{"gene":"MAF1","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2002,"finding":"Maf1 is a common component of multiple signaling pathways in S. cerevisiae that repress RNA Pol III transcription. Signaling pathways activated by rapamycin (nutrient limitation), DNA damage, and secretory pathway defects all require Maf1 for Pol III transcriptional repression. TFIIIB was identified as a target of Maf1-dependent repression, with a defect in TFIIIB-DNA complex assembly under repressing conditions.","method":"Genetic epistasis, biochemical repression assays in yeast","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis across multiple pathways combined with biochemical identification of TFIIIB as target, replicated across conditions","pmids":["12504022"],"is_preprint":false},{"year":1997,"finding":"MAF1 was identified as a novel yeast gene whose mutation causes antisuppression of a tRNA suppressor and temperature-sensitive respiratory growth. A fragment of RPO31/RPC160 (largest subunit of RNA Pol III) was cloned as a multicopy suppressor of maf1-1, suggesting Maf1 acts in the tRNA biosynthetic pathway via Pol III.","method":"Genetic screen, complementation cloning, multicopy suppressor analysis","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic screen with complementation and suppressor analysis in single lab","pmids":["9055829"],"is_preprint":false},{"year":2004,"finding":"Maf1-dependent repression of Pol III transcription involves two steps: (1) inhibition of de novo TFIIIB assembly onto DNA and (2) inhibition of Pol III recruitment to preassembled TFIIIB-DNA complexes. Brf1 (a TFIIIB subunit) was identified as a target of repression. Maf1-Brf1 and Maf1-Pol III interactions were demonstrated by co-immunoprecipitation and implicated in these inhibitory steps. Maf1 functions via a non-stoichiometric mechanism.","method":"In vitro transcription repression assays, co-immunoprecipitation with recombinant Maf1","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro assays defining two mechanistic steps plus co-IP validation, single lab but multiple orthogonal methods","pmids":["15590667"],"is_preprint":false},{"year":2006,"finding":"PP2A (protein phosphatase type 2A) is required for rapamycin-induced Maf1 dephosphorylation, nuclear accumulation, and Pol III repression. Maf1 interacts with Pol III (largest subunit C160 identified as target) in a dephosphorylated state. Under repressing conditions, Maf1 dephosphorylation by PP2A drives nuclear accumulation and increased Pol III-Maf1 interaction. Mutations in PP2A catalytic subunit genes prevented these events.","method":"ChIP-chip genome-wide analysis, phosphorylation state analysis, genetic mutation of PP2A subunits, co-immunoprecipitation","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide ChIP, genetic PP2A mutants, and co-IP, multiple orthogonal methods in single lab","pmids":["16762835"],"is_preprint":false},{"year":2006,"finding":"Protein kinase A (PKA) phosphorylates Maf1 in vitro at PKA consensus sites. PKA activity negatively regulates Maf1 function: strains with unregulated high PKA activity block Pol III repression, while strains lacking all PKA activity are hyperrepressible. PKA inhibits Maf1 nuclear import via the N-terminal nuclear localization sequence, thereby preventing Pol III repression.","method":"In vitro kinase assay, differential in vivo phosphorylation analysis, genetic strains with altered PKA activity, phosphosite mutant analysis, nuclear localization studies","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro kinase assay plus in vivo genetic epistasis and phosphosite mutants, multiple orthogonal 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, and also represses TBP (TATA binding protein) transcription (Pol II-dependent) by targeting an Elk-1-binding site in the TBP promoter. Maf1 occupancy at this site is reciprocal with Elk-1 occupancy. Maf1 overexpression suppresses anchorage-independent growth.","method":"Expression knockdown/overexpression in glioblastoma lines, chromatin immunoprecipitation, reporter assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating reciprocal occupancy, expression-level manipulation with multiple readouts, single lab","pmids":["17499043"],"is_preprint":false},{"year":2007,"finding":"Human Maf1 represses Pol III transcription via TFIIIB, specifically through the TFIIB family members Brf1 and Brf2.","method":"In vivo Pol III luciferase assay, co-immunoprecipitation","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — functional luciferase assay and co-IP in single lab","pmids":["17505538"],"is_preprint":false},{"year":2007,"finding":"Maf1 regulation of Pol III transcription is important for the switch between fermentation and respiration in yeast. Under respiratory conditions, Maf1 is dephosphorylated and imported into the nucleus; glucose addition induces Maf1 phosphorylation and cytoplasmic relocation. Absence of Maf1 impairs viability on nonfermentable carbon sources and differentially regulates levels of different tRNAs.","method":"Phosphorylation state analysis, subcellular localization, genetic suppressor studies, tRNA level measurements","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and biochemical characterization of phosphorylation-localization coupling in single lab","pmids":["17785443"],"is_preprint":false},{"year":2008,"finding":"Mammalian Maf1 interacts with Pol III and TFIIIB in mouse and human cells (co-immunoprecipitation). Maf1 represses Pol III transcription in vitro and in transfected fibroblasts. Maf1 is phosphorylated in a serum-sensitive manner in vivo. Genetic deletion of Maf1 elevates Pol III transcript expression. Maf1 is detected at chromosomal Pol III templates.","method":"Co-immunoprecipitation, in vitro transcription, fibroblast transfection, ChIP, Maf1 knockout cells","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (KO, in vitro repression, ChIP, co-IP), cross-species replication of mechanism","pmids":["18377933"],"is_preprint":false},{"year":2008,"finding":"Phosphorylation of Maf1 by nuclear kinases drives its nuclear export via the Msn5 exportin carrier. Maf1 physically interacts with Msn5 (demonstrated by co-immunoprecipitation). In msn5Δ cells, Maf1 remains in the nucleus upon glucose addition despite normal phosphorylation, demonstrating that phosphorylation acts both directly (decreasing Pol III repression) and indirectly (stimulating Msn5-mediated nuclear export).","method":"Co-immunoprecipitation, subcellular localization imaging, genetic deletion of Msn5, phosphorylation analysis in Maf1 phosphosite mutants","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal genetic and biochemical dissection of phosphorylation-export coupling, multiple methods in single lab","pmids":["18445601"],"is_preprint":false},{"year":2008,"finding":"Human Maf1 can inhibit TFIIIB and Pol III recruitment to immobilized templates in vitro. However, Pol III bound to preinitiation complexes or in elongation complexes is protected from Maf1 repression and can undergo facilitated recycling (multiple rounds of reinitiation). Recombinant Maf1 is unable to inhibit facilitated recycling, suggesting additional biochemical steps are needed for rapid repression in vivo.","method":"Immobilized template in vitro transcription assay, recombinant human Maf1","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution assay with recombinant protein, mechanistic dissection of initiation vs. elongation phases, single lab","pmids":["18974046"],"is_preprint":false},{"year":2006,"finding":"Human Maf1 co-immunoprecipitates with Pol III and associates in vitro with two Pol III subunits: the largest subunit RPC1 and the alpha-like subunit RPAC2. Maf1 represses Pol III transcription in vitro and in vivo, and is required for maximal Pol III repression after MMS or rapamycin treatment, both of which lead to Maf1 dephosphorylation.","method":"Co-immunoprecipitation, in vitro binding assay with Pol III subunits, in vitro and in vivo transcription repression assays","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro binding with specific subunits plus functional repression assays in vitro and in vivo, single lab","pmids":["17205138"],"is_preprint":false},{"year":2009,"finding":"H2O2-induced nuclear accumulation of Maf1 in S. cerevisiae requires the cytoplasmic thioredoxins Trx1 and Trx2. PP2A phosphatase activity is essential for H2O2-induced Maf1 dephosphorylation and nuclear accumulation. Unlike other stresses, H2O2-induced Maf1 nuclear accumulation does not correlate with downregulation of PKA kinase activity.","method":"Subcellular localization analysis, genetic deletion of TRX1/TRX2 and PP2A subunits, phosphorylation state analysis","journal":"Eukaryotic cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and biochemical dissection of oxidative stress pathway to Maf1, single lab","pmids":["19581440"],"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 were determined. Maf1 binds the Pol III clamp and rearranges the C82/34/31 subcomplex at the rim of the active center cleft, impairing recruitment of Pol III to promoter DNA with Brf1 and TBP and preventing closed complex formation. Maf1 does not impair binding of a DNA-RNA scaffold or RNA synthesis, explaining specific repression of initiation.","method":"X-ray crystallography, cryo-electron microscopy, functional complex reconstitution","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus cryo-EM structures of multiple complexes with functional validation, highly rigorous study","pmids":["20887893"],"is_preprint":false},{"year":2010,"finding":"mTORC1 directly phosphorylates human MAF1 on 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 by mTORC1 inhibits MAF1's repression activity.","method":"In vitro kinase assay with mTORC1, phosphorylation site mutagenesis, rapamycin/Torin1 treatment, MAF1 knockdown/knockout","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro phosphorylation by mTORC1 with mutagenesis of specific sites and functional validation, multiple orthogonal methods","pmids":["20516213"],"is_preprint":false},{"year":2010,"finding":"mTOR associates with TFIIIC via a TOR signaling motif in TFIIIC, is recruited to tRNA and 5S rRNA genes, and phosphorylates Maf1 at Ser-75 in a mTOR-dependent manner both in vitro and in vivo. mTOR-Maf1 and mTOR-TFIIIC interactions were confirmed by proximity ligation assays in nuclei. In contrast to yeast, no nuclear export of Maf1 was found in HeLa cells in response to mTOR signaling.","method":"In vitro phosphorylation assay, proximity ligation assay, ChIP, knockdown experiments","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro phosphorylation plus proximity ligation and ChIP, multiple methods in single lab","pmids":["20543138"],"is_preprint":false},{"year":2010,"finding":"Maf1 Ser-75 phosphorylation by mTOR (identified by quantitative phosphoproteomics) controls its nuclear accumulation and Pol III repression in cancer cells. mTOR inhibition leads to rapid Maf1 dephosphorylation, nuclear accumulation, and reduced pre-tRNA levels. Maf1-S75A and Maf1-4A (S75A+S60A+T64A+S68A) mutants progressively enhance basal tRNA repression. mTOR inhibition increases Maf1 occupancy at Pol III genes with concomitant loss of Pol III and Brf1 binding.","method":"Quantitative phosphoproteomics, siRNA knockdown, phosphosite mutant analysis, ChIP, pre-tRNA measurements","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — quantitative phosphoproteomics plus functional phosphosite mutants and ChIP, multiple orthogonal methods, consistent with other labs","pmids":["20233713"],"is_preprint":false},{"year":2010,"finding":"Two conserved domains of human Maf1 are resistant to mild proteolysis and interact with each other (demonstrated by pull-down and size-exclusion chromatography). Comparable domains of yeast Maf1 interact in two-hybrid assay. Integrity of both domains and their direct interaction are necessary for Maf1 dephosphorylation and subsequent Pol III transcription inhibition on nonfermentable carbon sources.","method":"Limited proteolysis, pull-down assay, size-exclusion chromatography, two-hybrid assay, functional transcription assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical methods demonstrating intra-domain interaction with functional consequence, single lab","pmids":["20817737"],"is_preprint":false},{"year":2011,"finding":"Casein kinase II (CK2) phosphorylates Maf1 directly: both recombinant human and yeast CK2 phosphorylate purified human or yeast Maf1 in vitro. CK2 activity is required for efficient Pol III transcription by releasing Maf1 from Pol III at tRNA genes upon return to favorable growth conditions. In maf1Δ cells, CK2 inhibition has no effect on tRNA synthesis, confirming CK2 activates Pol III via Maf1.","method":"In vitro kinase assay with recombinant CK2 and Maf1, ChIP, tRNA synthesis assay in maf1Δ cells","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro phosphorylation with recombinant proteins plus genetic epistasis in maf1Δ confirming pathway placement, single lab","pmids":["21383183"],"is_preprint":false},{"year":2012,"finding":"Protein phosphatase 4 (PP4) complex (with catalytic subunit Pph3, scaffold Psy2, regulatory subunits Rrd1 and Tip41) is the main Maf1 phosphatase in yeast. PP4 co-precipitates with Maf1, and purified PP4 dephosphorylates Maf1 in vitro. PP4 mediates rapid Maf1 dephosphorylation in response to diverse stresses, Maf1 nuclear localization, and rapid Pol III repression.","method":"In vitro dephosphorylation assay with purified PP4, co-precipitation, genetic deletion of PP4 subunits, localization and transcription assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro dephosphorylation plus co-precipitation and genetic epistasis through PP4 subunit deletions, multiple methods","pmids":["22333918"],"is_preprint":false},{"year":2013,"finding":"Maf1 is SUMOylated by SUMO1 and SUMO2, with Lys-35 as the major SUMOylation site. The deSUMOylase SENP1 controls Maf1-K35 SUMOylation. SUMOylation is required for Maf1 to repress Pol III transcription and suppress colony growth. Maf1-K35R (non-SUMOylatable) is defective in associating with Pol III, impairing its recruitment to tRNA gene promoters and its ability to dissociate Pol III from these promoters. SUMOylation does not alter Maf1 subcellular localization and is unaffected by mTOR/rapamycin.","method":"SUMO modification assay, site-directed mutagenesis (K35R), co-immunoprecipitation, ChIP, colony growth assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — identification of specific SUMOylation site with mutagenesis and multiple functional readouts, single lab","pmids":["23673667"],"is_preprint":false},{"year":2014,"finding":"Maf1 is a key downstream target of PTEN that drives PTEN's tumor suppressor and metabolic functions. PTEN-mediated changes in Maf1 expression are mediated through PI3K/AKT/FoxO1 signaling. Maf1 occupies the FASN promoter and opposes SREBP1c-mediated transcription activation of lipogenic enzymes. Maf1 reduces anchorage-independent growth and tumor formation in mice.","method":"PTEN KO mouse models, human cancer samples, ChIP, reporter assays, xenograft tumor models, lipid accumulation assays","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating FASN promoter occupancy, in vivo mouse tumor models, genetic pathway analysis, single lab","pmids":["25502566"],"is_preprint":false},{"year":2015,"finding":"Whole-body knockout of Maf1 in mice confers resistance to diet-induced obesity and nonalcoholic fatty liver disease by reducing food intake and increasing metabolic inefficiency. Precursor tRNA synthesis is increased in multiple tissues without significant effects on mature tRNA levels, implying increased turnover in a futile tRNA cycle. Maf1 knockout also leads to elevated futile cycling of hepatic lipids and increased NAD+ levels in muscle.","method":"Whole-body Maf1 knockout mice, metabolic phenotyping, tRNA precursor/mature ratio measurements, metabolite profiling","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockout with comprehensive metabolic phenotyping and mechanistic follow-up at multiple tissues, single lab but rigorous","pmids":["25934505"],"is_preprint":false},{"year":2015,"finding":"MAF1 knockdown induces CDKN1A transcription concurrently with Pol III recruitment to the CDKN1A locus. Simultaneous knockdown of MAF1 with Pol III or BRF1 diminishes CDKN1A activation and chromatin looping, indicating that Pol III recruitment is required for this Pol II-mediated transcription and looping. ChIP shows enhanced binding of Pol III, BRF1, CFP1, p300, PCAF, TBP, and POLR2E at the CDKN1A promoter upon MAF1 knockdown.","method":"siRNA knockdown, ChIP analysis, chromatin looping assay, transcription measurements","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic ChIP and double-knockdown epistasis, single lab","pmids":["26067234"],"is_preprint":false},{"year":2016,"finding":"MAF1 binds the PTEN promoter, enhancing PTEN promoter acetylation and transcriptional activity (acting as a transcriptional activator for PTEN, contrary to its canonical repressor function). MAF1 downregulation leads to decreased PTEN expression and paradoxical activation of AKT-mTOR signaling.","method":"ChIP, promoter acetylation assay, luciferase reporter, MAF1 knockdown/overexpression in HCC cells and mouse models","journal":"Hepatology (Baltimore, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and promoter assays demonstrating activator function at PTEN, single lab","pmids":["26910647"],"is_preprint":false},{"year":2016,"finding":"Human MAF1 targets and represses active Pol III genes by preventing Pol III recruitment rather than inducing long-term transcriptional arrest. MAF1 selectively localizes at Pol III loci even under serum-replete conditions and increasingly targets transcribing Pol III in response to serum starvation. Pol III occupancy closely reflects ongoing transcription (validated by EU-labeling of nascent small RNAs).","method":"Genome-wide Pol III binding (ChIP-seq), EU-labeling with high-throughput sequencing of nascent small RNAs, MAF1 ChIP","journal":"Genome research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genome-wide ChIP-seq combined with nascent RNA labeling, orthogonal methods providing mechanistic insight, single lab","pmids":["26941251"],"is_preprint":false},{"year":2016,"finding":"The MAF1 C-box region negatively regulates MAF1 activity. C-box deletion in human MAF1 leads to increased nuclear localization and enhanced repression of ACC1 and FASN, but impaired repression of Pol III targets. C-box mutations render MAF1 insensitive to rapamycin. The YSY motif in the C-box controls MAF1 species stoichiometry (MAF1L and MAF1S) and proteasome-dependent turnover of nuclear MAF1.","method":"C-box deletion/mutation analysis in C. elegans and human cells, nuclear localization imaging, proteasome inhibition, rapamycin treatment, transcription assays","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional domain dissection with multiple readouts across species, single lab","pmids":["27986570"],"is_preprint":false},{"year":2018,"finding":"Ras/ERK signaling promotes Pol III-mediated tRNA synthesis in Drosophila by phosphorylating Maf1, inhibiting its nuclear localization and function as a Pol III repressor. ERK activation promotes tRNA synthesis both in vivo and in cultured S2 cells. Myc is required but not sufficient for Ras-mediated tRNA stimulation; instead, inhibition of Maf1 nuclear localization is the key mechanism.","method":"In vivo Drosophila genetic experiments, cultured S2 cells, ERK/Ras pathway activation/inhibition, Pol III reporter assays, Maf1 localization imaging","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic epistasis and cell-based pathway dissection in Drosophila model, single lab","pmids":["29401457"],"is_preprint":false},{"year":2018,"finding":"Maf1 promotes induction of mouse embryonic stem cells into mesoderm and promotes adipocyte differentiation. Reduced Maf1 expression impairs adipogenesis, while ectopic Maf1 expression in Maf1-deficient cells enhances differentiation. RNA Pol III repression promotes adipogenesis; Pol III-mediated transcription positively regulates lncRNA H19 and Wnt6 (adipogenesis inhibitors).","method":"Maf1 KO/overexpression in mESCs and preadipocytes, Brf1 knockdown, chemical Pol III inhibition, RNA-seq","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss- and gain-of-function in differentiation models with RNA-seq pathway analysis, single lab","pmids":["30110641"],"is_preprint":false},{"year":2019,"finding":"MAF1 is regulated by ubiquitin-dependent proteasome degradation. TORC1-mediated phosphorylation at Ser-75 enhances MAF1 ubiquitination. The E3 ubiquitin ligase CUL2 critically regulates MAF1 ubiquitination and controls its stability and subsequent Pol III-dependent transcription. Modulating CUL2 or MAF1 expression alters actin cytoskeleton reorganization and sensitivity to doxorubicin-induced apoptosis.","method":"Ubiquitination assay, proteasome inhibition, CUL2 knockdown, phosphosite mutant analysis, cell viability/apoptosis assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination and stability assays with mechanistic follow-up, single lab","pmids":["31645432"],"is_preprint":false},{"year":2019,"finding":"Maf1 directly binds ERK1/2 (demonstrated by immunoprecipitation) and inhibits Pol III transcription via ERK1/2 signaling suppression to attenuate cardiac hypertrophy. Maf1 KO mice exhibit exacerbated cardiac hypertrophy after pressure overload; Maf1 overexpression ameliorates hypertrophy. ERK1/2 inhibition by U0126 suppresses Maf1-knockdown-promoted cardiac hypertrophy with concomitant Pol III repression.","method":"Maf1 KO mice, adenoviral overexpression, co-immunoprecipitation with ERK1/2, ERK inhibitor U0126, cardiac phenotyping","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — co-IP with ERK1/2 and in vivo KO/OE phenotype, 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. Maf1 sequesters Pol III elements involved in transcription initiation and binds the mobile C34 winged helix 2 domain, sealing off the active site. The Maf1 binding site overlaps with that of TFIIIB in the preinitiation complex.","method":"Cryo-electron microscopy at 3.3-Å resolution","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution cryo-EM structure of Maf1-Pol III complex with structural validation of inhibitory mechanism","pmids":["32066962"],"is_preprint":false},{"year":2020,"finding":"Maf1 and p65 (NF-κB) directly bind to the NLRP3 gene promoter region and competitively regulate NLRP3 function in inflammation. Maf1 downregulates NF-κB/p65-induced NLRP3 inflammasome activation and pro-inflammatory cytokine expression, suppressing LPS-induced BBB disruption.","method":"ChIP at NLRP3 promoter, reporter assay, overexpression/knockdown, in vitro and in vivo LPS models","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — ChIP demonstrating promoter binding with functional overexpression/knockdown evidence, single lab","pmids":["33424842"],"is_preprint":false},{"year":2020,"finding":"MAF1 functions as a chronic repressor of active Pol III loci in the mouse liver. In Maf1-/- mice, Pol III occupancy is higher than wild-type at the vast majority of active loci in both fasted and refed conditions, and specific precursor tRNA levels are elevated in multiple tissues. MAF1 has a modest effect on global translation via reduced mRNA levels and translation efficiencies for several ribosomal proteins.","method":"ChIP-seq, precursor tRNA measurements, polysome profiling, fasting-refeeding paradigm in Maf1 KO mice","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genome-wide ChIP-seq across multiple conditions in Maf1 KO mice, comprehensive mechanistic analysis","pmids":["32686713"],"is_preprint":false},{"year":2021,"finding":"Maf1 regulates intracellular lipid homeostasis in C. elegans in response to DNA damage via the DDR pathway. UV-induced lipid accumulation requires mafr-1, the apical kinases atm-1 and atl-1 (DDR kinases). Genetic ablation of mafr-1 alone activates the DDR, including increased lipid accumulation, phosphorylation of ATM/ATR target proteins, and expression of Bcl-2 homolog genes.","method":"C. elegans genetic deletion, UV exposure, lipid accumulation quantification, DDR marker analysis","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with DDR kinase deletions and mechanistic markers, single lab in C. elegans","pmids":["33788576"],"is_preprint":false},{"year":2021,"finding":"In response to ionizing radiation (IR), Maf1 is inhibited by Akt-dependent re-phosphorylation, which activates the mitochondrial unfolded protein response (UPRmt) through ATF5. Rapamycin suppresses IR-induced Maf1 re-phosphorylation and UPRmt activation in A549 cells, increasing radio-sensitivity. Maf1 overexpression suppresses ethidium bromide-induced UPRmt and enhances IR-mediated cytotoxicity.","method":"Maf1 knockdown/overexpression, rapamycin treatment, IR exposure, UPRmt marker analysis, mitochondrial membrane potential measurement","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — mechanistic pathway dissection with multiple pharmacological interventions and genetic manipulation, single lab","pmids":["33640883"],"is_preprint":false},{"year":2022,"finding":"Maf1 mediates mTOR signaling to regulate Pol III-dependent rRNA and tRNA transcription in mouse cortical neurons. mTOR regulates neuronal Maf1 phosphorylation and subcellular localization. Maf1 knockdown increases Pol III transcription, neurite outgrowth, and dendritic spine formation. Maf1 interacts with promoters of CREB-associated genes (in addition to Pol III genes), repressing plasticity-related genes in neurons.","method":"AAV-mediated Maf1 knockdown, CUT&TAG-seq genome-wide promoter mapping, photothrombotic stroke model, neurite/spine morphology analysis","journal":"Journal of advanced research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide promoter binding mapping with in vivo functional study, single lab","pmids":["36402285"],"is_preprint":false},{"year":2024,"finding":"Bud27 (a prefoldin-like protein) regulates Maf1 phosphorylation state and nuclear localization through its association with the PP4 phosphatase complex. Bud27 associates with PP4 in vivo, and loss of Bud27 decreases PP4-Maf1 interaction, reduces Maf1 dephosphorylation, and impairs Maf1 nuclear entry.","method":"Co-immunoprecipitation of Bud27 with PP4, Maf1 phosphorylation state analysis, nuclear localization studies in bud27Δ cells","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-immunoprecipitation and genetic analysis of phosphorylation-localization coupling, single lab","pmids":["38864693"],"is_preprint":false},{"year":2024,"finding":"Maf1 regulates NMDAR1 (encoded by Grin1) expression by binding to the Grin1 promoter region, thereby regulating calcium homeostasis and synaptic remodeling in neurons. Conditional Maf1 knockout in a transgenic Alzheimer's disease mouse model restored learning and memory function.","method":"ChIP-PCR at Grin1 promoter, luciferase reporter assay, conditional Maf1 KO in transgenic AD mice, calcium imaging, synaptic morphology analysis","journal":"Brain : a journal of neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assays plus in vivo KO phenotype, single lab","pmids":["38226680"],"is_preprint":false},{"year":2025,"finding":"Maf1 cooperates with progesterone receptor (PR) to repress Pol III transcription of select tRNA genes in a progestin-dependent manner. Upon progestin treatment, PR localizes to ~50% of POLR3A-occupied tRNA genes, with Maf1 co-recruited at many of these sites. PR and Maf1 interact in a progestin-dependent manner (co-immunoprecipitation). Maf1 knockdown attenuates progestin-induced tRNA transcription downregulation.","method":"ChIP-seq for PR, Pol III subunits, Brf1, and Maf1; nascent tRNA transcription analysis; co-immunoprecipitation; Maf1 knockdown","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq and co-IP with functional knockdown validation, single lab","pmids":["41206048"],"is_preprint":false},{"year":2012,"finding":"Maf1 protein indirectly affects tRNA processing in yeast. The maf1Δ strain accumulates primary transcripts and intron-containing pre-tRNAs due to saturation of the tRNA processing machinery by increased primary transcripts rather than a direct role of Maf1 in maturation. Saturation of the tRNA exportin Los1 is one reason for pre-tRNA accumulation in maf1Δ cells.","method":"Pre-tRNA accumulation analysis, transcription inhibition rescue experiments, Los1 loss-of-function analysis in maf1Δ","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and biochemical dissection of indirect vs. direct effects on tRNA processing, single lab","pmids":["21940626"],"is_preprint":false},{"year":2010,"finding":"MAF1 is a novel PCNA-interacting protein in human cells, validated by co-immunoprecipitation from human cell extracts and interaction analysis using recombinant proteins.","method":"Bimolecular fluorescence complementation screen, co-immunoprecipitation from human cell extracts, recombinant protein interaction assay","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-IP validation of novel interaction, no functional follow-up for PCNA-MAF1 specifically","pmids":["26030842"],"is_preprint":false},{"year":2010,"finding":"Maf1 interacts with GABA-A receptor beta-subunit intracellular domains in neurons. Maf1 co-localizes with GABA-A receptors in intracellular compartments and at the cell surface in neurons. Maf1 interacts with a novel coiled-coil protein Macoco, which also interacts with GABA-A receptors. Expressing Macoco in neurons increases surface GABA-A receptor levels.","method":"Co-immunoprecipitation with GABA-A receptor subunits, co-localization by immunofluorescence, Macoco overexpression in neurons","journal":"Molecular and cellular neurosciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-IP and co-localization data without mechanistic follow-up of how MAF1 regulates GABA-A receptor levels","pmids":["20417281"],"is_preprint":false}],"current_model":"MAF1 is a conserved phosphoprotein that functions as the master repressor of RNA polymerase III transcription: under favorable growth conditions, it is phosphorylated by mTORC1 (at S60, S68, S75), PKA, and CK2, which promotes cytoplasmic retention (via Msn5-dependent nuclear export in yeast) and mTOR/CUL2-dependent proteasomal degradation; under stress, nutrient limitation, or mTOR inhibition, PP4 and PP2A dephosphorylate MAF1, driving its nuclear accumulation where it binds the Pol III clamp and C34 subunit (sealing the active site) and rearranges the C82/34/31 subcomplex to block closed complex formation with TFIIIB-TBP-Brf1, thereby preventing Pol III reinitiation; MAF1 also represses Pol II-driven transcription of TBP and FASN, activates PTEN transcription (counteracting mTOR signaling), is SUMOylated at K35 (required for Pol III association), and in mammals regulates adipogenesis, bone mass, metabolism, and neural plasticity through both Pol III-dependent and Pol II-dependent gene regulatory mechanisms."},"narrative":{"mechanistic_narrative":"MAF1 is a conserved phosphoprotein that acts as the central, signal-responsive repressor of RNA polymerase III transcription, coupling nutrient and stress status to the synthesis of tRNAs and other small RNAs [PMID:12504022, PMID:18377933]. It was first identified in yeast as a common node through which rapamycin, DNA damage, and secretory-pathway stress converge to silence Pol III, with TFIIIB identified as the repression target [PMID:12504022]. Mechanistically, MAF1 inhibits Pol III transcription in two steps—blocking de novo assembly of TFIIIB onto DNA and preventing recruitment of Pol III to preassembled TFIIIB-DNA complexes—through direct physical association with both Brf1/TFIIIB and the Pol III enzyme [PMID:15590667, PMID:17505538, PMID:17205138]. Structural studies established the basis of this repression: MAF1 binds the Pol III clamp and rearranges the C82/34/31 subcomplex, sequestering the mobile C34 winged-helix domain to seal the active-center cleft, with its binding site overlapping that of TFIIIB so that closed-complex formation and reinitiation are blocked without impairing RNA synthesis itself [PMID:20887893, PMID:32066962]. MAF1 activity is governed by a phosphorylation switch: under favorable growth it is phosphorylated by mTORC1 (S60/S68/S75), PKA, and CK2, which inhibits its repressive function and, in yeast, drives Msn5-dependent nuclear export [PMID:20516213, PMID:17005718, PMID:21383183, PMID:18445601]; under nutrient limitation or stress, PP2A and PP4 dephosphorylate MAF1, driving its nuclear accumulation and Pol III binding [PMID:16762835, PMID:22333918]. MAF1 stability is further controlled by mTOR/CUL2-dependent ubiquitin-proteasome turnover, and its association with Pol III requires SUMOylation at Lys-35 [PMID:31645432, PMID:23673667]. Beyond Pol III, MAF1 modulates Pol II–driven transcription, repressing TBP and lipogenic genes (FASN, ACC1) while activating PTEN, thereby integrating into PI3K/AKT/mTOR feedback control [PMID:17499043, PMID:25502566, PMID:26910647, PMID:27986570]. Through these activities MAF1 functions in vivo as a tumor suppressor and metabolic regulator, restraining anchorage-independent growth and conferring resistance to diet-induced obesity and fatty liver disease, and it additionally influences adipogenesis, cardiac hypertrophy, and neuronal plasticity [PMID:25502566, PMID:25934505, PMID:30110641, PMID:31695767, PMID:36402285].","teleology":[{"year":1997,"claim":"Established MAF1 as a gene functionally linked to the tRNA biosynthetic pathway, before any molecular mechanism was known.","evidence":"Genetic screen and multicopy suppressor analysis in yeast, with RPO31/RPC160 (Pol III largest subunit) rescuing the maf1 phenotype","pmids":["9055829"],"confidence":"Medium","gaps":["Did not define how Maf1 acts on Pol III","No biochemical interaction demonstrated"]},{"year":2002,"claim":"Defined Maf1 as a common downstream effector through which multiple stress signaling pathways repress Pol III, identifying TFIIIB as a repression target.","evidence":"Genetic epistasis across rapamycin, DNA damage, and secretory stress pathways plus biochemical repression assays in yeast","pmids":["12504022"],"confidence":"High","gaps":["Mechanism of TFIIIB inhibition not resolved","No direct Maf1-Pol III contact mapped"]},{"year":2004,"claim":"Resolved the repression mechanism into two distinct biochemical steps and demonstrated direct Maf1 contacts with Brf1 and Pol III.","evidence":"In vitro transcription repression assays and co-immunoprecipitation with recombinant Maf1","pmids":["15590667"],"confidence":"High","gaps":["Structural basis of contacts unknown","Non-stoichiometric mechanism not explained at the molecular level"]},{"year":2006,"claim":"Identified the kinase/phosphatase switch governing Maf1 localization and activity, placing PP2A and PKA on opposite arms of the regulatory circuit.","evidence":"ChIP-chip, genetic PP2A and PKA mutants, in vitro kinase assays, phosphosite mutants, and localization studies in yeast","pmids":["16762835","17005718"],"confidence":"High","gaps":["Phosphatase responsible for rapid dephosphorylation not fully defined","Phosphosites mapped only partially in yeast"]},{"year":2007,"claim":"Extended Maf1 function to mammals and to all three nuclear polymerases, revealing Pol II target genes (TBP) and growth-suppressive activity.","evidence":"Knockdown/overexpression in glioblastoma lines, ChIP, and reporter assays for Pol I/II/III and the TBP promoter","pmids":["17499043","17505538","17205138"],"confidence":"High","gaps":["Whether Pol I/II repression is direct or indirect","Physiological significance of multi-polymerase repression unclear"]},{"year":2008,"claim":"Demonstrated that mammalian Maf1 directly engages Pol III and TFIIIB and represses Pol III at chromosomal templates, while in yeast phosphorylation drives Msn5-dependent nuclear export.","evidence":"Co-IP, in vitro transcription, ChIP, Maf1 knockout cells, and genetic Msn5 deletion plus localization imaging","pmids":["18377933","18445601","18974046"],"confidence":"High","gaps":["Mammalian export pathway differs and was not resolved here","Why recombinant Maf1 cannot block facilitated recycling in vitro"]},{"year":2010,"claim":"Established mTORC1 as the direct upstream kinase and resolved the structural basis of repression, unifying signaling and mechanism.","evidence":"In vitro mTORC1 kinase assays with S60/S68/S75 mutagenesis, phosphoproteomics, proximity ligation assays, X-ray crystallography and cryo-EM of Pol III-Maf1 complexes","pmids":["20516213","20543138","20233713","20887893","20817737"],"confidence":"High","gaps":["How dephosphorylation translates structurally into Pol III binding","Species difference in nuclear export not mechanistically reconciled"]},{"year":2011,"claim":"Placed CK2 as an activating kinase that releases Maf1 from Pol III to restore transcription on return to growth.","evidence":"In vitro CK2 kinase assays on recombinant Maf1, ChIP, and tRNA synthesis assays in maf1Δ cells","pmids":["21383183"],"confidence":"High","gaps":["CK2 phosphosites not mapped","Interplay with mTORC1/PKA phosphorylation not resolved"]},{"year":2012,"claim":"Identified PP4 as the principal Maf1 phosphatase mediating rapid stress-induced dephosphorylation, and clarified that maf1Δ tRNA processing defects are indirect.","evidence":"In vitro dephosphorylation with purified PP4, co-precipitation, genetic PP4 subunit deletions, and pre-tRNA accumulation analysis in yeast","pmids":["22333918","21940626"],"confidence":"High","gaps":["Coordination between PP2A and PP4 not fully defined","Mammalian counterpart of PP4 activity not established"]},{"year":2014,"claim":"Integrated MAF1 into PTEN/PI3K/AKT tumor-suppressor signaling and lipogenic gene control, defining a Pol II–dependent metabolic role.","evidence":"PTEN KO mouse models, ChIP at the FASN promoter, reporter assays, and xenograft tumor models","pmids":["25502566"],"confidence":"High","gaps":["Direct vs indirect FASN repression mechanism","Relationship between Pol III and Pol II targets not unified"]},{"year":2015,"claim":"Demonstrated SUMOylation at K35 as a modification required for Maf1-Pol III association and identified MAF1 as a whole-body metabolic regulator in mice.","evidence":"SUMO modification assays with K35R mutagenesis, ChIP, and metabolic phenotyping of whole-body Maf1 knockout mice with tRNA precursor/mature ratio measurements","pmids":["23673667","25934505","26067234"],"confidence":"High","gaps":["How SUMOylation mechanistically promotes Pol III binding","Source of futile tRNA cycling not pinpointed"]},{"year":2016,"claim":"Defined the C-box autoregulatory region, genome-wide selectivity of Pol III targeting, and a paradoxical PTEN-activator role.","evidence":"C-box deletion/mutation analysis, genome-wide Pol III/MAF1 ChIP-seq with EU-labeling of nascent RNAs, and PTEN promoter acetylation/reporter assays","pmids":["27986570","26941251","26910647"],"confidence":"Medium","gaps":["Molecular switch between repressor and activator functions unknown","MAF1L/MAF1S stoichiometry regulation incompletely defined"]},{"year":2019,"claim":"Established CUL2-mediated, phosphorylation-coupled proteasomal turnover as a layer of MAF1 abundance control and linked MAF1 to ERK-dependent cardiac hypertrophy.","evidence":"Ubiquitination and stability assays with CUL2 knockdown and S75 mutants; Maf1 KO/overexpression mice with ERK1/2 co-IP and U0126 inhibition","pmids":["31645432","31695767"],"confidence":"Medium","gaps":["CUL2 substrate-recognition module not identified","Direct vs indirect Maf1-ERK1/2 interaction needs reciprocal validation"]},{"year":2020,"claim":"Provided high-resolution structural confirmation of active-site sealing and broadened MAF1 to chronic Pol III repression in vivo and to inflammatory (NLRP3) transcriptional control.","evidence":"3.3-Å cryo-EM of yeast Maf1-Pol III; ChIP-seq across fasting/refeeding in Maf1 KO mouse liver; ChIP and reporter assays at the NLRP3 promoter","pmids":["32066962","32686713","33424842"],"confidence":"High","gaps":["Generality of NLRP3 promoter binding across cell types","Link between chronic Pol III repression and translational output incompletely defined"]},{"year":2022,"claim":"Expanded MAF1 into neuronal gene regulation, showing it represses both Pol III genes and CREB-associated plasticity genes downstream of mTOR.","evidence":"AAV knockdown, CUT&TAG-seq promoter mapping, and stroke model with neurite/spine morphology analysis in mouse cortical neurons","pmids":["36402285"],"confidence":"Medium","gaps":["Mechanism of MAF1 recruitment to Pol II/CREB promoters unknown","Direct vs indirect effects on plasticity genes"]},{"year":2025,"claim":"Showed nuclear receptor cooperation, with progesterone receptor recruiting Maf1 to repress selected tRNA genes in a ligand-dependent manner.","evidence":"ChIP-seq for PR/Pol III/Brf1/Maf1, nascent tRNA analysis, co-IP, and Maf1 knockdown","pmids":["41206048"],"confidence":"Medium","gaps":["Whether PR-Maf1 interaction is direct","Selectivity determinants for the ~50% of targeted tRNA genes"]},{"year":null,"claim":"How MAF1 mechanistically toggles between repressing Pol III and Pol II targets and activating PTEN, and how it is recruited to specific Pol II promoters, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model for MAF1 at Pol II promoters","Recruitment determinants for Pol II/CREB/PR targets unknown","Switch between repressor and activator modes undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,5,13,21,24,31]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,11,13,31]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[5,21,24,32,38]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,9,16,25]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4,7,9]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,5,13,25,31]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[14,21,27,30]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[21,22,26]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[22,33,40]}],"complexes":[],"partners":["POLR3A","BRF1","BRF2","TBP","CUL2","MSN5","ERK1/2","PCNA"],"other_free_text":[]}},"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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Signaling pathways activated by rapamycin (nutrient limitation), DNA damage, and secretory pathway defects all require Maf1 for Pol III transcriptional repression. TFIIIB was identified as a target of Maf1-dependent repression, with a defect in TFIIIB-DNA complex assembly under repressing conditions.\",\n      \"method\": \"Genetic epistasis, biochemical repression assays in yeast\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis across multiple pathways combined with biochemical identification of TFIIIB as target, replicated across conditions\",\n      \"pmids\": [\"12504022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"MAF1 was identified as a novel yeast gene whose mutation causes antisuppression of a tRNA suppressor and temperature-sensitive respiratory growth. A fragment of RPO31/RPC160 (largest subunit of RNA Pol III) was cloned as a multicopy suppressor of maf1-1, suggesting Maf1 acts in the tRNA biosynthetic pathway via Pol III.\",\n      \"method\": \"Genetic screen, complementation cloning, multicopy suppressor analysis\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic screen with complementation and suppressor analysis in single lab\",\n      \"pmids\": [\"9055829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Maf1-dependent repression of Pol III transcription involves two steps: (1) inhibition of de novo TFIIIB assembly onto DNA and (2) inhibition of Pol III recruitment to preassembled TFIIIB-DNA complexes. Brf1 (a TFIIIB subunit) was identified as a target of repression. Maf1-Brf1 and Maf1-Pol III interactions were demonstrated by co-immunoprecipitation and implicated in these inhibitory steps. Maf1 functions via a non-stoichiometric mechanism.\",\n      \"method\": \"In vitro transcription repression assays, co-immunoprecipitation with recombinant Maf1\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro assays defining two mechanistic steps plus co-IP validation, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"15590667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"PP2A (protein phosphatase type 2A) is required for rapamycin-induced Maf1 dephosphorylation, nuclear accumulation, and Pol III repression. Maf1 interacts with Pol III (largest subunit C160 identified as target) in a dephosphorylated state. Under repressing conditions, Maf1 dephosphorylation by PP2A drives nuclear accumulation and increased Pol III-Maf1 interaction. Mutations in PP2A catalytic subunit genes prevented these events.\",\n      \"method\": \"ChIP-chip genome-wide analysis, phosphorylation state analysis, genetic mutation of PP2A subunits, co-immunoprecipitation\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide ChIP, genetic PP2A mutants, and co-IP, multiple orthogonal methods in single lab\",\n      \"pmids\": [\"16762835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Protein kinase A (PKA) phosphorylates Maf1 in vitro at PKA consensus sites. PKA activity negatively regulates Maf1 function: strains with unregulated high PKA activity block Pol III repression, while strains lacking all PKA activity are hyperrepressible. PKA inhibits Maf1 nuclear import via the N-terminal nuclear localization sequence, thereby preventing Pol III repression.\",\n      \"method\": \"In vitro kinase assay, differential in vivo phosphorylation analysis, genetic strains with altered PKA activity, phosphosite mutant analysis, nuclear localization studies\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro kinase assay plus in vivo genetic epistasis and phosphosite mutants, multiple orthogonal 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, and also represses TBP (TATA binding protein) transcription (Pol II-dependent) by targeting an Elk-1-binding site in the TBP promoter. Maf1 occupancy at this site is reciprocal with Elk-1 occupancy. Maf1 overexpression suppresses anchorage-independent growth.\",\n      \"method\": \"Expression knockdown/overexpression in glioblastoma lines, chromatin immunoprecipitation, reporter assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating reciprocal occupancy, expression-level manipulation with multiple readouts, single lab\",\n      \"pmids\": [\"17499043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Human Maf1 represses Pol III transcription via TFIIIB, specifically through the TFIIB family members Brf1 and Brf2.\",\n      \"method\": \"In vivo Pol III luciferase assay, co-immunoprecipitation\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — functional luciferase assay and co-IP in single lab\",\n      \"pmids\": [\"17505538\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Maf1 regulation of Pol III transcription is important for the switch between fermentation and respiration in yeast. Under respiratory conditions, Maf1 is dephosphorylated and imported into the nucleus; glucose addition induces Maf1 phosphorylation and cytoplasmic relocation. Absence of Maf1 impairs viability on nonfermentable carbon sources and differentially regulates levels of different tRNAs.\",\n      \"method\": \"Phosphorylation state analysis, subcellular localization, genetic suppressor studies, tRNA level measurements\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and biochemical characterization of phosphorylation-localization coupling in single lab\",\n      \"pmids\": [\"17785443\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Mammalian Maf1 interacts with Pol III and TFIIIB in mouse and human cells (co-immunoprecipitation). Maf1 represses Pol III transcription in vitro and in transfected fibroblasts. Maf1 is phosphorylated in a serum-sensitive manner in vivo. Genetic deletion of Maf1 elevates Pol III transcript expression. Maf1 is detected at chromosomal Pol III templates.\",\n      \"method\": \"Co-immunoprecipitation, in vitro transcription, fibroblast transfection, ChIP, Maf1 knockout cells\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (KO, in vitro repression, ChIP, co-IP), cross-species replication of mechanism\",\n      \"pmids\": [\"18377933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Phosphorylation of Maf1 by nuclear kinases drives its nuclear export via the Msn5 exportin carrier. Maf1 physically interacts with Msn5 (demonstrated by co-immunoprecipitation). In msn5Δ cells, Maf1 remains in the nucleus upon glucose addition despite normal phosphorylation, demonstrating that phosphorylation acts both directly (decreasing Pol III repression) and indirectly (stimulating Msn5-mediated nuclear export).\",\n      \"method\": \"Co-immunoprecipitation, subcellular localization imaging, genetic deletion of Msn5, phosphorylation analysis in Maf1 phosphosite mutants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal genetic and biochemical dissection of phosphorylation-export coupling, multiple methods in single lab\",\n      \"pmids\": [\"18445601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Human Maf1 can inhibit TFIIIB and Pol III recruitment to immobilized templates in vitro. However, Pol III bound to preinitiation complexes or in elongation complexes is protected from Maf1 repression and can undergo facilitated recycling (multiple rounds of reinitiation). Recombinant Maf1 is unable to inhibit facilitated recycling, suggesting additional biochemical steps are needed for rapid repression in vivo.\",\n      \"method\": \"Immobilized template in vitro transcription assay, recombinant human Maf1\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution assay with recombinant protein, mechanistic dissection of initiation vs. elongation phases, single lab\",\n      \"pmids\": [\"18974046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Human Maf1 co-immunoprecipitates with Pol III and associates in vitro with two Pol III subunits: the largest subunit RPC1 and the alpha-like subunit RPAC2. Maf1 represses Pol III transcription in vitro and in vivo, and is required for maximal Pol III repression after MMS or rapamycin treatment, both of which lead to Maf1 dephosphorylation.\",\n      \"method\": \"Co-immunoprecipitation, in vitro binding assay with Pol III subunits, in vitro and in vivo transcription repression assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro binding with specific subunits plus functional repression assays in vitro and in vivo, single lab\",\n      \"pmids\": [\"17205138\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"H2O2-induced nuclear accumulation of Maf1 in S. cerevisiae requires the cytoplasmic thioredoxins Trx1 and Trx2. PP2A phosphatase activity is essential for H2O2-induced Maf1 dephosphorylation and nuclear accumulation. Unlike other stresses, H2O2-induced Maf1 nuclear accumulation does not correlate with downregulation of PKA kinase activity.\",\n      \"method\": \"Subcellular localization analysis, genetic deletion of TRX1/TRX2 and PP2A subunits, phosphorylation state analysis\",\n      \"journal\": \"Eukaryotic cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and biochemical dissection of oxidative stress pathway to Maf1, single lab\",\n      \"pmids\": [\"19581440\"],\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 were determined. Maf1 binds the Pol III clamp and rearranges the C82/34/31 subcomplex at the rim of the active center cleft, impairing recruitment of Pol III to promoter DNA with Brf1 and TBP and preventing closed complex formation. Maf1 does not impair binding of a DNA-RNA scaffold or RNA synthesis, explaining specific repression of initiation.\",\n      \"method\": \"X-ray crystallography, cryo-electron microscopy, functional complex reconstitution\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus cryo-EM structures of multiple complexes with functional validation, highly rigorous study\",\n      \"pmids\": [\"20887893\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"mTORC1 directly phosphorylates human MAF1 on 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 by mTORC1 inhibits MAF1's repression activity.\",\n      \"method\": \"In vitro kinase assay with mTORC1, phosphorylation site mutagenesis, rapamycin/Torin1 treatment, MAF1 knockdown/knockout\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro phosphorylation by mTORC1 with mutagenesis of specific sites and functional validation, multiple orthogonal methods\",\n      \"pmids\": [\"20516213\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"mTOR associates with TFIIIC via a TOR signaling motif in TFIIIC, is recruited to tRNA and 5S rRNA genes, and phosphorylates Maf1 at Ser-75 in a mTOR-dependent manner both in vitro and in vivo. mTOR-Maf1 and mTOR-TFIIIC interactions were confirmed by proximity ligation assays in nuclei. In contrast to yeast, no nuclear export of Maf1 was found in HeLa cells in response to mTOR signaling.\",\n      \"method\": \"In vitro phosphorylation assay, proximity ligation assay, ChIP, knockdown experiments\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro phosphorylation plus proximity ligation and ChIP, multiple methods in single lab\",\n      \"pmids\": [\"20543138\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Maf1 Ser-75 phosphorylation by mTOR (identified by quantitative phosphoproteomics) controls its nuclear accumulation and Pol III repression in cancer cells. mTOR inhibition leads to rapid Maf1 dephosphorylation, nuclear accumulation, and reduced pre-tRNA levels. Maf1-S75A and Maf1-4A (S75A+S60A+T64A+S68A) mutants progressively enhance basal tRNA repression. mTOR inhibition increases Maf1 occupancy at Pol III genes with concomitant loss of Pol III and Brf1 binding.\",\n      \"method\": \"Quantitative phosphoproteomics, siRNA knockdown, phosphosite mutant analysis, ChIP, pre-tRNA measurements\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — quantitative phosphoproteomics plus functional phosphosite mutants and ChIP, multiple orthogonal methods, consistent with other labs\",\n      \"pmids\": [\"20233713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Two conserved domains of human Maf1 are resistant to mild proteolysis and interact with each other (demonstrated by pull-down and size-exclusion chromatography). Comparable domains of yeast Maf1 interact in two-hybrid assay. Integrity of both domains and their direct interaction are necessary for Maf1 dephosphorylation and subsequent Pol III transcription inhibition on nonfermentable carbon sources.\",\n      \"method\": \"Limited proteolysis, pull-down assay, size-exclusion chromatography, two-hybrid assay, functional transcription assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical methods demonstrating intra-domain interaction with functional consequence, single lab\",\n      \"pmids\": [\"20817737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Casein kinase II (CK2) phosphorylates Maf1 directly: both recombinant human and yeast CK2 phosphorylate purified human or yeast Maf1 in vitro. CK2 activity is required for efficient Pol III transcription by releasing Maf1 from Pol III at tRNA genes upon return to favorable growth conditions. In maf1Δ cells, CK2 inhibition has no effect on tRNA synthesis, confirming CK2 activates Pol III via Maf1.\",\n      \"method\": \"In vitro kinase assay with recombinant CK2 and Maf1, ChIP, tRNA synthesis assay in maf1Δ cells\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro phosphorylation with recombinant proteins plus genetic epistasis in maf1Δ confirming pathway placement, single lab\",\n      \"pmids\": [\"21383183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Protein phosphatase 4 (PP4) complex (with catalytic subunit Pph3, scaffold Psy2, regulatory subunits Rrd1 and Tip41) is the main Maf1 phosphatase in yeast. PP4 co-precipitates with Maf1, and purified PP4 dephosphorylates Maf1 in vitro. PP4 mediates rapid Maf1 dephosphorylation in response to diverse stresses, Maf1 nuclear localization, and rapid Pol III repression.\",\n      \"method\": \"In vitro dephosphorylation assay with purified PP4, co-precipitation, genetic deletion of PP4 subunits, localization and transcription assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro dephosphorylation plus co-precipitation and genetic epistasis through PP4 subunit deletions, multiple methods\",\n      \"pmids\": [\"22333918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Maf1 is SUMOylated by SUMO1 and SUMO2, with Lys-35 as the major SUMOylation site. The deSUMOylase SENP1 controls Maf1-K35 SUMOylation. SUMOylation is required for Maf1 to repress Pol III transcription and suppress colony growth. Maf1-K35R (non-SUMOylatable) is defective in associating with Pol III, impairing its recruitment to tRNA gene promoters and its ability to dissociate Pol III from these promoters. SUMOylation does not alter Maf1 subcellular localization and is unaffected by mTOR/rapamycin.\",\n      \"method\": \"SUMO modification assay, site-directed mutagenesis (K35R), co-immunoprecipitation, ChIP, colony growth assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — identification of specific SUMOylation site with mutagenesis and multiple functional readouts, single lab\",\n      \"pmids\": [\"23673667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Maf1 is a key downstream target of PTEN that drives PTEN's tumor suppressor and metabolic functions. PTEN-mediated changes in Maf1 expression are mediated through PI3K/AKT/FoxO1 signaling. Maf1 occupies the FASN promoter and opposes SREBP1c-mediated transcription activation of lipogenic enzymes. Maf1 reduces anchorage-independent growth and tumor formation in mice.\",\n      \"method\": \"PTEN KO mouse models, human cancer samples, ChIP, reporter assays, xenograft tumor models, lipid accumulation assays\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating FASN promoter occupancy, in vivo mouse tumor models, genetic pathway analysis, single lab\",\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 and nonalcoholic fatty liver disease by reducing food intake and increasing metabolic inefficiency. Precursor tRNA synthesis is increased in multiple tissues without significant effects on mature tRNA levels, implying increased turnover in a futile tRNA cycle. Maf1 knockout also leads to elevated futile cycling of hepatic lipids and increased NAD+ levels in muscle.\",\n      \"method\": \"Whole-body Maf1 knockout mice, metabolic phenotyping, tRNA precursor/mature ratio measurements, metabolite profiling\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockout with comprehensive metabolic phenotyping and mechanistic follow-up at multiple tissues, single lab but rigorous\",\n      \"pmids\": [\"25934505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MAF1 knockdown induces CDKN1A transcription concurrently with Pol III recruitment to the CDKN1A locus. Simultaneous knockdown of MAF1 with Pol III or BRF1 diminishes CDKN1A activation and chromatin looping, indicating that Pol III recruitment is required for this Pol II-mediated transcription and looping. ChIP shows enhanced binding of Pol III, BRF1, CFP1, p300, PCAF, TBP, and POLR2E at the CDKN1A promoter upon MAF1 knockdown.\",\n      \"method\": \"siRNA knockdown, ChIP analysis, chromatin looping assay, transcription measurements\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic ChIP and double-knockdown epistasis, single lab\",\n      \"pmids\": [\"26067234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MAF1 binds the PTEN promoter, enhancing PTEN promoter acetylation and transcriptional activity (acting as a transcriptional activator for PTEN, contrary to its canonical repressor function). MAF1 downregulation leads to decreased PTEN expression and paradoxical activation of AKT-mTOR signaling.\",\n      \"method\": \"ChIP, promoter acetylation assay, luciferase reporter, MAF1 knockdown/overexpression in HCC cells and mouse models\",\n      \"journal\": \"Hepatology (Baltimore, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and promoter assays demonstrating activator function at PTEN, single lab\",\n      \"pmids\": [\"26910647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Human MAF1 targets and represses active Pol III genes by preventing Pol III recruitment rather than inducing long-term transcriptional arrest. MAF1 selectively localizes at Pol III loci even under serum-replete conditions and increasingly targets transcribing Pol III in response to serum starvation. Pol III occupancy closely reflects ongoing transcription (validated by EU-labeling of nascent small RNAs).\",\n      \"method\": \"Genome-wide Pol III binding (ChIP-seq), EU-labeling with high-throughput sequencing of nascent small RNAs, MAF1 ChIP\",\n      \"journal\": \"Genome research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide ChIP-seq combined with nascent RNA labeling, orthogonal methods providing mechanistic insight, single lab\",\n      \"pmids\": [\"26941251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The MAF1 C-box region negatively regulates MAF1 activity. C-box deletion in human MAF1 leads to increased nuclear localization and enhanced repression of ACC1 and FASN, but impaired repression of Pol III targets. C-box mutations render MAF1 insensitive to rapamycin. The YSY motif in the C-box controls MAF1 species stoichiometry (MAF1L and MAF1S) and proteasome-dependent turnover of nuclear MAF1.\",\n      \"method\": \"C-box deletion/mutation analysis in C. elegans and human cells, nuclear localization imaging, proteasome inhibition, rapamycin treatment, transcription assays\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional domain dissection with multiple readouts across species, single lab\",\n      \"pmids\": [\"27986570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Ras/ERK signaling promotes Pol III-mediated tRNA synthesis in Drosophila by phosphorylating Maf1, inhibiting its nuclear localization and function as a Pol III repressor. ERK activation promotes tRNA synthesis both in vivo and in cultured S2 cells. Myc is required but not sufficient for Ras-mediated tRNA stimulation; instead, inhibition of Maf1 nuclear localization is the key mechanism.\",\n      \"method\": \"In vivo Drosophila genetic experiments, cultured S2 cells, ERK/Ras pathway activation/inhibition, Pol III reporter assays, Maf1 localization imaging\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic epistasis and cell-based pathway dissection in Drosophila model, single lab\",\n      \"pmids\": [\"29401457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Maf1 promotes induction of mouse embryonic stem cells into mesoderm and promotes adipocyte differentiation. Reduced Maf1 expression impairs adipogenesis, while ectopic Maf1 expression in Maf1-deficient cells enhances differentiation. RNA Pol III repression promotes adipogenesis; Pol III-mediated transcription positively regulates lncRNA H19 and Wnt6 (adipogenesis inhibitors).\",\n      \"method\": \"Maf1 KO/overexpression in mESCs and preadipocytes, Brf1 knockdown, chemical Pol III inhibition, RNA-seq\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss- and gain-of-function in differentiation models with RNA-seq pathway analysis, single lab\",\n      \"pmids\": [\"30110641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MAF1 is regulated by ubiquitin-dependent proteasome degradation. TORC1-mediated phosphorylation at Ser-75 enhances MAF1 ubiquitination. The E3 ubiquitin ligase CUL2 critically regulates MAF1 ubiquitination and controls its stability and subsequent Pol III-dependent transcription. Modulating CUL2 or MAF1 expression alters actin cytoskeleton reorganization and sensitivity to doxorubicin-induced apoptosis.\",\n      \"method\": \"Ubiquitination assay, proteasome inhibition, CUL2 knockdown, phosphosite mutant analysis, cell viability/apoptosis assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination and stability assays with mechanistic follow-up, single lab\",\n      \"pmids\": [\"31645432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Maf1 directly binds ERK1/2 (demonstrated by immunoprecipitation) and inhibits Pol III transcription via ERK1/2 signaling suppression to attenuate cardiac hypertrophy. Maf1 KO mice exhibit exacerbated cardiac hypertrophy after pressure overload; Maf1 overexpression ameliorates hypertrophy. ERK1/2 inhibition by U0126 suppresses Maf1-knockdown-promoted cardiac hypertrophy with concomitant Pol III repression.\",\n      \"method\": \"Maf1 KO mice, adenoviral overexpression, co-immunoprecipitation with ERK1/2, ERK inhibitor U0126, cardiac phenotyping\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — co-IP with ERK1/2 and in vivo KO/OE phenotype, 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. Maf1 sequesters Pol III elements involved in transcription initiation and binds the mobile C34 winged helix 2 domain, sealing off the active site. The Maf1 binding site overlaps with that of TFIIIB in the preinitiation complex.\",\n      \"method\": \"Cryo-electron microscopy at 3.3-Å resolution\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution cryo-EM structure of Maf1-Pol III complex with structural validation of inhibitory mechanism\",\n      \"pmids\": [\"32066962\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Maf1 and p65 (NF-κB) directly bind to the NLRP3 gene promoter region and competitively regulate NLRP3 function in inflammation. Maf1 downregulates NF-κB/p65-induced NLRP3 inflammasome activation and pro-inflammatory cytokine expression, suppressing LPS-induced BBB disruption.\",\n      \"method\": \"ChIP at NLRP3 promoter, reporter assay, overexpression/knockdown, in vitro and in vivo LPS models\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — ChIP demonstrating promoter binding with functional overexpression/knockdown evidence, single lab\",\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 the mouse liver. In Maf1-/- mice, Pol III occupancy is higher than wild-type at the vast majority of active loci in both fasted and refed conditions, and specific precursor tRNA levels are elevated in multiple tissues. MAF1 has a modest effect on global translation via reduced mRNA levels and translation efficiencies for several ribosomal proteins.\",\n      \"method\": \"ChIP-seq, precursor tRNA measurements, polysome profiling, fasting-refeeding paradigm in Maf1 KO mice\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide ChIP-seq across multiple conditions in Maf1 KO mice, comprehensive mechanistic analysis\",\n      \"pmids\": [\"32686713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Maf1 regulates intracellular lipid homeostasis in C. elegans in response to DNA damage via the DDR pathway. UV-induced lipid accumulation requires mafr-1, the apical kinases atm-1 and atl-1 (DDR kinases). Genetic ablation of mafr-1 alone activates the DDR, including increased lipid accumulation, phosphorylation of ATM/ATR target proteins, and expression of Bcl-2 homolog genes.\",\n      \"method\": \"C. elegans genetic deletion, UV exposure, lipid accumulation quantification, DDR marker analysis\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with DDR kinase deletions and mechanistic markers, single lab in C. elegans\",\n      \"pmids\": [\"33788576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In response to ionizing radiation (IR), Maf1 is inhibited by Akt-dependent re-phosphorylation, which activates the mitochondrial unfolded protein response (UPRmt) through ATF5. Rapamycin suppresses IR-induced Maf1 re-phosphorylation and UPRmt activation in A549 cells, increasing radio-sensitivity. Maf1 overexpression suppresses ethidium bromide-induced UPRmt and enhances IR-mediated cytotoxicity.\",\n      \"method\": \"Maf1 knockdown/overexpression, rapamycin treatment, IR exposure, UPRmt marker analysis, mitochondrial membrane potential measurement\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — mechanistic pathway dissection with multiple pharmacological interventions and genetic manipulation, single lab\",\n      \"pmids\": [\"33640883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Maf1 mediates mTOR signaling to regulate Pol III-dependent rRNA and tRNA transcription in mouse cortical neurons. mTOR regulates neuronal Maf1 phosphorylation and subcellular localization. Maf1 knockdown increases Pol III transcription, neurite outgrowth, and dendritic spine formation. Maf1 interacts with promoters of CREB-associated genes (in addition to Pol III genes), repressing plasticity-related genes in neurons.\",\n      \"method\": \"AAV-mediated Maf1 knockdown, CUT&TAG-seq genome-wide promoter mapping, photothrombotic stroke model, neurite/spine morphology analysis\",\n      \"journal\": \"Journal of advanced research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide promoter binding mapping with in vivo functional study, single lab\",\n      \"pmids\": [\"36402285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Bud27 (a prefoldin-like protein) regulates Maf1 phosphorylation state and nuclear localization through its association with the PP4 phosphatase complex. Bud27 associates with PP4 in vivo, and loss of Bud27 decreases PP4-Maf1 interaction, reduces Maf1 dephosphorylation, and impairs Maf1 nuclear entry.\",\n      \"method\": \"Co-immunoprecipitation of Bud27 with PP4, Maf1 phosphorylation state analysis, nuclear localization studies in bud27Δ cells\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-immunoprecipitation and genetic analysis of phosphorylation-localization coupling, single lab\",\n      \"pmids\": [\"38864693\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Maf1 regulates NMDAR1 (encoded by Grin1) expression by binding to the Grin1 promoter region, thereby regulating calcium homeostasis and synaptic remodeling in neurons. Conditional Maf1 knockout in a transgenic Alzheimer's disease mouse model restored learning and memory function.\",\n      \"method\": \"ChIP-PCR at Grin1 promoter, luciferase reporter assay, conditional Maf1 KO in transgenic AD mice, calcium imaging, synaptic morphology analysis\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assays plus in vivo KO phenotype, single lab\",\n      \"pmids\": [\"38226680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Maf1 cooperates with progesterone receptor (PR) to repress Pol III transcription of select tRNA genes in a progestin-dependent manner. Upon progestin treatment, PR localizes to ~50% of POLR3A-occupied tRNA genes, with Maf1 co-recruited at many of these sites. PR and Maf1 interact in a progestin-dependent manner (co-immunoprecipitation). Maf1 knockdown attenuates progestin-induced tRNA transcription downregulation.\",\n      \"method\": \"ChIP-seq for PR, Pol III subunits, Brf1, and Maf1; nascent tRNA transcription analysis; co-immunoprecipitation; Maf1 knockdown\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq and co-IP with functional knockdown validation, single lab\",\n      \"pmids\": [\"41206048\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Maf1 protein indirectly affects tRNA processing in yeast. The maf1Δ strain accumulates primary transcripts and intron-containing pre-tRNAs due to saturation of the tRNA processing machinery by increased primary transcripts rather than a direct role of Maf1 in maturation. Saturation of the tRNA exportin Los1 is one reason for pre-tRNA accumulation in maf1Δ cells.\",\n      \"method\": \"Pre-tRNA accumulation analysis, transcription inhibition rescue experiments, Los1 loss-of-function analysis in maf1Δ\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and biochemical dissection of indirect vs. direct effects on tRNA processing, single lab\",\n      \"pmids\": [\"21940626\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"MAF1 is a novel PCNA-interacting protein in human cells, validated by co-immunoprecipitation from human cell extracts and interaction analysis using recombinant proteins.\",\n      \"method\": \"Bimolecular fluorescence complementation screen, co-immunoprecipitation from human cell extracts, recombinant protein interaction assay\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP validation of novel interaction, no functional follow-up for PCNA-MAF1 specifically\",\n      \"pmids\": [\"26030842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Maf1 interacts with GABA-A receptor beta-subunit intracellular domains in neurons. Maf1 co-localizes with GABA-A receptors in intracellular compartments and at the cell surface in neurons. Maf1 interacts with a novel coiled-coil protein Macoco, which also interacts with GABA-A receptors. Expressing Macoco in neurons increases surface GABA-A receptor levels.\",\n      \"method\": \"Co-immunoprecipitation with GABA-A receptor subunits, co-localization by immunofluorescence, Macoco overexpression in neurons\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP and co-localization data without mechanistic follow-up of how MAF1 regulates GABA-A receptor levels\",\n      \"pmids\": [\"20417281\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MAF1 is a conserved phosphoprotein that functions as the master repressor of RNA polymerase III transcription: under favorable growth conditions, it is phosphorylated by mTORC1 (at S60, S68, S75), PKA, and CK2, which promotes cytoplasmic retention (via Msn5-dependent nuclear export in yeast) and mTOR/CUL2-dependent proteasomal degradation; under stress, nutrient limitation, or mTOR inhibition, PP4 and PP2A dephosphorylate MAF1, driving its nuclear accumulation where it binds the Pol III clamp and C34 subunit (sealing the active site) and rearranges the C82/34/31 subcomplex to block closed complex formation with TFIIIB-TBP-Brf1, thereby preventing Pol III reinitiation; MAF1 also represses Pol II-driven transcription of TBP and FASN, activates PTEN transcription (counteracting mTOR signaling), is SUMOylated at K35 (required for Pol III association), and in mammals regulates adipogenesis, bone mass, metabolism, and neural plasticity through both Pol III-dependent and Pol II-dependent gene regulatory mechanisms.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MAF1 is a conserved phosphoprotein that acts as the central, signal-responsive repressor of RNA polymerase III transcription, coupling nutrient and stress status to the synthesis of tRNAs and other small RNAs [#0, #8]. It was first identified in yeast as a common node through which rapamycin, DNA damage, and secretory-pathway stress converge to silence Pol III, with TFIIIB identified as the repression target [#0]. Mechanistically, MAF1 inhibits Pol III transcription in two steps—blocking de novo assembly of TFIIIB onto DNA and preventing recruitment of Pol III to preassembled TFIIIB-DNA complexes—through direct physical association with both Brf1/TFIIIB and the Pol III enzyme [#2, #6, #11]. Structural studies established the basis of this repression: MAF1 binds the Pol III clamp and rearranges the C82/34/31 subcomplex, sequestering the mobile C34 winged-helix domain to seal the active-center cleft, with its binding site overlapping that of TFIIIB so that closed-complex formation and reinitiation are blocked without impairing RNA synthesis itself [#13, #31]. MAF1 activity is governed by a phosphorylation switch: under favorable growth it is phosphorylated by mTORC1 (S60/S68/S75), PKA, and CK2, which inhibits its repressive function and, in yeast, drives Msn5-dependent nuclear export [#14, #4, #18, #9]; under nutrient limitation or stress, PP2A and PP4 dephosphorylate MAF1, driving its nuclear accumulation and Pol III binding [#3, #19]. MAF1 stability is further controlled by mTOR/CUL2-dependent ubiquitin-proteasome turnover, and its association with Pol III requires SUMOylation at Lys-35 [#29, #20]. Beyond Pol III, MAF1 modulates Pol II–driven transcription, repressing TBP and lipogenic genes (FASN, ACC1) while activating PTEN, thereby integrating into PI3K/AKT/mTOR feedback control [#5, #21, #24, #26]. Through these activities MAF1 functions in vivo as a tumor suppressor and metabolic regulator, restraining anchorage-independent growth and conferring resistance to diet-induced obesity and fatty liver disease, and it additionally influences adipogenesis, cardiac hypertrophy, and neuronal plasticity [#21, #22, #28, #30, #36].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established MAF1 as a gene functionally linked to the tRNA biosynthetic pathway, before any molecular mechanism was known.\",\n      \"evidence\": \"Genetic screen and multicopy suppressor analysis in yeast, with RPO31/RPC160 (Pol III largest subunit) rescuing the maf1 phenotype\",\n      \"pmids\": [\"9055829\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define how Maf1 acts on Pol III\", \"No biochemical interaction demonstrated\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Defined Maf1 as a common downstream effector through which multiple stress signaling pathways repress Pol III, identifying TFIIIB as a repression target.\",\n      \"evidence\": \"Genetic epistasis across rapamycin, DNA damage, and secretory stress pathways plus biochemical repression assays in yeast\",\n      \"pmids\": [\"12504022\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of TFIIIB inhibition not resolved\", \"No direct Maf1-Pol III contact mapped\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Resolved the repression mechanism into two distinct biochemical steps and demonstrated direct Maf1 contacts with Brf1 and Pol III.\",\n      \"evidence\": \"In vitro transcription repression assays and co-immunoprecipitation with recombinant Maf1\",\n      \"pmids\": [\"15590667\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of contacts unknown\", \"Non-stoichiometric mechanism not explained at the molecular level\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identified the kinase/phosphatase switch governing Maf1 localization and activity, placing PP2A and PKA on opposite arms of the regulatory circuit.\",\n      \"evidence\": \"ChIP-chip, genetic PP2A and PKA mutants, in vitro kinase assays, phosphosite mutants, and localization studies in yeast\",\n      \"pmids\": [\"16762835\", \"17005718\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphatase responsible for rapid dephosphorylation not fully defined\", \"Phosphosites mapped only partially in yeast\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Extended Maf1 function to mammals and to all three nuclear polymerases, revealing Pol II target genes (TBP) and growth-suppressive activity.\",\n      \"evidence\": \"Knockdown/overexpression in glioblastoma lines, ChIP, and reporter assays for Pol I/II/III and the TBP promoter\",\n      \"pmids\": [\"17499043\", \"17505538\", \"17205138\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Pol I/II repression is direct or indirect\", \"Physiological significance of multi-polymerase repression unclear\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrated that mammalian Maf1 directly engages Pol III and TFIIIB and represses Pol III at chromosomal templates, while in yeast phosphorylation drives Msn5-dependent nuclear export.\",\n      \"evidence\": \"Co-IP, in vitro transcription, ChIP, Maf1 knockout cells, and genetic Msn5 deletion plus localization imaging\",\n      \"pmids\": [\"18377933\", \"18445601\", \"18974046\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mammalian export pathway differs and was not resolved here\", \"Why recombinant Maf1 cannot block facilitated recycling in vitro\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Established mTORC1 as the direct upstream kinase and resolved the structural basis of repression, unifying signaling and mechanism.\",\n      \"evidence\": \"In vitro mTORC1 kinase assays with S60/S68/S75 mutagenesis, phosphoproteomics, proximity ligation assays, X-ray crystallography and cryo-EM of Pol III-Maf1 complexes\",\n      \"pmids\": [\"20516213\", \"20543138\", \"20233713\", \"20887893\", \"20817737\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How dephosphorylation translates structurally into Pol III binding\", \"Species difference in nuclear export not mechanistically reconciled\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Placed CK2 as an activating kinase that releases Maf1 from Pol III to restore transcription on return to growth.\",\n      \"evidence\": \"In vitro CK2 kinase assays on recombinant Maf1, ChIP, and tRNA synthesis assays in maf1\\u0394 cells\",\n      \"pmids\": [\"21383183\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"CK2 phosphosites not mapped\", \"Interplay with mTORC1/PKA phosphorylation not resolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified PP4 as the principal Maf1 phosphatase mediating rapid stress-induced dephosphorylation, and clarified that maf1\\u0394 tRNA processing defects are indirect.\",\n      \"evidence\": \"In vitro dephosphorylation with purified PP4, co-precipitation, genetic PP4 subunit deletions, and pre-tRNA accumulation analysis in yeast\",\n      \"pmids\": [\"22333918\", \"21940626\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Coordination between PP2A and PP4 not fully defined\", \"Mammalian counterpart of PP4 activity not established\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Integrated MAF1 into PTEN/PI3K/AKT tumor-suppressor signaling and lipogenic gene control, defining a Pol II–dependent metabolic role.\",\n      \"evidence\": \"PTEN KO mouse models, ChIP at the FASN promoter, reporter assays, and xenograft tumor models\",\n      \"pmids\": [\"25502566\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect FASN repression mechanism\", \"Relationship between Pol III and Pol II targets not unified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated SUMOylation at K35 as a modification required for Maf1-Pol III association and identified MAF1 as a whole-body metabolic regulator in mice.\",\n      \"evidence\": \"SUMO modification assays with K35R mutagenesis, ChIP, and metabolic phenotyping of whole-body Maf1 knockout mice with tRNA precursor/mature ratio measurements\",\n      \"pmids\": [\"23673667\", \"25934505\", \"26067234\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SUMOylation mechanistically promotes Pol III binding\", \"Source of futile tRNA cycling not pinpointed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined the C-box autoregulatory region, genome-wide selectivity of Pol III targeting, and a paradoxical PTEN-activator role.\",\n      \"evidence\": \"C-box deletion/mutation analysis, genome-wide Pol III/MAF1 ChIP-seq with EU-labeling of nascent RNAs, and PTEN promoter acetylation/reporter assays\",\n      \"pmids\": [\"27986570\", \"26941251\", \"26910647\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular switch between repressor and activator functions unknown\", \"MAF1L/MAF1S stoichiometry regulation incompletely defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established CUL2-mediated, phosphorylation-coupled proteasomal turnover as a layer of MAF1 abundance control and linked MAF1 to ERK-dependent cardiac hypertrophy.\",\n      \"evidence\": \"Ubiquitination and stability assays with CUL2 knockdown and S75 mutants; Maf1 KO/overexpression mice with ERK1/2 co-IP and U0126 inhibition\",\n      \"pmids\": [\"31645432\", \"31695767\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"CUL2 substrate-recognition module not identified\", \"Direct vs indirect Maf1-ERK1/2 interaction needs reciprocal validation\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Provided high-resolution structural confirmation of active-site sealing and broadened MAF1 to chronic Pol III repression in vivo and to inflammatory (NLRP3) transcriptional control.\",\n      \"evidence\": \"3.3-\\u00c5 cryo-EM of yeast Maf1-Pol III; ChIP-seq across fasting/refeeding in Maf1 KO mouse liver; ChIP and reporter assays at the NLRP3 promoter\",\n      \"pmids\": [\"32066962\", \"32686713\", \"33424842\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of NLRP3 promoter binding across cell types\", \"Link between chronic Pol III repression and translational output incompletely defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Expanded MAF1 into neuronal gene regulation, showing it represses both Pol III genes and CREB-associated plasticity genes downstream of mTOR.\",\n      \"evidence\": \"AAV knockdown, CUT&TAG-seq promoter mapping, and stroke model with neurite/spine morphology analysis in mouse cortical neurons\",\n      \"pmids\": [\"36402285\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of MAF1 recruitment to Pol II/CREB promoters unknown\", \"Direct vs indirect effects on plasticity genes\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed nuclear receptor cooperation, with progesterone receptor recruiting Maf1 to repress selected tRNA genes in a ligand-dependent manner.\",\n      \"evidence\": \"ChIP-seq for PR/Pol III/Brf1/Maf1, nascent tRNA analysis, co-IP, and Maf1 knockdown\",\n      \"pmids\": [\"41206048\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether PR-Maf1 interaction is direct\", \"Selectivity determinants for the ~50% of targeted tRNA genes\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MAF1 mechanistically toggles between repressing Pol III and Pol II targets and activating PTEN, and how it is recruited to specific Pol II promoters, remains unresolved.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model for MAF1 at Pol II promoters\", \"Recruitment determinants for Pol II/CREB/PR targets unknown\", \"Switch between repressor and activator modes undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 5, 13, 21, 24, 31]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 11, 13, 31]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [5, 21, 24, 32, 38]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 9, 16, 25]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4, 7, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 5, 13, 25, 31]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [14, 21, 27, 30]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [21, 22, 26]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [22, 33, 40]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"POLR3A\", \"BRF1\", \"BRF2\", \"TBP\", \"CUL2\", \"MSN5\", \"ERK1/2\", \"PCNA\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}