\n      \"pmids\": [\"22169041\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not map which histone marks are direct substrates versus secondary\", \"Generality of the locus-specific recruitment mechanism untested at this stage\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Generalized the locus-specific activator model to HSC quiescence and NK maturation, showing MYSM1 directs transcription factor recruitment (Gata2/Runx1, NFIL3) at defined enhancers.\",\n      \"evidence\": \"Mysm1(-/-) mice with ChIP at Gfi1 and ID2 loci plus co-immunoprecipitation\",\n      \"pmids\": [\"24014243\", \"24062447\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether TF recruitment is a direct consequence of H2A deubiquitination not established\", \"Single-lab Co-IP for NFIL3 interaction\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extended the chromatin-activator role to myeloid/dendritic lineage by showing MYSM1 enables PU.1 recruitment selectively at Flt3.\",\n      \"evidence\": \"Mysm1(-/-) mice with ChIP at Flt3 promoter and in vitro DC differentiation assays\",\n      \"pmids\": [\"25217698\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Basis for locus selectivity (Flt3 but not GM-CSF-\\u03b1/M-CSFR) unexplained\", \"Single lab\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified p53 as the central downstream effector of MYSM1 loss and PUMA as the non-redundant apoptotic mediator, explaining why diverse hematopoietic defects share one cause.\",\n      \"evidence\": \"Mysm1(-/-)p53(-/-) and Mysm1(-/-)Puma(-/-) double-knockout mice with Co-IP and ChIP at PUMA/p21 promoters\",\n      \"pmids\": [\"25710881\", \"25613381\", \"26768662\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which MYSM1 loss elevates p53 protein not fully resolved\", \"Whether MYSM1-p53 promoter antagonism requires DUB activity at this stage untested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Confirmed disease causality in humans, linking a catalytic-site mutation to immunodeficiency and validating the catalytic domain's requirement via natural reversion.\",\n      \"evidence\": \"Whole-exome sequencing and immunophenotyping of a patient with in vivo HSC reversion\",\n      \"pmids\": [\"26220525\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single case\", \"Molecular consequence of the missense allele on substrate spectrum not characterized\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Revealed a distinct cytoplasmic, immune-regulatory function in which MYSM1 uses separable domains to engage and inactivate innate signaling adaptors, broadening MYSM1 beyond a nuclear histone enzyme.\",\n      \"evidence\": \"Co-IP of MYSM1 with TRAF3/TRAF6, SWIRM and MPN domain mutagenesis, and Mysm1-deficient mice challenged with microbial stimuli\",\n      \"pmids\": [\"26474655\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"What triggers cytoplasmic relocalization on stimulation not defined\", \"K63-chain editing specificity versus other DUBs unaddressed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Added further hematopoietic loci (Pax5) and an IRF2/IRF8\\u2192p53 regulatory link, sharpening the locus-specific activator network upstream of the p53 axis.\",\n      \"evidence\": \"Mysm1-deficient mice with ChIP at Pax5 and promoter reporter assays for IRF2/IRF8\",\n      \"pmids\": [\"26348977\", \"27277682\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect regulation of IRF promoters unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Distinguished the cell-intrinsic source of MYSM1 function, establishing that hematopoietic-progenitor MYSM1, not niche expression, drives HSC maintenance.\",\n      \"evidence\": \"Bone marrow chimeras with non-hematopoietic Mysm1 ablation; MYSM1/miR-150/FLT3 axis defined by ChIP\",\n      \"pmids\": [\"27833034\", \"27590507\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Negative niche result does not exclude subtle non-hematopoietic roles\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended cytoplasmic immune regulation to the cGAS-STING axis and localized MYSM1 to DNA damage sites, hinting at a DDR role.\",\n      \"evidence\": \"Co-IP and K63-ubiquitination assays for STING; \\u03b3H2AX co-localization and MS interactome after etoposide\",\n      \"pmids\": [\"33086059\", \"32466590\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"DDR interactome lacks functional validation (Low confidence)\", \"Whether STING editing uses the same domains as TRAF editing not tested directly\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed MYSM1 acts as an epigenetic regulator in cancer via H2AK119ub1 removal and links its loss to oncogenic signaling and cMYC-driven translation.\",\n      \"evidence\": \"ChIP/H2AK119ub1 ChIP at miR-200/CDH1 in CRC and cMYC lymphoma genetic models with ribosomal gene/protein synthesis readouts\",\n      \"pmids\": [\"34706761\", \"34114734\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Context-dependent tumor-suppressor versus oncogenic roles not unified\", \"Single lab per finding\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated that DUB catalytic activity is required for essentially all MYSM1 functions in vivo, unifying histone and non-histone activities under a single enzymatic requirement.\",\n      \"evidence\": \"CRISPR Mysm1 D660N catalytic-dead knock-in and inducible Mysm1fl/DN mice with comprehensive hematopoietic/immune profiling\",\n      \"pmids\": [\"36611064\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not separate which substrates are rate-limiting for which phenotype\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established non-histone deubiquitination as a bona fide MYSM1 activity by showing direct ER\\u03b1 deubiquitination/stabilization and a DDR-termination function, plus a druggable MPN active site.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, ChIP, and Imatinib docking for ER\\u03b1; patient and U2OS cells with \\u03b3H2AX kinetics for DDR termination\",\n      \"pmids\": [\"38177530\", \"38065233\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"DDR-termination substrate(s) not identified\", \"Imatinib-MPN interaction in vivo relevance untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Refined the developmental requirement to progenitor stages and extended epigenetic control to neural stem cells via Id4, while broadening cardiac non-histone substrates (TRIM21).\",\n      \"evidence\": \"Conditional DC models with Mysm1DN; Nestin-Cre KO with CUT&Tag and Id4 rescue; Co-IP/MS for TRIM21 with MPN domain mapping\",\n      \"pmids\": [\"38316548\", \"38342917\", \"39695708\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Substrate hierarchy across tissues unresolved\", \"Single lab per substrate\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Expanded the non-histone substrate repertoire (STAT1, PARP1, RIPK2, TRAF2/3) defining tissue-specific deubiquitination outcomes in cardiac, inflammatory, and oncogenic settings.\",\n      \"evidence\": \"Co-IP/MS, site-specific ubiquitination assays, MPN/SWIRM domain mapping, and AAV9 or KO in vivo disease models\",\n      \"pmids\": [\"39897566\", \"39907013\", \"39746943\", \"41162619\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Determinants of substrate selectivity across contexts unknown\", \"Each substrate validated in a single lab/disease model\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MYSM1 achieves locus- and substrate-selectivity\\u2014choosing among histone H2A, innate-immune adaptors, and diverse non-histone proteins in a context-dependent manner\\u2014remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural basis for substrate discrimination defined\", \"No unifying model for nuclear versus cytoplasmic partitioning\", \"DDR-termination substrate uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [8, 15, 21, 22, 24, 26, 27, 28, 29]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 8, 22]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 2, 4, 9, 17, 23]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [0, 17, 23]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1, 2, 23]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [8, 15]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [16, 20]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 2, 4, 9, 23]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [8, 15, 29]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [0, 17, 23]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [5, 7]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [20]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"TRAF3\", \"TRAF6\", \"STING\", \"TP53\", \"STAT1\", \"PARP1\", \"TRIM21\", \"RIPK2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}