{"gene":"MAF1","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":2002,"finding":"Maf1 is an essential mediator of RNA polymerase III transcriptional repression in S. cerevisiae, required for repression in response to rapamycin-induced nutrient limitation, DNA damage, and secretory pathway defects. Biochemically, Maf1-dependent repression targets TFIIIB, with a defect in TFIIIB-DNA complex assembly under repressing conditions.","method":"Genetic epistasis (signaling pathway analysis), biochemical studies (TFIIIB-DNA complex assembly assay)","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods, foundational paper replicated across multiple subsequent studies","pmids":["12504022"],"is_preprint":false},{"year":2004,"finding":"Maf1-dependent repression of Pol III transcription in yeast involves two steps: inhibition of de novo TFIIIB assembly onto DNA and inhibition of Pol III recruitment to preassembled TFIIIB-DNA complexes. Maf1 physically interacts with Brf1 and Pol III, as shown by co-immunoprecipitation, and acts by a non-stoichiometric mechanism.","method":"In vitro transcription assays with yeast extracts, co-immunoprecipitation, recombinant Maf1 inhibition assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro reconstitution with recombinant protein plus co-IP, multiple orthogonal approaches","pmids":["15590667"],"is_preprint":false},{"year":2006,"finding":"Maf1 is a general and direct repressor of all yeast Pol III-transcribed genes genome-wide. Under repressing conditions (rapamycin), Maf1 is dephosphorylated and accumulates in the nucleus, directly interacting with the largest Pol III subunit C160. Protein phosphatase type 2A (PP2A) is required for rapamycin-induced Maf1 dephosphorylation, nuclear accumulation, and Pol III repression.","method":"ChIP-chip (genome-wide), co-immunoprecipitation, PP2A mutant analysis, phosphorylation state analysis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 — genome-wide ChIP, reciprocal co-IP, genetic analysis, replicated by concurrent independent study","pmids":["16762835"],"is_preprint":false},{"year":2006,"finding":"Maf1 is phosphorylated under favorable growth conditions and rapidly dephosphorylated under diverse stress/nutrient-limitation conditions, leading to nuclear localization, physical association with Pol III, and targeting to Pol III-transcribed genes genome-wide. Maf1 mutants defective in dephosphorylation fail to accumulate in the nucleus and cannot associate with Pol III.","method":"ChIP-chip, phosphorylation state analysis, subcellular fractionation, co-immunoprecipitation, Maf1 phosphomutant analysis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods, genome-wide analysis, concurrent independent replication","pmids":["16762836"],"is_preprint":false},{"year":2006,"finding":"Protein kinase A (PKA) negatively regulates Maf1 function in yeast by phosphorylating it in vitro and in vivo, inhibiting nuclear import of Maf1 via the N-terminal nuclear localization sequence. Strains with high PKA activity block Pol III repression; strains lacking PKA are hyperrepressible. A PKA-independent step is also required for nuclear Maf1 to repress Pol III.","method":"In vitro kinase assay (PKA phosphorylation of Maf1), in vivo phosphorylation analysis, PKA activity manipulation, nuclear localization analysis, phosphosite mutagenesis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 — direct in vitro kinase assay plus in vivo genetic and localization studies, multiple methods","pmids":["17005718"],"is_preprint":false},{"year":2007,"finding":"Human Maf1 negatively regulates transcription by all three nuclear RNA polymerases (Pol I, II, and III). Maf1 represses Pol I- and Pol III-dependent transcription directly, and represses Pol II transcription in part by targeting an Elk-1-binding site in the TBP promoter. Maf1 occupancy at Pol III genes is inversely correlated with TFIIIB and Pol III occupancy. Maf1 overexpression suppresses anchorage-independent growth.","method":"ChIP, luciferase reporter assays, RNA analysis in glioblastoma cell lines, gain/loss-of-function experiments","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods across three RNA polymerase systems, strong mechanistic follow-up","pmids":["17499043"],"is_preprint":false},{"year":2007,"finding":"Human Maf1 represses Pol III transcription in vivo through physical interaction with the TFIIB family members Brf1 and Brf2, components of TFIIIB.","method":"In vivo luciferase reporter assay, co-immunoprecipitation","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 3 — single lab co-IP and reporter assay, but consistent with yeast mechanistic data","pmids":["17505538"],"is_preprint":false},{"year":2008,"finding":"Mammalian Maf1 represses Pol III transcription in vitro and in transfected fibroblasts; genetic deletion of Maf1 elevates Pol III transcript levels. Maf1 interacts with Pol III and TFIIIB and is phosphorylated in a serum-sensitive manner in vivo.","method":"In vitro transcription assay, genetic KO fibroblasts, co-immunoprecipitation, ChIP, phosphorylation analysis","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro transcription reconstitution plus KO genetic confirmation and co-IP, multiple methods","pmids":["18377933"],"is_preprint":false},{"year":2008,"finding":"In yeast, nuclear export of phosphorylated Maf1 is dependent on the exportin Msn5; Maf1 physically interacts with Msn5. Phosphorylation of Maf1 inside the nucleus acts both directly to relieve Pol III repression and indirectly by stimulating Msn5-mediated nuclear export.","method":"Co-immunoprecipitation, subcellular fractionation/localization, msn5Δ mutant analysis, phosphomutant analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP plus genetic epistasis and localization studies with multiple mutants","pmids":["18445601"],"is_preprint":false},{"year":2008,"finding":"In a human Pol III in vitro system, recombinant Maf1 inhibits recruitment of TFIIIB and Pol III to immobilized templates. However, Pol III bound in preinitiation or elongation complexes is protected from Maf1 repression, and Maf1 cannot inhibit facilitated recycling, indicating additional biochemical steps are required for rapid repression in vivo.","method":"Immobilized template transcription assay (in vitro), recombinant human Maf1","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — reconstituted in vitro system with recombinant protein and immobilized template assay","pmids":["18974046"],"is_preprint":false},{"year":2009,"finding":"In yeast, hydrogen peroxide-induced nuclear accumulation of Maf1 requires cytoplasmic thioredoxins Trx1 and Trx2, and PP2A phosphatase activity is required for H2O2-induced Maf1 dephosphorylation and nuclear accumulation, independent of PKA downregulation.","method":"Subcellular localization analysis, thioredoxin mutant analysis, PP2A inhibitor/mutant analysis, phosphorylation state analysis","journal":"Eukaryotic cell","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis with multiple mutants and localization, single lab study","pmids":["19581440"],"is_preprint":false},{"year":2010,"finding":"mTOR associates with TFIIIC via a TOR signaling motif on TFIIIC and localizes to tRNA and 5S rRNA gene loci. mTOR phosphorylates Maf1 at serine 75 in vitro and in vivo, relieving Pol III repression. In HeLa cells, unlike in yeast, no nuclear export of Maf1 occurs in response to mTOR signaling.","method":"Proximity ligation assay, in vitro kinase assay (mTOR phosphorylation of Maf1 at S75), ChIP, in vivo phosphorylation analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro kinase assay plus proximity ligation assay plus ChIP; replicated by concurrent independent studies","pmids":["20543138"],"is_preprint":false},{"year":2010,"finding":"mTORC1 directly phosphorylates human MAF1 mainly at residues S60, S68, and S75, inhibiting its Pol III repression function. MAF1 is absolutely required for Pol III repression in response to serum starvation or TORC1 inhibition by rapamycin or Torin1. Phosphorylation at these sites negatively regulates MAF1 repressor activity.","method":"In vitro kinase assay (mTORC1 directly phosphorylating MAF1), phosphosite mutagenesis (S60A, S68A, S75A), RNAi knockdown, Pol III transcription assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 — direct in vitro kinase reconstitution with mutagenesis validation, multiple orthogonal methods, replicated by concurrent studies","pmids":["20516213"],"is_preprint":false},{"year":2010,"finding":"mTOR inhibition leads to dephosphorylation of Maf1 at Ser-75, nuclear accumulation, increased Maf1 occupancy at Pol III-dependent genes, and concomitant reduction in Pol III and Brf1 binding. Maf1 phosphomutants (S75A, 4A) progressively enhance basal repression of tRNA transcription. mTORC1 itself associates with Pol III gene loci.","method":"Quantitative phosphoproteomics, ChIP, phosphosite mutagenesis, RNAi knockdown, pre-tRNA quantification","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — quantitative phosphoproteomics plus ChIP plus mutagenesis, replicated across concurrent studies","pmids":["20233713"],"is_preprint":false},{"year":2010,"finding":"Crystal structure of Maf1 and cryo-EM structures of Pol III, active Pol III-DNA-RNA complex, and repressive Pol III-Maf1 complex reveal that Maf1 binds the Pol III clamp and rearranges the Pol III-specific subcomplex C82/34/31 at the rim of the active center cleft, impairing Pol III recruitment to promoter DNA-TFIIIB-TBP complexes and preventing closed complex formation, without impairing RNA synthesis from a preformed scaffold.","method":"X-ray crystallography (Maf1 structure), cryo-EM (Pol III-Maf1 complex), functional validation","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus cryo-EM with functional mechanistic interpretation, highly cited foundational structural study","pmids":["20887893"],"is_preprint":false},{"year":2010,"finding":"Full repression of Pol III transcription requires interaction between the two conserved domains of Maf1. The N-terminal and C-terminal domains of human Maf1 interact with each other (pulldown, size-exclusion chromatography); yeast Maf1 domains interact in two-hybrid assay. Integrity of both domains and their direct interaction are necessary for Maf1 dephosphorylation and inhibition of Pol III transcription.","method":"Pull-down assay, size-exclusion chromatography, yeast two-hybrid, limited proteolysis, functional complementation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal biochemical methods demonstrating intramolecular domain interaction with functional consequence","pmids":["20817737"],"is_preprint":false},{"year":2011,"finding":"Casein kinase II (CK2) phosphorylates Maf1 in vitro (both human and yeast Maf1 by recombinant human and yeast CK2). CK2 activity is required for the release of Maf1 from Pol III at tRNA genes and for subsequent tRNA transcription activation when yeast shift from repressive to favorable conditions. CK2 associates with tRNA genes, and its association is enhanced in the absence of Maf1.","method":"In vitro kinase assay (CK2 phosphorylating Maf1), ChIP, CK2 inhibitor treatment, maf1Δ epistasis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 — direct in vitro kinase assay with recombinant proteins plus ChIP and genetic epistasis","pmids":["21383183"],"is_preprint":false},{"year":2012,"finding":"Protein phosphatase 4 (PP4) complex (catalytic subunit Pph3, scaffold Psy2, regulatory subunits Rrd1/Tip41) is the main Maf1 phosphatase in yeast. A portion of PP4 co-precipitates with Maf1, and purified PP4 dephosphorylates Maf1 in vitro. PP4 activity is required for Maf1 nuclear localization and rapid Pol III repression in response to diverse stresses.","method":"In vitro phosphatase assay (purified PP4 dephosphorylating Maf1), co-immunoprecipitation, genetic analysis of PP4 subunit mutants, nuclear localization assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstituted phosphatase assay plus co-IP plus genetic epistasis, multiple orthogonal methods","pmids":["22333918"],"is_preprint":false},{"year":2013,"finding":"Maf1 is SUMOylated by both SUMO1 and SUMO2, with Lys-35 as the major SUMOylation site; the deSUMOylase SENP1 controls Maf1K35 SUMOylation. SUMOylation at K35 is required for Maf1's ability to associate with Pol III and to be recruited to tRNA gene promoters; SUMOylation is independent of mTOR-dependent phosphorylation. SUMOylation does not alter Maf1 subcellular localization but is required for Pol III dissociation from gene promoters.","method":"Mutagenesis (K35R and other Lys mutants), SUMOylation assays, ChIP, co-immunoprecipitation, SENP1 functional analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — site-specific mutagenesis plus ChIP plus co-IP, multiple methods in single study","pmids":["23673667"],"is_preprint":false},{"year":2014,"finding":"Maf1 is a downstream target of PTEN/PI3K/AKT/FoxO1 signaling. PTEN-mediated changes in Maf1 expression are mediated through PI3K/AKT/FoxO1 signaling. Maf1 occupies the FASN promoter and opposes SREBP1c-mediated transcription, thereby inhibiting intracellular lipid accumulation. Maf1 reduces anchorage-independent growth and tumor formation in mice.","method":"ChIP, gene reporter assay, mouse tumor models, in vivo diet-induced PI3K activation, genetic KO/KD","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 — ChIP plus in vivo genetic models plus pathway epistasis, multiple orthogonal methods","pmids":["25502566"],"is_preprint":false},{"year":2015,"finding":"Whole-body knockout of Maf1 in mice confers resistance to diet-induced obesity. Loss of Maf1 increases precursor tRNA synthesis without significant effects on mature tRNA levels, implying a futile tRNA cycle. Elevated futile cycling of hepatic lipids was also observed. Maf1-/- mice show increased NAD+ levels and elevated autophagy via spermidine.","method":"Maf1 knockout mouse model, metabolic measurements, precursor tRNA analysis, metabolite profiling","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 — clean KO with specific metabolic phenotype readouts and mechanistic RNA cycle interpretation","pmids":["25934505"],"is_preprint":false},{"year":2015,"finding":"MAF1 represses CDKN1A (p21) expression through a Pol III-dependent mechanism. MAF1 knockdown induces CDKN1A transcription concurrent with Pol III recruitment; simultaneous knockdown of Pol III or BRF1 abolishes this activation, indicating Pol III recruitment is required. MAF1 knockdown enhances binding of Pol III, BRF1, CFP1, p300, PCAF, TBP, and POLR2E to the CDKN1A promoter.","method":"ChIP, RNAi knockdown (MAF1, Pol III, BRF1), gene expression analysis, ChIP after sequential KD","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — multiple ChIP experiments with sequential KD epistasis, mechanistic pathway placement","pmids":["26067234"],"is_preprint":false},{"year":2016,"finding":"MAF1 binds to the PTEN promoter, enhancing PTEN promoter acetylation and activity, functioning as a transcriptional activator of PTEN. MAF1 downregulation paradoxically leads to activation of AKT-mTOR signaling through decreased PTEN expression. MAF1 displays tumor-suppressor activity in hepatocellular carcinoma models.","method":"ChIP, luciferase promoter reporter assay, gene KD/OE, in vitro and in vivo cancer models","journal":"Hepatology","confidence":"High","confidence_rationale":"Tier 2 — ChIP plus promoter reporter plus multiple in vivo/in vitro cancer models","pmids":["26910647"],"is_preprint":false},{"year":2016,"finding":"Human MAF1 genome-wide occupancy in human fibroblasts is largely confined to Pol III loci even under serum-replete conditions, and MAF1 increasingly targets transcribing Pol III in response to serum starvation in an mTORC1-dependent manner. MAF1 prevents Pol III recruitment rather than inducing long-term transcriptional arrest.","method":"ChIP-seq, EU-labeling with sequencing of nascent small RNAs, genome-wide Pol III occupancy profiling","journal":"Genome research","confidence":"High","confidence_rationale":"Tier 2 — genome-wide ChIP-seq plus nascent RNA sequencing, multiple orthogonal methods","pmids":["26941251"],"is_preprint":false},{"year":2018,"finding":"Ras/ERK signaling promotes Pol III-mediated tRNA synthesis in Drosophila by phosphorylating and inhibiting nuclear localization and function of the Pol III repressor Maf1. Pol III function is required for Ras/ERK-driven proliferation in epithelial and stem cells; Myc is required but not sufficient for Ras-mediated tRNA stimulation.","method":"Genetic epistasis in Drosophila, in vivo tRNA synthesis assay, nuclear localization analysis, ERK pathway manipulation","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis in vivo with multiple tissue types and pathway manipulations","pmids":["29401457"],"is_preprint":false},{"year":2018,"finding":"Maf1 and repression of Pol III-mediated transcription promote induction of mouse embryonic stem cells into mesoderm and adipocyte differentiation. Pol III-mediated transcription positively regulates long non-coding RNA H19 and Wnt6, established adipogenesis inhibitors. Reduced Maf1 expression impairs adipogenesis.","method":"Maf1 KD/OE in mESCs and preadipocytes, Brf1 KD, chemical Pol III inhibition, RNA-seq, adipogenesis assays","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KD/OE with differentiation phenotype plus RNA-seq, single lab study","pmids":["30110641"],"is_preprint":false},{"year":2019,"finding":"MAF1 ubiquitination is enhanced upon mTORC1-mediated phosphorylation at Ser-75, and the E3 ubiquitin ligase CUL2 critically regulates MAF1 ubiquitination and protein stability. Loss of MAF1 due to proteasomal degradation derepresses Pol III transcription and modulates doxorubicin sensitivity in hepatocellular carcinoma.","method":"Ubiquitination assays, proteasome inhibitor experiments, CUL2 KD, phosphomutant analysis, Pol III transcription assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — direct biochemical ubiquitination assays plus genetic KD with mechanistic follow-up, multiple methods","pmids":["31645432"],"is_preprint":false},{"year":2019,"finding":"Maf1 mediates mTOR signaling to regulate Pol III-dependent tRNA transcription in cardiac cardiomyocytes. Maf1 directly binds ERK1/2 by co-immunoprecipitation, and ERK1/2 regulates Pol III transcription. Maf1 knockout exacerbates cardiac hypertrophy while Maf1 overexpression ameliorates it by inhibiting Pol III transcription via ERK1/2 suppression.","method":"Maf1 KO mouse model, adenoviral Maf1 OE, ERK inhibitor treatment, co-immunoprecipitation, Pol III transcription analysis, cardiac phenotype readouts","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2-3 — co-IP plus in vivo KO/OE with cardiac phenotype, but ERK1/2-Maf1 interaction is from single lab","pmids":["31695767"],"is_preprint":false},{"year":2020,"finding":"Cryo-EM structure of yeast Maf1 bound to Pol III at 3.3-Å resolution shows Maf1 sequesters Pol III elements involved in transcription initiation, binds the mobile C34 winged helix 2 domain, seals off the active site, and overlaps with the TFIIIB binding site in the preinitiation complex.","method":"Cryo-EM structure determination (3.3-Å resolution)","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 — high-resolution cryo-EM structural determination with mechanistic interpretation","pmids":["32066962"],"is_preprint":false},{"year":2020,"finding":"Maf1 directly binds to the NLRP3 gene promoter region and competitively regulates NLRP3 expression with NF-κB/p65, suppressing NLRP3 inflammasome activation and blood-brain barrier disruption in sepsis-associated encephalopathy.","method":"ChIP (promoter binding), luciferase reporter assay, NLRP3 OE rescue experiment, in vivo LPS model","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2-3 — ChIP plus reporter assay plus in vivo model, single lab study","pmids":["33424842"],"is_preprint":false},{"year":2020,"finding":"MAF1 functions as a chronic repressor of active Pol III loci in mouse liver in both fasted and refed conditions, and modulates pol III occupancy under different nutritional states. In Maf1-/- mice, Pol III occupancy and precursor tRNA levels are higher than wild-type in multiple organs regardless of fasting/refeeding.","method":"Pol III ChIP-seq, precursor tRNA quantification, Maf1 KO mouse model in fasting/refeeding paradigm","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 — genome-wide ChIP-seq in KO mouse with defined physiological conditions","pmids":["32686713"],"is_preprint":false},{"year":2021,"finding":"Maf1 mediates mTOR signaling to regulate Pol III-dependent rRNA and tRNA transcription in cortical neurons. mTOR regulates Maf1 phosphorylation and subcellular localization in neurons. Maf1 knockdown increases Pol III transcription, neurite outgrowth, and dendritic spine formation. In response to photothrombotic stroke, Maf1 expression increases and accumulates in nuclei of peri-infarct neurons, and Maf1 knockdown enhances neural plasticity and functional recovery. Maf1 binds promoters of CREB-associated genes involved in neural plasticity.","method":"AAV-mediated Maf1 KD in vivo, CUT&TAG-seq (genome-wide promoter binding), photothrombotic stroke model, live imaging of neuronal morphology","journal":"Journal of advanced research","confidence":"High","confidence_rationale":"Tier 2 — direct genome-wide promoter binding assay plus in vivo functional KD with specific phenotypic readouts","pmids":["36402285"],"is_preprint":false},{"year":2021,"finding":"In C. elegans, mafr-1 deficiency in the absence of UV activates the DNA damage response (DDR), including phosphorylation of ATM/ATR target proteins. UV-induced intracellular lipid accumulation requires mafr-1, atm-1, and atl-1 (DDR apical kinases), placing Maf1 as a component of the DDR pathway for lipid homeostasis.","method":"Genetic epistasis in C. elegans (mafr-1 KO, atm-1/atl-1 mutants), UV dose-response, lipid accumulation assay, DDR marker analysis","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis with multiple mutants and defined phenotype, single lab study in C. elegans","pmids":["33788576"],"is_preprint":false},{"year":2022,"finding":"MAF1 promotes osteoblast differentiation and regulates bone mass. MAF1 overexpression in mesenchymal lineage cells (Prx1-Cre;LSL-MAF1 mice) increases bone mass and enhances osteoblastogenesis. MAF1 induces genes known to promote osteoblast differentiation, and osteoblast-differentiating genes display codon bias, suggesting a tRNA-based translational mechanism.","method":"Conditional MAF1 OE mouse model, global Maf1 KO mouse, ex vivo osteoblastogenesis assay, RNA-seq","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — conditional genetic mouse model with specific cellular phenotype plus transcriptomic analysis","pmids":["35611941"],"is_preprint":false},{"year":2024,"finding":"Maf1 regulates the expression of NMDAR1 by binding to the promoter region of Grin1, further regulating calcium homeostasis and synaptic remodelling in neurons. Conditional KO of Maf1 in a mouse model of Alzheimer's disease restored learning and memory function.","method":"ChIP-PCR (Maf1 binding to Grin1 promoter), luciferase reporter assay, conditional KO mouse model, calcium imaging","journal":"Brain : a journal of neurology","confidence":"Medium","confidence_rationale":"Tier 2-3 — ChIP plus reporter assay plus conditional KO, single lab study","pmids":["38226680"],"is_preprint":false},{"year":2024,"finding":"Bud27 (a prefoldin-like protein) regulates Maf1 phosphorylation and nuclear localization by associating with the Maf1 phosphatase PP4 in vivo. Lack of Bud27 decreases the PP4-Maf1 interaction, reduces Maf1 dephosphorylation, and impairs Maf1 nuclear entry, thereby affecting Pol III transcription repression.","method":"Co-immunoprecipitation (Bud27-PP4 interaction), phosphorylation state analysis, subcellular localization, genetic analysis","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2-3 — co-IP plus phosphorylation analysis plus localization, single lab study","pmids":["38864693"],"is_preprint":false},{"year":2024,"finding":"Progesterone receptor (PR) co-recruits with Maf1 to approximately half of Pol III-occupied tRNA genes upon progestin treatment and specifically represses approximately one-third of highly expressed tRNA genes. Maf1 knockdown significantly reduces PR-mediated tRNA transcription downregulation, demonstrating that Maf1 is necessary for PR-mediated Pol III repression.","method":"ChIP-seq (PR, POLR3A, Brf1, Maf1), nascent tRNA transcription assay, Maf1 RNAi knockdown epistasis","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — genome-wide ChIP-seq plus nascent RNA assay plus genetic epistasis; preprint, not yet peer-reviewed","pmids":["39763804"],"is_preprint":true},{"year":2015,"finding":"MAF1 interacts with PCNA in human cells, as identified by bimolecular fluorescence complementation screen and validated by co-immunoprecipitation from human cell extracts and with recombinant proteins, suggesting a potential role for MAF1 in DNA replication or repair.","method":"Bimolecular fluorescence complementation (BiFC) screen, co-immunoprecipitation from human cell extracts, recombinant protein interaction analysis","journal":"Cell cycle","confidence":"Low","confidence_rationale":"Tier 3 — single BiFC screen plus co-IP, no functional mechanistic follow-up for MAF1-PCNA interaction","pmids":["26030842"],"is_preprint":false},{"year":2010,"finding":"In neurons, Maf1 interacts with GABA-A receptor beta-subunit intracellular domains and co-localizes with GABA-A receptors in intracellular compartments and at the cell surface. Maf1 forms a complex with a novel protein Macoco, which also interacts with GABA-A receptors, and Macoco expression increases surface GABA-A receptor levels.","method":"Co-immunoprecipitation, subcellular localization/co-localization in neurons, Macoco overexpression assay for surface receptor quantification","journal":"Molecular and cellular neurosciences","confidence":"Low","confidence_rationale":"Tier 3 — single lab co-IP and co-localization; functional link between MAF1 and GABA-A receptor biology is indirect and not mechanistically developed","pmids":["20417281"],"is_preprint":false}],"current_model":"MAF1 is a conserved master repressor of RNA polymerase III transcription that is regulated by phosphorylation: under favorable growth conditions, mTORC1 (and in yeast also PKA and Sch9) phosphorylates MAF1 to promote cytoplasmic retention and inhibit its repressor activity, while diverse stress signals trigger dephosphorylation by PP2A and PP4 phosphatases, causing MAF1 nuclear accumulation, direct physical association with the Pol III clamp (sealing the active site and displacing C82/34/31 from the cleft), and competitive exclusion of TFIIIB from Pol III promoters, thereby preventing transcription initiation; additionally, MAF1 SUMOylation at K35 (reversed by SENP1) and CUL2-mediated ubiquitination (enhanced by mTOR phosphorylation at S75) further tune its activity and stability, while in mammalian cells MAF1 also regulates Pol I and Pol II transcription—functioning as a repressor of TBP and lipogenic genes (e.g., FASN) and as a transcriptional activator of the tumor suppressor PTEN—linking nutrient-sensing mTOR signaling to broad control of biosynthetic capacity, lipid metabolism, and oncogenesis."},"narrative":{"teleology":[{"year":2002,"claim":"Identification of Maf1 as a dedicated Pol III repressor resolved how diverse stress signals converge on a single target—TFIIIB—to shut down Pol III transcription.","evidence":"Genetic epistasis and TFIIIB–DNA assembly assays in S. cerevisiae under rapamycin, DNA damage, and secretory stress","pmids":["12504022"],"confidence":"High","gaps":["Mechanism of TFIIIB inhibition not resolved at molecular level","Kinases and phosphatases controlling Maf1 unknown","Whether Maf1 contacts Pol III directly was untested"]},{"year":2004,"claim":"Demonstration that Maf1 inhibits both de novo TFIIIB assembly and Pol III recruitment to preformed complexes, and physically contacts Brf1 and Pol III, established a two-step repression mechanism.","evidence":"In vitro transcription with recombinant Maf1, co-immunoprecipitation in yeast","pmids":["15590667"],"confidence":"High","gaps":["Structural basis of Maf1–Pol III interaction unknown","Whether Maf1 functions genome-wide was not addressed"]},{"year":2006,"claim":"Genome-wide ChIP and phosphorylation studies established that Maf1 is a global Pol III repressor whose nuclear localization and activity are controlled by a phosphorylation switch: PKA phosphorylation retains Maf1 in the cytoplasm, while PP2A-mediated dephosphorylation drives nuclear import and Pol III association.","evidence":"ChIP-chip, subcellular fractionation, PP2A and PKA mutant analyses, phosphosite mutagenesis in S. cerevisiae","pmids":["16762835","16762836","17005718"],"confidence":"High","gaps":["Identity of phosphatase(s) beyond PP2A uncertain","Mechanism by which phosphorylation directly controls repressor activity in the nucleus unclear","Relevance to mammalian cells untested"]},{"year":2007,"claim":"Extension to human cells revealed that MAF1 represses not only Pol III but also Pol I and Pol II transcription—including TBP itself—broadening its role from a Pol III-specific factor to a multi-polymerase transcriptional regulator with tumor-suppressive properties.","evidence":"ChIP, reporter assays, gain/loss-of-function in glioblastoma lines; co-IP of MAF1 with human Brf1 and Brf2","pmids":["17499043","17505538"],"confidence":"High","gaps":["Mechanisms of Pol I and Pol II repression not molecularly defined","In vivo tumor-suppressor function not yet tested in animal models"]},{"year":2008,"claim":"In vitro reconstitution with human factors and identification of the yeast exportin Msn5 clarified that phosphorylated Maf1 is actively exported from the nucleus and that Maf1 blocks new Pol III recruitment but cannot displace preformed initiation or elongation complexes.","evidence":"Immobilized template transcription assay with recombinant human MAF1; Msn5 co-IP and msn5Δ analysis in yeast","pmids":["18974046","18445601","18377933"],"confidence":"High","gaps":["How cells clear pre-engaged Pol III from active genes under acute stress remained unresolved","Mammalian export mechanism not identified"]},{"year":2010,"claim":"Three concurrent studies demonstrated that mTORC1 directly phosphorylates MAF1 at S60/S68/S75 to relieve Pol III repression, establishing the mTOR–MAF1 axis as the central nutrient-sensing mechanism controlling Pol III output in mammalian cells.","evidence":"In vitro mTORC1 kinase assays, phosphosite mutagenesis, ChIP, rapamycin/Torin1 treatment in human cells","pmids":["20543138","20516213","20233713"],"confidence":"High","gaps":["Whether mTOR-dependent phosphorylation also regulates MAF1 stability was unknown","Functional consequences of individual phosphosites not fully separated"]},{"year":2010,"claim":"Crystal structure of Maf1 and cryo-EM of the Pol III–Maf1 complex revealed the structural mechanism: Maf1 binds the Pol III clamp, rearranges C82/34/31, seals the active-site cleft, and overlaps with the TFIIIB binding surface, explaining how it blocks closed-complex formation.","evidence":"X-ray crystallography (Maf1) and cryo-EM (Pol III–Maf1, Pol III–DNA–RNA) with functional validation","pmids":["20887893"],"confidence":"High","gaps":["Resolution limited; a near-atomic-resolution structure was still needed","Intramolecular domain rearrangement upon phosphorylation not structurally captured"]},{"year":2011,"claim":"Identification of CK2 as a kinase that phosphorylates Maf1 to release it from Pol III at tRNA genes provided the reactivation arm of the Pol III phosphorylation cycle.","evidence":"In vitro CK2 kinase assay on human and yeast Maf1, ChIP, CK2 inhibitor treatment in yeast","pmids":["21383183"],"confidence":"High","gaps":["CK2 phosphosites on Maf1 not mapped","Whether CK2 functions analogously in mammalian Maf1 reactivation untested"]},{"year":2012,"claim":"Identification of the PP4 complex (Pph3/Psy2/Rrd1/Tip41) as the principal Maf1 phosphatase resolved how stress signals trigger rapid Maf1 dephosphorylation and nuclear entry.","evidence":"In vitro phosphatase assay with purified PP4, co-IP, PP4 subunit mutant analysis in yeast","pmids":["22333918"],"confidence":"High","gaps":["PP4 regulation of mammalian MAF1 not demonstrated","How PP4 is itself activated by diverse stresses remained unclear"]},{"year":2013,"claim":"Discovery of MAF1 SUMOylation at K35 (reversed by SENP1) established a phosphorylation-independent regulatory layer required for MAF1 association with Pol III and promoter recruitment.","evidence":"K35R mutagenesis, SUMOylation assays, ChIP, SENP1 functional analysis in human cells","pmids":["23673667"],"confidence":"High","gaps":["Structural basis of how SUMOylation enables Pol III binding unknown","Upstream signals controlling MAF1 SUMOylation not identified"]},{"year":2014,"claim":"Demonstration that MAF1 directly binds and represses the FASN promoter (opposing SREBP1c) and is transcriptionally regulated by PTEN/PI3K/AKT/FoxO1 signaling linked MAF1 to lipid metabolism and tumor suppression in vivo.","evidence":"ChIP, promoter reporter assays, mouse tumor xenograft models, diet-induced PI3K pathway activation","pmids":["25502566"],"confidence":"High","gaps":["Other lipogenic gene targets of MAF1 not mapped genome-wide","Mechanism of MAF1 action at Pol II promoters distinct from Pol III repression not defined"]},{"year":2015,"claim":"Maf1 knockout mice showed resistance to diet-induced obesity despite elevated precursor tRNA synthesis with unchanged mature tRNA levels, revealing a metabolically costly futile tRNA cycle that increases energy expenditure, NAD+, and autophagy.","evidence":"Maf1-/- whole-body KO mouse model with metabolic phenotyping and precursor tRNA quantification","pmids":["25934505"],"confidence":"High","gaps":["Mechanism coupling futile tRNA cycling to NAD+ elevation not molecularly defined","Contribution of non-Pol III MAF1 targets to metabolic phenotype not separated"]},{"year":2016,"claim":"MAF1 was shown to activate PTEN transcription and its genome-wide occupancy was mapped by ChIP-seq, confirming that MAF1 predominantly occupies Pol III loci and dynamically increases association with transcribing Pol III upon mTORC1 inhibition, while also functioning at select Pol II promoters.","evidence":"ChIP-seq in human fibroblasts, nascent small RNA sequencing, ChIP at PTEN promoter, cancer models","pmids":["26941251","26910647"],"confidence":"High","gaps":["How MAF1 switches from Pol III repressor to Pol II activator at PTEN mechanistically unresolved","Whether MAF1 genome occupancy changes in cancer contexts not profiled"]},{"year":2019,"claim":"Discovery that mTORC1 phosphorylation at S75 enhances CUL2-mediated ubiquitination and proteasomal degradation of MAF1 revealed a protein-stability layer by which mTOR signaling derepresses Pol III.","evidence":"Ubiquitination assays, CUL2 knockdown, proteasome inhibition, phosphomutant analysis in hepatocellular carcinoma cells","pmids":["31645432"],"confidence":"High","gaps":["Other E3 ligases or deubiquitinases regulating MAF1 not identified","Whether CUL2 pathway operates in non-cancer cells unknown"]},{"year":2020,"claim":"A 3.3-Å cryo-EM structure of yeast Maf1–Pol III provided near-atomic detail of the repression mechanism: Maf1 engages the C34 winged-helix-2 domain, seals the active site, and overlaps the TFIIIB binding surface in the preinitiation complex.","evidence":"Cryo-EM at 3.3-Å resolution of the yeast Pol III–Maf1 complex","pmids":["32066962"],"confidence":"High","gaps":["Structure of phosphorylated or SUMOylated Maf1 not determined","Human Pol III–MAF1 structural complex not available"]},{"year":2022,"claim":"Conditional MAF1 overexpression in mesenchymal lineage cells increased bone mass and osteoblastogenesis, demonstrating that MAF1-mediated Pol III repression influences differentiation through tRNA-dependent translational control.","evidence":"Prx1-Cre;LSL-MAF1 conditional OE and Maf1-/- KO mice, ex vivo osteoblastogenesis assays, RNA-seq","pmids":["35611941"],"confidence":"High","gaps":["Direct evidence for codon-usage-dependent translational regulation by MAF1-altered tRNA pools not provided","Whether osteoblast phenotype is Pol III-dependent or reflects Pol II targets of MAF1 untested"]},{"year":2024,"claim":"MAF1 was found to regulate Grin1 (NMDAR1) expression by direct promoter binding, linking MAF1 to calcium homeostasis and synaptic remodeling; conditional Maf1 KO improved cognition in an Alzheimer's disease mouse model.","evidence":"ChIP-PCR at Grin1 promoter, luciferase reporter, conditional KO in Alzheimer's model mice, calcium imaging","pmids":["38226680"],"confidence":"Medium","gaps":["Single-lab study; independent replication needed","Mechanism by which MAF1 activates or represses Grin1 transcription not resolved","Whether neuronal MAF1 functions primarily through Pol III or Pol II targets is unclear"]},{"year":null,"claim":"Key unresolved questions include how MAF1 mechanistically switches between Pol III repressor, Pol II repressor, and Pol II activator functions; the structural basis of phosphorylation- and SUMOylation-dependent conformational changes; and the relative contributions of Pol III versus Pol II target regulation to organismal phenotypes in metabolism, neuroplasticity, and cancer.","evidence":"","pmids":[],"confidence":"High","gaps":["No structure of phosphorylated or SUMOylated MAF1","Genome-wide map of Pol II targets directly bound by MAF1 lacking","Tissue-specific relative importance of Pol III vs Pol II repression unexplored"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,2,5,14,19,22,28]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[19,22,29,34]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,9,14,23,28]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[2,3,4,11,13,23,31]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3,4,8]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,2,5,14,19,22,23,28]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,11,12,13,19,24,26]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[19,20,25]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[12,18,26]}],"complexes":[],"partners":["POLR3A","BRF1","BRF2","PPH3","CUL2","SENP1","MTOR","CSNK2A1"],"other_free_text":[]},"mechanistic_narrative":"MAF1 is a conserved master repressor of RNA polymerase III transcription that integrates nutrient, stress, and growth-factor signaling to control biosynthetic capacity, lipid metabolism, and cell proliferation. Under favorable growth conditions, mTORC1 (and in yeast PKA and CK2) phosphorylates MAF1 at multiple sites (S60, S68, S75), promoting its cytoplasmic retention and CUL2-mediated ubiquitin–proteasomal degradation; stress or nutrient limitation triggers PP2A- and PP4-dependent dephosphorylation, nuclear accumulation, and direct engagement of the Pol III clamp, where MAF1 seals the active-site cleft, displaces the C82/34/31 subcomplex, and competitively excludes TFIIIB from promoter DNA, thereby blocking transcription initiation of tRNA, 5S rRNA, and other Pol III targets genome-wide [PMID:12504022, PMID:20887893, PMID:32066962, PMID:20516213, PMID:22333918, PMID:31645432]. SUMOylation at K35, reversed by SENP1, is independently required for MAF1 association with Pol III and promoter recruitment [PMID:23673667]. In mammalian cells, MAF1 additionally functions as a Pol II transcriptional regulator—repressing TBP and FASN (opposing SREBP1c-driven lipogenesis) and activating PTEN transcription—thereby linking Pol III repression to PI3K/AKT signaling, lipid homeostasis, and tumor suppression, as demonstrated by resistance to diet-induced obesity in Maf1-knockout mice and suppression of tumorigenesis upon MAF1 overexpression [PMID:17499043, PMID:25502566, PMID:26910647, PMID:25934505]."},"prefetch_data":{"uniprot":{"accession":"Q9H063","full_name":"Repressor of RNA polymerase III transcription MAF1 homolog","aliases":[],"length_aa":256,"mass_kda":28.8,"function":"Plays a role in the repression of RNA polymerase III-mediated transcription in response to changing nutritional, environmental and cellular stress conditions to balance the production of highly abundant tRNAs, 5S rRNA, and other small non-coding RNAs with cell growth and maintenance (PubMed:18377933, PubMed:20233713, PubMed:20516213, PubMed:20543138). Also plays a key role in cell fate determination by promoting mesorderm induction and adipocyte differentiation (By similarity). Mechanistically, associates with the RNA polymerase III clamp and thereby impairs its recruitment to the complex made of the promoter DNA, TBP and the initiation factor TFIIIB (PubMed:17505538, PubMed:20887893). When nutrients are available and mTOR kinase is active, MAF1 is hyperphosphorylated and RNA polymerase III is engaged in transcription. Stress-induced MAF1 dephosphorylation results in nuclear localization, increased targeting of gene-bound RNA polymerase III and a decrease in the transcriptional readout (PubMed:26941251). Additionally, may also regulate RNA polymerase I and RNA polymerase II-dependent transcription through its ability to regulate expression of the central initiation factor TBP (PubMed:17499043)","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9H063/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MAF1","classification":"Not Classified","n_dependent_lines":60,"n_total_lines":1208,"dependency_fraction":0.04966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"POLR1C","stoichiometry":10.0},{"gene":"POLR2F","stoichiometry":10.0},{"gene":"POLR2H","stoichiometry":10.0},{"gene":"POLR2E","stoichiometry":4.0},{"gene":"POLR3B","stoichiometry":4.0},{"gene":"POLR3F","stoichiometry":4.0},{"gene":"POLR2K","stoichiometry":0.2},{"gene":"POLR3E","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/MAF1","total_profiled":1310},"omim":[{"mim_id":"610210","title":"MAF1 HOMOLOG, NEGATIVE REGULATOR OF RNA POLYMERASE III; MAF1","url":"https://www.omim.org/entry/610210"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MAF1"},"hgnc":{"alias_symbol":["DKFZp586G1123"],"prev_symbol":[]},"alphafold":{"accession":"Q9H063","domains":[{"cath_id":"3.40.1000.50","chopping":"1-62_86-206","consensus_level":"medium","plddt":91.1421,"start":1,"end":206}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H063","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H063-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H063-F1-predicted_aligned_error_v6.png","plddt_mean":76.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MAF1","jax_strain_url":"https://www.jax.org/strain/search?query=MAF1"},"sequence":{"accession":"Q9H063","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H063.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H063/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H063"}},"corpus_meta":[{"pmid":"12504022","id":"PMC_12504022","title":"Maf1 is an essential 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rapamycin-induced nutrient limitation, DNA damage, and secretory pathway defects. Biochemically, Maf1-dependent repression targets TFIIIB, with a defect in TFIIIB-DNA complex assembly under repressing conditions.\",\n      \"method\": \"Genetic epistasis (signaling pathway analysis), biochemical studies (TFIIIB-DNA complex assembly assay)\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods, foundational paper replicated across multiple subsequent studies\",\n      \"pmids\": [\"12504022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Maf1-dependent repression of Pol III transcription in yeast involves two steps: inhibition of de novo TFIIIB assembly onto DNA and inhibition of Pol III recruitment to preassembled TFIIIB-DNA complexes. Maf1 physically interacts with Brf1 and Pol III, as shown by co-immunoprecipitation, and acts by a non-stoichiometric mechanism.\",\n      \"method\": \"In vitro transcription assays with yeast extracts, co-immunoprecipitation, recombinant Maf1 inhibition assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro reconstitution with recombinant protein plus co-IP, multiple orthogonal approaches\",\n      \"pmids\": [\"15590667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Maf1 is a general and direct repressor of all yeast Pol III-transcribed genes genome-wide. Under repressing conditions (rapamycin), Maf1 is dephosphorylated and accumulates in the nucleus, directly interacting with the largest Pol III subunit C160. Protein phosphatase type 2A (PP2A) is required for rapamycin-induced Maf1 dephosphorylation, nuclear accumulation, and Pol III repression.\",\n      \"method\": \"ChIP-chip (genome-wide), co-immunoprecipitation, PP2A mutant analysis, phosphorylation state analysis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide ChIP, reciprocal co-IP, genetic analysis, replicated by concurrent independent study\",\n      \"pmids\": [\"16762835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Maf1 is phosphorylated under favorable growth conditions and rapidly dephosphorylated under diverse stress/nutrient-limitation conditions, leading to nuclear localization, physical association with Pol III, and targeting to Pol III-transcribed genes genome-wide. Maf1 mutants defective in dephosphorylation fail to accumulate in the nucleus and cannot associate with Pol III.\",\n      \"method\": \"ChIP-chip, phosphorylation state analysis, subcellular fractionation, co-immunoprecipitation, Maf1 phosphomutant analysis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods, genome-wide analysis, concurrent independent replication\",\n      \"pmids\": [\"16762836\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Protein kinase A (PKA) negatively regulates Maf1 function in yeast by phosphorylating it in vitro and in vivo, inhibiting nuclear import of Maf1 via the N-terminal nuclear localization sequence. Strains with high PKA activity block Pol III repression; strains lacking PKA are hyperrepressible. A PKA-independent step is also required for nuclear Maf1 to repress Pol III.\",\n      \"method\": \"In vitro kinase assay (PKA phosphorylation of Maf1), in vivo phosphorylation analysis, PKA activity manipulation, nuclear localization analysis, phosphosite mutagenesis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct in vitro kinase assay plus in vivo genetic and localization studies, multiple methods\",\n      \"pmids\": [\"17005718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Human Maf1 negatively regulates transcription by all three nuclear RNA polymerases (Pol I, II, and III). Maf1 represses Pol I- and Pol III-dependent transcription directly, and represses Pol II transcription in part by targeting an Elk-1-binding site in the TBP promoter. Maf1 occupancy at Pol III genes is inversely correlated with TFIIIB and Pol III occupancy. Maf1 overexpression suppresses anchorage-independent growth.\",\n      \"method\": \"ChIP, luciferase reporter assays, RNA analysis in glioblastoma cell lines, gain/loss-of-function experiments\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods across three RNA polymerase systems, strong mechanistic follow-up\",\n      \"pmids\": [\"17499043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Human Maf1 represses Pol III transcription in vivo through physical interaction with the TFIIB family members Brf1 and Brf2, components of TFIIIB.\",\n      \"method\": \"In vivo luciferase reporter assay, co-immunoprecipitation\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab co-IP and reporter assay, but consistent with yeast mechanistic data\",\n      \"pmids\": [\"17505538\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Mammalian Maf1 represses Pol III transcription in vitro and in transfected fibroblasts; genetic deletion of Maf1 elevates Pol III transcript levels. Maf1 interacts with Pol III and TFIIIB and is phosphorylated in a serum-sensitive manner in vivo.\",\n      \"method\": \"In vitro transcription assay, genetic KO fibroblasts, co-immunoprecipitation, ChIP, phosphorylation analysis\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro transcription reconstitution plus KO genetic confirmation and co-IP, multiple methods\",\n      \"pmids\": [\"18377933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"In yeast, nuclear export of phosphorylated Maf1 is dependent on the exportin Msn5; Maf1 physically interacts with Msn5. Phosphorylation of Maf1 inside the nucleus acts both directly to relieve Pol III repression and indirectly by stimulating Msn5-mediated nuclear export.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation/localization, msn5Δ mutant analysis, phosphomutant analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP plus genetic epistasis and localization studies with multiple mutants\",\n      \"pmids\": [\"18445601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"In a human Pol III in vitro system, recombinant Maf1 inhibits recruitment of TFIIIB and Pol III to immobilized templates. However, Pol III bound in preinitiation or elongation complexes is protected from Maf1 repression, and Maf1 cannot inhibit facilitated recycling, indicating additional biochemical steps are required for rapid repression in vivo.\",\n      \"method\": \"Immobilized template transcription assay (in vitro), recombinant human Maf1\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro system with recombinant protein and immobilized template assay\",\n      \"pmids\": [\"18974046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"In yeast, hydrogen peroxide-induced nuclear accumulation of Maf1 requires cytoplasmic thioredoxins Trx1 and Trx2, and PP2A phosphatase activity is required for H2O2-induced Maf1 dephosphorylation and nuclear accumulation, independent of PKA downregulation.\",\n      \"method\": \"Subcellular localization analysis, thioredoxin mutant analysis, PP2A inhibitor/mutant analysis, phosphorylation state analysis\",\n      \"journal\": \"Eukaryotic cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with multiple mutants and localization, single lab study\",\n      \"pmids\": [\"19581440\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"mTOR associates with TFIIIC via a TOR signaling motif on TFIIIC and localizes to tRNA and 5S rRNA gene loci. mTOR phosphorylates Maf1 at serine 75 in vitro and in vivo, relieving Pol III repression. In HeLa cells, unlike in yeast, no nuclear export of Maf1 occurs in response to mTOR signaling.\",\n      \"method\": \"Proximity ligation assay, in vitro kinase assay (mTOR phosphorylation of Maf1 at S75), ChIP, in vivo phosphorylation analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro kinase assay plus proximity ligation assay plus ChIP; replicated by concurrent independent studies\",\n      \"pmids\": [\"20543138\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"mTORC1 directly phosphorylates human MAF1 mainly at residues S60, S68, and S75, inhibiting its Pol III repression function. MAF1 is absolutely required for Pol III repression in response to serum starvation or TORC1 inhibition by rapamycin or Torin1. Phosphorylation at these sites negatively regulates MAF1 repressor activity.\",\n      \"method\": \"In vitro kinase assay (mTORC1 directly phosphorylating MAF1), phosphosite mutagenesis (S60A, S68A, S75A), RNAi knockdown, Pol III transcription assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct in vitro kinase reconstitution with mutagenesis validation, multiple orthogonal methods, replicated by concurrent studies\",\n      \"pmids\": [\"20516213\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"mTOR inhibition leads to dephosphorylation of Maf1 at Ser-75, nuclear accumulation, increased Maf1 occupancy at Pol III-dependent genes, and concomitant reduction in Pol III and Brf1 binding. Maf1 phosphomutants (S75A, 4A) progressively enhance basal repression of tRNA transcription. mTORC1 itself associates with Pol III gene loci.\",\n      \"method\": \"Quantitative phosphoproteomics, ChIP, phosphosite mutagenesis, RNAi knockdown, pre-tRNA quantification\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — quantitative phosphoproteomics plus ChIP plus mutagenesis, replicated across concurrent studies\",\n      \"pmids\": [\"20233713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Crystal structure of Maf1 and cryo-EM structures of Pol III, active Pol III-DNA-RNA complex, and repressive Pol III-Maf1 complex reveal that Maf1 binds the Pol III clamp and rearranges the Pol III-specific subcomplex C82/34/31 at the rim of the active center cleft, impairing Pol III recruitment to promoter DNA-TFIIIB-TBP complexes and preventing closed complex formation, without impairing RNA synthesis from a preformed scaffold.\",\n      \"method\": \"X-ray crystallography (Maf1 structure), cryo-EM (Pol III-Maf1 complex), functional validation\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus cryo-EM with functional mechanistic interpretation, highly cited foundational structural study\",\n      \"pmids\": [\"20887893\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Full repression of Pol III transcription requires interaction between the two conserved domains of Maf1. The N-terminal and C-terminal domains of human Maf1 interact with each other (pulldown, size-exclusion chromatography); yeast Maf1 domains interact in two-hybrid assay. Integrity of both domains and their direct interaction are necessary for Maf1 dephosphorylation and inhibition of Pol III transcription.\",\n      \"method\": \"Pull-down assay, size-exclusion chromatography, yeast two-hybrid, limited proteolysis, functional complementation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal biochemical methods demonstrating intramolecular domain interaction with functional consequence\",\n      \"pmids\": [\"20817737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Casein kinase II (CK2) phosphorylates Maf1 in vitro (both human and yeast Maf1 by recombinant human and yeast CK2). CK2 activity is required for the release of Maf1 from Pol III at tRNA genes and for subsequent tRNA transcription activation when yeast shift from repressive to favorable conditions. CK2 associates with tRNA genes, and its association is enhanced in the absence of Maf1.\",\n      \"method\": \"In vitro kinase assay (CK2 phosphorylating Maf1), ChIP, CK2 inhibitor treatment, maf1Δ epistasis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct in vitro kinase assay with recombinant proteins plus ChIP and genetic epistasis\",\n      \"pmids\": [\"21383183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Protein phosphatase 4 (PP4) complex (catalytic subunit Pph3, scaffold Psy2, regulatory subunits Rrd1/Tip41) is the main Maf1 phosphatase in yeast. A portion of PP4 co-precipitates with Maf1, and purified PP4 dephosphorylates Maf1 in vitro. PP4 activity is required for Maf1 nuclear localization and rapid Pol III repression in response to diverse stresses.\",\n      \"method\": \"In vitro phosphatase assay (purified PP4 dephosphorylating Maf1), co-immunoprecipitation, genetic analysis of PP4 subunit mutants, nuclear localization assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstituted phosphatase assay plus co-IP plus genetic epistasis, multiple orthogonal methods\",\n      \"pmids\": [\"22333918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Maf1 is SUMOylated by both SUMO1 and SUMO2, with Lys-35 as the major SUMOylation site; the deSUMOylase SENP1 controls Maf1K35 SUMOylation. SUMOylation at K35 is required for Maf1's ability to associate with Pol III and to be recruited to tRNA gene promoters; SUMOylation is independent of mTOR-dependent phosphorylation. SUMOylation does not alter Maf1 subcellular localization but is required for Pol III dissociation from gene promoters.\",\n      \"method\": \"Mutagenesis (K35R and other Lys mutants), SUMOylation assays, ChIP, co-immunoprecipitation, SENP1 functional analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — site-specific mutagenesis plus ChIP plus co-IP, multiple methods in single study\",\n      \"pmids\": [\"23673667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Maf1 is a downstream target of PTEN/PI3K/AKT/FoxO1 signaling. PTEN-mediated changes in Maf1 expression are mediated through PI3K/AKT/FoxO1 signaling. Maf1 occupies the FASN promoter and opposes SREBP1c-mediated transcription, thereby inhibiting intracellular lipid accumulation. Maf1 reduces anchorage-independent growth and tumor formation in mice.\",\n      \"method\": \"ChIP, gene reporter assay, mouse tumor models, in vivo diet-induced PI3K activation, genetic KO/KD\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus in vivo genetic models plus pathway epistasis, multiple orthogonal methods\",\n      \"pmids\": [\"25502566\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Whole-body knockout of Maf1 in mice confers resistance to diet-induced obesity. Loss of Maf1 increases precursor tRNA synthesis without significant effects on mature tRNA levels, implying a futile tRNA cycle. Elevated futile cycling of hepatic lipids was also observed. Maf1-/- mice show increased NAD+ levels and elevated autophagy via spermidine.\",\n      \"method\": \"Maf1 knockout mouse model, metabolic measurements, precursor tRNA analysis, metabolite profiling\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with specific metabolic phenotype readouts and mechanistic RNA cycle interpretation\",\n      \"pmids\": [\"25934505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MAF1 represses CDKN1A (p21) expression through a Pol III-dependent mechanism. MAF1 knockdown induces CDKN1A transcription concurrent with Pol III recruitment; simultaneous knockdown of Pol III or BRF1 abolishes this activation, indicating Pol III recruitment is required. MAF1 knockdown enhances binding of Pol III, BRF1, CFP1, p300, PCAF, TBP, and POLR2E to the CDKN1A promoter.\",\n      \"method\": \"ChIP, RNAi knockdown (MAF1, Pol III, BRF1), gene expression analysis, ChIP after sequential KD\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple ChIP experiments with sequential KD epistasis, mechanistic pathway placement\",\n      \"pmids\": [\"26067234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MAF1 binds to the PTEN promoter, enhancing PTEN promoter acetylation and activity, functioning as a transcriptional activator of PTEN. MAF1 downregulation paradoxically leads to activation of AKT-mTOR signaling through decreased PTEN expression. MAF1 displays tumor-suppressor activity in hepatocellular carcinoma models.\",\n      \"method\": \"ChIP, luciferase promoter reporter assay, gene KD/OE, in vitro and in vivo cancer models\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus promoter reporter plus multiple in vivo/in vitro cancer models\",\n      \"pmids\": [\"26910647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Human MAF1 genome-wide occupancy in human fibroblasts is largely confined to Pol III loci even under serum-replete conditions, and MAF1 increasingly targets transcribing Pol III in response to serum starvation in an mTORC1-dependent manner. MAF1 prevents Pol III recruitment rather than inducing long-term transcriptional arrest.\",\n      \"method\": \"ChIP-seq, EU-labeling with sequencing of nascent small RNAs, genome-wide Pol III occupancy profiling\",\n      \"journal\": \"Genome research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide ChIP-seq plus nascent RNA sequencing, multiple orthogonal methods\",\n      \"pmids\": [\"26941251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Ras/ERK signaling promotes Pol III-mediated tRNA synthesis in Drosophila by phosphorylating and inhibiting nuclear localization and function of the Pol III repressor Maf1. Pol III function is required for Ras/ERK-driven proliferation in epithelial and stem cells; Myc is required but not sufficient for Ras-mediated tRNA stimulation.\",\n      \"method\": \"Genetic epistasis in Drosophila, in vivo tRNA synthesis assay, nuclear localization analysis, ERK pathway manipulation\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in vivo with multiple tissue types and pathway manipulations\",\n      \"pmids\": [\"29401457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Maf1 and repression of Pol III-mediated transcription promote induction of mouse embryonic stem cells into mesoderm and adipocyte differentiation. Pol III-mediated transcription positively regulates long non-coding RNA H19 and Wnt6, established adipogenesis inhibitors. Reduced Maf1 expression impairs adipogenesis.\",\n      \"method\": \"Maf1 KD/OE in mESCs and preadipocytes, Brf1 KD, chemical Pol III inhibition, RNA-seq, adipogenesis assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KD/OE with differentiation phenotype plus RNA-seq, single lab study\",\n      \"pmids\": [\"30110641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MAF1 ubiquitination is enhanced upon mTORC1-mediated phosphorylation at Ser-75, and the E3 ubiquitin ligase CUL2 critically regulates MAF1 ubiquitination and protein stability. Loss of MAF1 due to proteasomal degradation derepresses Pol III transcription and modulates doxorubicin sensitivity in hepatocellular carcinoma.\",\n      \"method\": \"Ubiquitination assays, proteasome inhibitor experiments, CUL2 KD, phosphomutant analysis, Pol III transcription assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct biochemical ubiquitination assays plus genetic KD with mechanistic follow-up, multiple methods\",\n      \"pmids\": [\"31645432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Maf1 mediates mTOR signaling to regulate Pol III-dependent tRNA transcription in cardiac cardiomyocytes. Maf1 directly binds ERK1/2 by co-immunoprecipitation, and ERK1/2 regulates Pol III transcription. Maf1 knockout exacerbates cardiac hypertrophy while Maf1 overexpression ameliorates it by inhibiting Pol III transcription via ERK1/2 suppression.\",\n      \"method\": \"Maf1 KO mouse model, adenoviral Maf1 OE, ERK inhibitor treatment, co-immunoprecipitation, Pol III transcription analysis, cardiac phenotype readouts\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — co-IP plus in vivo KO/OE with cardiac phenotype, but ERK1/2-Maf1 interaction is from single lab\",\n      \"pmids\": [\"31695767\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Cryo-EM structure of yeast Maf1 bound to Pol III at 3.3-Å resolution shows Maf1 sequesters Pol III elements involved in transcription initiation, binds the mobile C34 winged helix 2 domain, seals off the active site, and overlaps with the TFIIIB binding site in the preinitiation complex.\",\n      \"method\": \"Cryo-EM structure determination (3.3-Å resolution)\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution cryo-EM structural determination with mechanistic interpretation\",\n      \"pmids\": [\"32066962\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Maf1 directly binds to the NLRP3 gene promoter region and competitively regulates NLRP3 expression with NF-κB/p65, suppressing NLRP3 inflammasome activation and blood-brain barrier disruption in sepsis-associated encephalopathy.\",\n      \"method\": \"ChIP (promoter binding), luciferase reporter assay, NLRP3 OE rescue experiment, in vivo LPS model\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — ChIP plus reporter assay plus in vivo model, single lab study\",\n      \"pmids\": [\"33424842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MAF1 functions as a chronic repressor of active Pol III loci in mouse liver in both fasted and refed conditions, and modulates pol III occupancy under different nutritional states. In Maf1-/- mice, Pol III occupancy and precursor tRNA levels are higher than wild-type in multiple organs regardless of fasting/refeeding.\",\n      \"method\": \"Pol III ChIP-seq, precursor tRNA quantification, Maf1 KO mouse model in fasting/refeeding paradigm\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide ChIP-seq in KO mouse with defined physiological conditions\",\n      \"pmids\": [\"32686713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Maf1 mediates mTOR signaling to regulate Pol III-dependent rRNA and tRNA transcription in cortical neurons. mTOR regulates Maf1 phosphorylation and subcellular localization in neurons. Maf1 knockdown increases Pol III transcription, neurite outgrowth, and dendritic spine formation. In response to photothrombotic stroke, Maf1 expression increases and accumulates in nuclei of peri-infarct neurons, and Maf1 knockdown enhances neural plasticity and functional recovery. Maf1 binds promoters of CREB-associated genes involved in neural plasticity.\",\n      \"method\": \"AAV-mediated Maf1 KD in vivo, CUT&TAG-seq (genome-wide promoter binding), photothrombotic stroke model, live imaging of neuronal morphology\",\n      \"journal\": \"Journal of advanced research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct genome-wide promoter binding assay plus in vivo functional KD with specific phenotypic readouts\",\n      \"pmids\": [\"36402285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In C. elegans, mafr-1 deficiency in the absence of UV activates the DNA damage response (DDR), including phosphorylation of ATM/ATR target proteins. UV-induced intracellular lipid accumulation requires mafr-1, atm-1, and atl-1 (DDR apical kinases), placing Maf1 as a component of the DDR pathway for lipid homeostasis.\",\n      \"method\": \"Genetic epistasis in C. elegans (mafr-1 KO, atm-1/atl-1 mutants), UV dose-response, lipid accumulation assay, DDR marker analysis\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with multiple mutants and defined phenotype, single lab study in C. elegans\",\n      \"pmids\": [\"33788576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MAF1 promotes osteoblast differentiation and regulates bone mass. MAF1 overexpression in mesenchymal lineage cells (Prx1-Cre;LSL-MAF1 mice) increases bone mass and enhances osteoblastogenesis. MAF1 induces genes known to promote osteoblast differentiation, and osteoblast-differentiating genes display codon bias, suggesting a tRNA-based translational mechanism.\",\n      \"method\": \"Conditional MAF1 OE mouse model, global Maf1 KO mouse, ex vivo osteoblastogenesis assay, RNA-seq\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional genetic mouse model with specific cellular phenotype plus transcriptomic analysis\",\n      \"pmids\": [\"35611941\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Maf1 regulates the expression of NMDAR1 by binding to the promoter region of Grin1, further regulating calcium homeostasis and synaptic remodelling in neurons. Conditional KO of Maf1 in a mouse model of Alzheimer's disease restored learning and memory function.\",\n      \"method\": \"ChIP-PCR (Maf1 binding to Grin1 promoter), luciferase reporter assay, conditional KO mouse model, calcium imaging\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — ChIP plus reporter assay plus conditional KO, single lab study\",\n      \"pmids\": [\"38226680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Bud27 (a prefoldin-like protein) regulates Maf1 phosphorylation and nuclear localization by associating with the Maf1 phosphatase PP4 in vivo. Lack of Bud27 decreases the PP4-Maf1 interaction, reduces Maf1 dephosphorylation, and impairs Maf1 nuclear entry, thereby affecting Pol III transcription repression.\",\n      \"method\": \"Co-immunoprecipitation (Bud27-PP4 interaction), phosphorylation state analysis, subcellular localization, genetic analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — co-IP plus phosphorylation analysis plus localization, single lab study\",\n      \"pmids\": [\"38864693\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Progesterone receptor (PR) co-recruits with Maf1 to approximately half of Pol III-occupied tRNA genes upon progestin treatment and specifically represses approximately one-third of highly expressed tRNA genes. Maf1 knockdown significantly reduces PR-mediated tRNA transcription downregulation, demonstrating that Maf1 is necessary for PR-mediated Pol III repression.\",\n      \"method\": \"ChIP-seq (PR, POLR3A, Brf1, Maf1), nascent tRNA transcription assay, Maf1 RNAi knockdown epistasis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide ChIP-seq plus nascent RNA assay plus genetic epistasis; preprint, not yet peer-reviewed\",\n      \"pmids\": [\"39763804\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MAF1 interacts with PCNA in human cells, as identified by bimolecular fluorescence complementation screen and validated by co-immunoprecipitation from human cell extracts and with recombinant proteins, suggesting a potential role for MAF1 in DNA replication or repair.\",\n      \"method\": \"Bimolecular fluorescence complementation (BiFC) screen, co-immunoprecipitation from human cell extracts, recombinant protein interaction analysis\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single BiFC screen plus co-IP, no functional mechanistic follow-up for MAF1-PCNA interaction\",\n      \"pmids\": [\"26030842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In neurons, Maf1 interacts with GABA-A receptor beta-subunit intracellular domains and co-localizes with GABA-A receptors in intracellular compartments and at the cell surface. Maf1 forms a complex with a novel protein Macoco, which also interacts with GABA-A receptors, and Macoco expression increases surface GABA-A receptor levels.\",\n      \"method\": \"Co-immunoprecipitation, subcellular localization/co-localization in neurons, Macoco overexpression assay for surface receptor quantification\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab co-IP and co-localization; functional link between MAF1 and GABA-A receptor biology is indirect and not mechanistically developed\",\n      \"pmids\": [\"20417281\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MAF1 is a conserved master repressor of RNA polymerase III transcription that is regulated by phosphorylation: under favorable growth conditions, mTORC1 (and in yeast also PKA and Sch9) phosphorylates MAF1 to promote cytoplasmic retention and inhibit its repressor activity, while diverse stress signals trigger dephosphorylation by PP2A and PP4 phosphatases, causing MAF1 nuclear accumulation, direct physical association with the Pol III clamp (sealing the active site and displacing C82/34/31 from the cleft), and competitive exclusion of TFIIIB from Pol III promoters, thereby preventing transcription initiation; additionally, MAF1 SUMOylation at K35 (reversed by SENP1) and CUL2-mediated ubiquitination (enhanced by mTOR phosphorylation at S75) further tune its activity and stability, while in mammalian cells MAF1 also regulates Pol I and Pol II transcription—functioning as a repressor of TBP and lipogenic genes (e.g., FASN) and as a transcriptional activator of the tumor suppressor PTEN—linking nutrient-sensing mTOR signaling to broad control of biosynthetic capacity, lipid metabolism, and oncogenesis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MAF1 is a conserved master repressor of RNA polymerase III transcription that integrates nutrient, stress, and growth-factor signaling to control biosynthetic capacity, lipid metabolism, and cell proliferation. Under favorable growth conditions, mTORC1 (and in yeast PKA and CK2) phosphorylates MAF1 at multiple sites (S60, S68, S75), promoting its cytoplasmic retention and CUL2-mediated ubiquitin–proteasomal degradation; stress or nutrient limitation triggers PP2A- and PP4-dependent dephosphorylation, nuclear accumulation, and direct engagement of the Pol III clamp, where MAF1 seals the active-site cleft, displaces the C82/34/31 subcomplex, and competitively excludes TFIIIB from promoter DNA, thereby blocking transcription initiation of tRNA, 5S rRNA, and other Pol III targets genome-wide [PMID:12504022, PMID:20887893, PMID:32066962, PMID:20516213, PMID:22333918, PMID:31645432]. SUMOylation at K35, reversed by SENP1, is independently required for MAF1 association with Pol III and promoter recruitment [PMID:23673667]. In mammalian cells, MAF1 additionally functions as a Pol II transcriptional regulator—repressing TBP and FASN (opposing SREBP1c-driven lipogenesis) and activating PTEN transcription—thereby linking Pol III repression to PI3K/AKT signaling, lipid homeostasis, and tumor suppression, as demonstrated by resistance to diet-induced obesity in Maf1-knockout mice and suppression of tumorigenesis upon MAF1 overexpression [PMID:17499043, PMID:25502566, PMID:26910647, PMID:25934505].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Identification of Maf1 as a dedicated Pol III repressor resolved how diverse stress signals converge on a single target—TFIIIB—to shut down Pol III transcription.\",\n      \"evidence\": \"Genetic epistasis and TFIIIB–DNA assembly assays in S. cerevisiae under rapamycin, DNA damage, and secretory stress\",\n      \"pmids\": [\"12504022\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of TFIIIB inhibition not resolved at molecular level\", \"Kinases and phosphatases controlling Maf1 unknown\", \"Whether Maf1 contacts Pol III directly was untested\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstration that Maf1 inhibits both de novo TFIIIB assembly and Pol III recruitment to preformed complexes, and physically contacts Brf1 and Pol III, established a two-step repression mechanism.\",\n      \"evidence\": \"In vitro transcription with recombinant Maf1, co-immunoprecipitation in yeast\",\n      \"pmids\": [\"15590667\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of Maf1–Pol III interaction unknown\", \"Whether Maf1 functions genome-wide was not addressed\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Genome-wide ChIP and phosphorylation studies established that Maf1 is a global Pol III repressor whose nuclear localization and activity are controlled by a phosphorylation switch: PKA phosphorylation retains Maf1 in the cytoplasm, while PP2A-mediated dephosphorylation drives nuclear import and Pol III association.\",\n      \"evidence\": \"ChIP-chip, subcellular fractionation, PP2A and PKA mutant analyses, phosphosite mutagenesis in S. cerevisiae\",\n      \"pmids\": [\"16762835\", \"16762836\", \"17005718\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of phosphatase(s) beyond PP2A uncertain\", \"Mechanism by which phosphorylation directly controls repressor activity in the nucleus unclear\", \"Relevance to mammalian cells untested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Extension to human cells revealed that MAF1 represses not only Pol III but also Pol I and Pol II transcription—including TBP itself—broadening its role from a Pol III-specific factor to a multi-polymerase transcriptional regulator with tumor-suppressive properties.\",\n      \"evidence\": \"ChIP, reporter assays, gain/loss-of-function in glioblastoma lines; co-IP of MAF1 with human Brf1 and Brf2\",\n      \"pmids\": [\"17499043\", \"17505538\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanisms of Pol I and Pol II repression not molecularly defined\", \"In vivo tumor-suppressor function not yet tested in animal models\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"In vitro reconstitution with human factors and identification of the yeast exportin Msn5 clarified that phosphorylated Maf1 is actively exported from the nucleus and that Maf1 blocks new Pol III recruitment but cannot displace preformed initiation or elongation complexes.\",\n      \"evidence\": \"Immobilized template transcription assay with recombinant human MAF1; Msn5 co-IP and msn5Δ analysis in yeast\",\n      \"pmids\": [\"18974046\", \"18445601\", \"18377933\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How cells clear pre-engaged Pol III from active genes under acute stress remained unresolved\", \"Mammalian export mechanism not identified\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Three concurrent studies demonstrated that mTORC1 directly phosphorylates MAF1 at S60/S68/S75 to relieve Pol III repression, establishing the mTOR–MAF1 axis as the central nutrient-sensing mechanism controlling Pol III output in mammalian cells.\",\n      \"evidence\": \"In vitro mTORC1 kinase assays, phosphosite mutagenesis, ChIP, rapamycin/Torin1 treatment in human cells\",\n      \"pmids\": [\"20543138\", \"20516213\", \"20233713\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether mTOR-dependent phosphorylation also regulates MAF1 stability was unknown\", \"Functional consequences of individual phosphosites not fully separated\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Crystal structure of Maf1 and cryo-EM of the Pol III–Maf1 complex revealed the structural mechanism: Maf1 binds the Pol III clamp, rearranges C82/34/31, seals the active-site cleft, and overlaps with the TFIIIB binding surface, explaining how it blocks closed-complex formation.\",\n      \"evidence\": \"X-ray crystallography (Maf1) and cryo-EM (Pol III–Maf1, Pol III–DNA–RNA) with functional validation\",\n      \"pmids\": [\"20887893\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Resolution limited; a near-atomic-resolution structure was still needed\", \"Intramolecular domain rearrangement upon phosphorylation not structurally captured\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identification of CK2 as a kinase that phosphorylates Maf1 to release it from Pol III at tRNA genes provided the reactivation arm of the Pol III phosphorylation cycle.\",\n      \"evidence\": \"In vitro CK2 kinase assay on human and yeast Maf1, ChIP, CK2 inhibitor treatment in yeast\",\n      \"pmids\": [\"21383183\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"CK2 phosphosites on Maf1 not mapped\", \"Whether CK2 functions analogously in mammalian Maf1 reactivation untested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identification of the PP4 complex (Pph3/Psy2/Rrd1/Tip41) as the principal Maf1 phosphatase resolved how stress signals trigger rapid Maf1 dephosphorylation and nuclear entry.\",\n      \"evidence\": \"In vitro phosphatase assay with purified PP4, co-IP, PP4 subunit mutant analysis in yeast\",\n      \"pmids\": [\"22333918\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"PP4 regulation of mammalian MAF1 not demonstrated\", \"How PP4 is itself activated by diverse stresses remained unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Discovery of MAF1 SUMOylation at K35 (reversed by SENP1) established a phosphorylation-independent regulatory layer required for MAF1 association with Pol III and promoter recruitment.\",\n      \"evidence\": \"K35R mutagenesis, SUMOylation assays, ChIP, SENP1 functional analysis in human cells\",\n      \"pmids\": [\"23673667\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of how SUMOylation enables Pol III binding unknown\", \"Upstream signals controlling MAF1 SUMOylation not identified\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstration that MAF1 directly binds and represses the FASN promoter (opposing SREBP1c) and is transcriptionally regulated by PTEN/PI3K/AKT/FoxO1 signaling linked MAF1 to lipid metabolism and tumor suppression in vivo.\",\n      \"evidence\": \"ChIP, promoter reporter assays, mouse tumor xenograft models, diet-induced PI3K pathway activation\",\n      \"pmids\": [\"25502566\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Other lipogenic gene targets of MAF1 not mapped genome-wide\", \"Mechanism of MAF1 action at Pol II promoters distinct from Pol III repression not defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Maf1 knockout mice showed resistance to diet-induced obesity despite elevated precursor tRNA synthesis with unchanged mature tRNA levels, revealing a metabolically costly futile tRNA cycle that increases energy expenditure, NAD+, and autophagy.\",\n      \"evidence\": \"Maf1-/- whole-body KO mouse model with metabolic phenotyping and precursor tRNA quantification\",\n      \"pmids\": [\"25934505\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism coupling futile tRNA cycling to NAD+ elevation not molecularly defined\", \"Contribution of non-Pol III MAF1 targets to metabolic phenotype not separated\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"MAF1 was shown to activate PTEN transcription and its genome-wide occupancy was mapped by ChIP-seq, confirming that MAF1 predominantly occupies Pol III loci and dynamically increases association with transcribing Pol III upon mTORC1 inhibition, while also functioning at select Pol II promoters.\",\n      \"evidence\": \"ChIP-seq in human fibroblasts, nascent small RNA sequencing, ChIP at PTEN promoter, cancer models\",\n      \"pmids\": [\"26941251\", \"26910647\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How MAF1 switches from Pol III repressor to Pol II activator at PTEN mechanistically unresolved\", \"Whether MAF1 genome occupancy changes in cancer contexts not profiled\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Discovery that mTORC1 phosphorylation at S75 enhances CUL2-mediated ubiquitination and proteasomal degradation of MAF1 revealed a protein-stability layer by which mTOR signaling derepresses Pol III.\",\n      \"evidence\": \"Ubiquitination assays, CUL2 knockdown, proteasome inhibition, phosphomutant analysis in hepatocellular carcinoma cells\",\n      \"pmids\": [\"31645432\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Other E3 ligases or deubiquitinases regulating MAF1 not identified\", \"Whether CUL2 pathway operates in non-cancer cells unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"A 3.3-Å cryo-EM structure of yeast Maf1–Pol III provided near-atomic detail of the repression mechanism: Maf1 engages the C34 winged-helix-2 domain, seals the active site, and overlaps the TFIIIB binding surface in the preinitiation complex.\",\n      \"evidence\": \"Cryo-EM at 3.3-Å resolution of the yeast Pol III–Maf1 complex\",\n      \"pmids\": [\"32066962\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of phosphorylated or SUMOylated Maf1 not determined\", \"Human Pol III–MAF1 structural complex not available\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Conditional MAF1 overexpression in mesenchymal lineage cells increased bone mass and osteoblastogenesis, demonstrating that MAF1-mediated Pol III repression influences differentiation through tRNA-dependent translational control.\",\n      \"evidence\": \"Prx1-Cre;LSL-MAF1 conditional OE and Maf1-/- KO mice, ex vivo osteoblastogenesis assays, RNA-seq\",\n      \"pmids\": [\"35611941\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct evidence for codon-usage-dependent translational regulation by MAF1-altered tRNA pools not provided\", \"Whether osteoblast phenotype is Pol III-dependent or reflects Pol II targets of MAF1 untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"MAF1 was found to regulate Grin1 (NMDAR1) expression by direct promoter binding, linking MAF1 to calcium homeostasis and synaptic remodeling; conditional Maf1 KO improved cognition in an Alzheimer's disease mouse model.\",\n      \"evidence\": \"ChIP-PCR at Grin1 promoter, luciferase reporter, conditional KO in Alzheimer's model mice, calcium imaging\",\n      \"pmids\": [\"38226680\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab study; independent replication needed\", \"Mechanism by which MAF1 activates or represses Grin1 transcription not resolved\", \"Whether neuronal MAF1 functions primarily through Pol III or Pol II targets is unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include how MAF1 mechanistically switches between Pol III repressor, Pol II repressor, and Pol II activator functions; the structural basis of phosphorylation- and SUMOylation-dependent conformational changes; and the relative contributions of Pol III versus Pol II target regulation to organismal phenotypes in metabolism, neuroplasticity, and cancer.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structure of phosphorylated or SUMOylated MAF1\", \"Genome-wide map of Pol II targets directly bound by MAF1 lacking\", \"Tissue-specific relative importance of Pol III vs Pol II repression unexplored\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 2, 5, 14, 19, 22, 28]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [19, 22, 29, 34]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 9, 14, 23, 28]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2, 3, 4, 11, 13, 23, 31]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3, 4, 8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 2, 5, 14, 19, 22, 23, 28]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 11, 12, 13, 19, 24, 26]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [19, 20, 25]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [12, 18, 26]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"POLR3A\",\n      \"BRF1\",\n      \"BRF2\",\n      \"PPH3\",\n      \"CUL2\",\n      \"SENP1\",\n      \"MTOR\",\n      \"CSNK2A1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}