{"gene":"SUPV3L1","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":1992,"finding":"The yeast SUV3 gene encodes an 84-kDa protein with a mitochondrial targeting presequence and conserved sequence motifs of ATP-dependent RNA helicases; the SUV3-1 gain-of-function mutation is a Val→Leu substitution in a conserved helicase motif block, causing accumulation of excised group I introns in mitochondria.","method":"Gene cloning by colony Northern hybridization, sequence analysis, and mutant allele identification","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct cloning and sequencing with mutant allele identification; foundational paper replicated by subsequent studies","pmids":["1379722"],"is_preprint":false},{"year":1990,"finding":"The SUV3-1 mutation causes over-accumulation of excised group I intron RNAs, lowers levels of cob and cox1 mRNAs, and blocks dodecamer cleavage in yeast mitochondria, establishing SUV3 as a key regulator of mitochondrial post-transcriptional processes including RNA stability and splicing.","method":"Northern hybridization survey of mitochondrial RNAs in SUV3-1 and suv3 deletion strains","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic Northern blotting across multiple mitochondrial genes; replicated and extended by later studies","pmids":["2158076"],"is_preprint":false},{"year":1995,"finding":"SUV3 is required for stability of intron-containing mitochondrial transcripts in a cumulative manner depending on intron number; loss of SUV3 decreases mRNA levels without accumulating high-molecular-weight precursors or affecting transcription.","method":"Northern hybridization of mitochondrial RNAs in strains with defined combinations of cytb and cox1 introns combined with SUV3 gene disruption","journal":"Current genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic genetic epistasis with controlled mitochondrial genome backgrounds; replicated across multiple intron combinations","pmids":["8529267"],"is_preprint":false},{"year":1995,"finding":"The suv3 protein is required for proper processing of r1 intron-containing 21S rRNA transcripts; in its absence, the excised r1 intron pattern is altered and mature 21S rRNA is ~50-fold reduced.","method":"Northern analysis of mitochondrial RNA in suv3 disruption strain carrying r1-only intron genome","journal":"Current genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — single lab, clean genetic system with Northern analysis, one defined intron background","pmids":["7736607"],"is_preprint":false},{"year":1998,"finding":"The PET127 gene (involved in 5'-end processing of mitochondrial mRNAs) can suppress SUV3 or DSS1 gene disruptions, suggesting functional coupling between 5' and 3' ends of mitochondrial mRNAs and placing SUV3/DSS1 degradosome activity in a pathway coordinated with 5'-end processing.","method":"Genetic suppression by PET127 on low- and high-copy vectors in SUV3/DSS1 disruption strains","journal":"Acta biochimica Polonica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean epistasis by genetic suppression; single lab, single method","pmids":["10397341"],"is_preprint":false},{"year":1999,"finding":"Human SUPV3L1 (hSUV3) encodes a protein with a mitochondrial leader sequence that is the human homologue of yeast Suv3 helicase, conserved across eukaryotes and Rhodobacter sphaeroides.","method":"cDNA cloning, sequencing, Northern blot, and EST database analysis","journal":"Acta biochimica Polonica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct cDNA cloning with sequence and expression analysis; single lab","pmids":["10453991"],"is_preprint":false},{"year":2002,"finding":"Overexpression of the yeast mitochondrial helicase Mss116 can partially suppress the loss of SUV3, restoring respiratory competence and normalizing COB and ATP6/8 mRNA levels, indicating functional overlap between these two distinct RNA helicase classes in mitochondrial RNA metabolism.","method":"Multicopy plasmid suppression, respiratory growth assays, and Northern blotting in SUV3-deleted strains","journal":"Yeast (Chichester, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic suppression with molecular readouts; single lab","pmids":["12402239"],"is_preprint":false},{"year":2007,"finding":"Human SUV3 localizes not only to mitochondria but also to the nucleus; siRNA-mediated knockdown in HeLa cells causes cell cycle perturbations, p53 induction, and both AIF-dependent and caspase-dependent apoptosis.","method":"siRNA knockdown, cell cycle analysis, apoptosis assays (AIF and caspase pathway), subcellular fractionation/localization","journal":"Biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD with defined cellular phenotypes and pathway placement; single lab","pmids":["17352692"],"is_preprint":false},{"year":2007,"finding":"Human SUV3 protein physically interacts with BLM helicase (Kd ~0.5 nM) and WRN helicase (Kd ~5 nM) as measured by ELISA binding assay; SUV3 knockdown in HeLa cells elevates sister chromatid exchange frequency, indicating a role in homologous recombination suppression.","method":"ELISA binding assay for protein-protein interaction, sister chromatid exchange assay after siRNA knockdown","journal":"Mechanisms of ageing and development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assay with Kd measurement plus functional SCE assay; single lab, two orthogonal methods","pmids":["17961633"],"is_preprint":false},{"year":2008,"finding":"Knockdown of hSUV3 in mammalian cells causes accumulation of shortened polyadenylated mitochondrial RNA species, impaired mitochondrial protein synthesis, increased reactive oxygen species, decreased membrane potential and ATP production, reduced mtDNA copy number, and shift of mitochondrial morphology from tubular to granular, leading to senescence or cell death.","method":"siRNA knockdown, mitochondrial RNA analysis, protein synthesis assay, ROS measurement, membrane potential assay, mtDNA copy number quantification, fluorescence microscopy of mitochondrial morphology","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods in a single study with defined molecular and cellular phenotypes; broadly consistent with yeast and subsequent human studies","pmids":["18678873"],"is_preprint":false},{"year":2009,"finding":"Purified human SUV3 dimer and PNPase trimer form a 330-kDa heteropentamer (2 SUV3 + 3 PNPase) that degrades double-stranded RNA with 3'-to-5' directionality and preference for substrates with 3' overhang, in an ATP-dependent manner; deletion of SUV3 residues 510-514 abolishes stable complex formation and dsRNA degradation but not helicase activity; ATPase-dead or RNA-binding-dead SUV3 mutants can still bind PNPase but the resulting complexes fail to degrade dsRNA, establishing that intact helicase activity is essential for degradosome function.","method":"Purified protein reconstitution, gel filtration molecular sizing, in vitro RNA degradation assays, site-directed mutagenesis, biochemical interaction assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with purified components, mutagenesis, molecular sizing, and directional RNA degradation assays in a single rigorous study","pmids":["19509288"],"is_preprint":false},{"year":2009,"finding":"Conditional disruption of Supv3L1 in the mouse (using Mx1-Cre or tamoxifen-inducible Esr1/Cre) causes postnatal growth delay, loss of adipose tissue and muscle mass, severe skin abnormalities (ichthyosis, epidermal thickening, dermal atrophy), premature aging, and death; keratinocyte-specific ablation confirms atrophic skin changes, establishing Supv3L1 as essential for skin barrier maintenance.","method":"Conditional gene disruption (Cre/lox), histology, and phenotypic analysis in mice","journal":"Mammalian genome : official journal of the International Mammalian Genome Society","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean conditional KO in multiple tissue contexts with defined phenotypic readouts; replicated with two independent Cre drivers","pmids":["19145458"],"is_preprint":false},{"year":2010,"finding":"Yeast Suv3p acts indirectly through the degradosome (with Dss1p) to promote splicing of the aI5beta group I intron by degrading excised aI5beta ribonucleoprotein (RNP), thereby recycling the limiting splicing cofactor Mrs1p; sequestration of Mrs1p in stable excised intron RNPs accounts for reduced splicing in suv3 mutants.","method":"Genetic epistasis using suv3-1 allele (retains stable mtDNA), overexpression/depletion of Mrs1p, intron RNP analysis, and RNA metabolic assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic and biochemical approaches including epistasis, overexpression rescue, and RNP analysis; provides mechanistic model for indirect splicing role","pmids":["20064926"],"is_preprint":false},{"year":2011,"finding":"SUV3 ATPase-dead (K245A) and CC-region deletion (ΔCC, residues ~511-518) mutants lose both degradosome activity and mtDNA maintenance; V272L (RNA-binding mutant) loses degradosome activity but retains mtDNA maintenance under intronless background; wild-type SUV3 and V272L, but not K245A or ΔCC, associate with active mtDNA replication origins and facilitate mtDNA replication, establishing a direct role for SUV3 in mtDNA maintenance independent of intron turnover that requires intact ATPase activity and the CC region.","method":"Inducible knockdown with structure-function mutagenesis in yeast, intronless mtDNA genetic backgrounds, chromatin immunoprecipitation at mtDNA replication origins","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic mutagenesis with genetic epistasis across multiple alleles and defined mtDNA backgrounds; multiple orthogonal methods","pmids":["21911497"],"is_preprint":false},{"year":2011,"finding":"Human hSuv3 physically interacts with RPA (replication protein A) and FEN1 (flap endonuclease 1) in the nucleus; low amounts of RPA inhibit hSuv3 helicase activity on forked substrates in vitro (while mitochondrial SSB does not, indicating specificity); hSuv3 stimulates FEN1 flap endonuclease activity in vitro independently of flap length.","method":"Co-immunoprecipitation of hSuv3 complexes, in vitro helicase activity assays with RPA or mtSSB, in vitro FEN1 endonuclease stimulation assay","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus in vitro functional assays; single lab, two orthogonal methods","pmids":["21846330"],"is_preprint":false},{"year":2011,"finding":"X-ray crystal structures of human Suv3 in complex with the non-hydrolysable ATP analog AMPPNP (2.08 Å) and with a 5-nucleotide RNA strand (2.9 Å) reveal a four-domain architecture: two RecA-like domains (typical of SF2 helicases) forming a ring with a C-terminal all-helical domain through which the nucleotide strand threads, and an N-terminal helical domain positioned externally; unique structural features suggest Suv3 constitutes a separate helicase subfamily.","method":"X-ray crystallography with functional validation","journal":"Acta crystallographica. Section D, Biological crystallography","confidence":"High","confidence_rationale":"Tier 1 / Strong — two independent crystal structures at near-atomic resolution with AMPPNP and RNA ligands","pmids":["22101826"],"is_preprint":false},{"year":2012,"finding":"Heterozygous mSuv3+/− mice accumulate increased mitochondrial DNA mutations and have decreased mtDNA copy numbers, leading to tumor development at multiple sites and shortened lifespan; these phenotypes are transmitted maternally, demonstrating a causative mitochondrial etiology.","method":"Mouse genetics (heterozygous knockout), mtDNA mutation analysis, mtDNA copy number quantification, tumor histology, maternal transmission analysis","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo animal model with multiple orthogonal readouts (mtDNA mutation, copy number, tumorigenesis, lifespan, maternal transmission)","pmids":["22562243"],"is_preprint":false},{"year":2014,"finding":"SUV3·PNPase complex interacts with mitochondrial polyadenylation polymerase (mtPAP) under low inorganic phosphate (Pi) conditions; SUV3 bridges mtPAP (via SUV3 N-terminal residues ~100-104) and PNPase (via SUV3 C-terminal residues ~510-514) simultaneously; SUV3 enhances mtPAP polyadenylation activity through its ssRNA binding domain; the reconstituted SUV3·PNPase·mtPAP complex (SUV3 dimer + mtPAP dimer + PNPase trimer) can lengthen or shorten mt-mRNA poly(A) tails depending on Pi/ATP ratios; poly(A) tail lengths in cells are modulated by altering mitochondrial matrix Pi via selective inhibition of respiratory chain or ATP synthase.","method":"Purified protein reconstitution, in vitro binding assays with defined SUV3 mutants, molecular sizing, in vitro polyadenylation and RNA degradation assays, cellular Pi manipulation with respiratory chain inhibitors","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with mutagenesis to map binding sites, multiple functional assays, and cellular validation; single lab but multiple orthogonal methods","pmids":["24770417"],"is_preprint":false},{"year":2014,"finding":"Human hSuv3 helicase and ATPase activities are strictly dependent on specific divalent cations; multiple NTPs and dNTPs can support helicase activity at low concentrations (cofactor-dependent), but only ATP supports helicase activity at higher nucleotide concentrations, suggesting that hSuv3 DNA unwinding capacity is sensitive to local inorganic cofactor availability.","method":"In vitro biochemical helicase and ATPase assays with varied divalent cations and nucleotide cofactors","journal":"Biochimie","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro biochemical characterization; single lab, single method type","pmids":["25446650"],"is_preprint":false},{"year":2015,"finding":"Loss of dmsuv3 (Drosophila SUV3) causes accumulation of mitochondrial mRNAs without increasing rRNA levels, severe decrease in mitochondrial tRNAs with accumulation of unprocessed polycistronic precursor transcripts, reduced mitochondrial translation, respiratory chain complex deficiency, and pupal lethality; these processing defects occur independently of PNPase, establishing SUV3 as predominantly required for processing of mitochondrial polycistronic transcripts in metazoans.","method":"Drosophila loss-of-function genetics, Northern blotting, mitochondrial translation assay, respiratory chain complex activity measurement","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic model in Drosophila with multiple orthogonal molecular readouts; extends function to metazoan context","pmids":["26152302"],"is_preprint":false},{"year":2017,"finding":"Human SUV3 helicase localizes to HeLa cell nucleoli (in addition to mitochondria); nuclear-targeted SUV3 constructs establish that the cell growth rate impairment upon SUV3 depletion is due to nuclear (not mitochondrial) SUV3 function; SUV3 is not detectable in DNA-repair foci.","method":"Fluorescence microscopy with nuclear-targeted SUV3 constructs, siRNA knockdown with cell growth assays, co-localization with nucleolar markers","journal":"Acta biochimica Polonica","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization with nuclear-targeted constructs to dissect nuclear vs. mitochondrial function; single lab, moderate follow-up","pmids":["28291845"],"is_preprint":false},{"year":2018,"finding":"The mitochondrial degradosome (SUV3·PNPase) together with the G-quadruplex-melting protein GRSF1 restricts mitochondrial antisense RNAs, including those forming G-quadruplex structures.","method":"Molecular and biochemical characterization of SUV3-PNPase-GRSF1 complex activity on antisense mt-RNAs","journal":"Molecular & cellular oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — abstract provides limited methodological detail; single lab report","pmids":["30525095"],"is_preprint":false},{"year":2022,"finding":"Dimeric assembly of human Suv3 via its C-terminal tail (CTT) is required for efficient RNA unwinding: CTT-truncated monomeric Suv3 (Suv3ΔC) has ~6-7-fold lower RNA binding and unwinding activities, cannot bind RNA independently of ATP/ADP, and fails to interact with PNPase; crystal structure of apo-Suv3ΔC and SAXS structures of dimeric Suv3 and PNPase-Suv3 complex show dimeric Suv3 caps on top of PNPase via S1 domain interactions forming a dumbbell-shaped degradosome.","method":"Mutagenesis of CTT domain, in vitro RNA binding and unwinding assays, crystal structure of truncation mutant, SAXS of native complexes, PNPase binding assay","journal":"Protein science : a publication of the Protein Society","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure + SAXS + mutagenesis + multiple in vitro functional assays in one study; rigorous multi-method approach","pmids":["35481630"],"is_preprint":false},{"year":2022,"finding":"A homozygous truncating SUPV3L1 mutation in two siblings causes mitochondrial RNA processing defects including reduction of mature ND6 mRNA and accumulation of double-stranded RNA in patient fibroblasts; lentiviral complementation with full-length SUPV3L1 cDNA partly restores these RNA phenotypes, confirming pathogenicity.","method":"Patient fibroblast analysis, RT-PCR/Northern blot for mt-RNA processing, dsRNA immunostaining, lentiviral cDNA complementation","journal":"Journal of inherited metabolic disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic disease model with complementation rescue; multiple RNA readouts, single lab","pmids":["35023579"],"is_preprint":false},{"year":2025,"finding":"SUPV3L1 and endoribonuclease ELAC2 form a conserved complex that rapidly degrades mitochondria-encoded circular RNAs (mecciRNAs); SUV3 knockdown leads to accumulation of mitochondrial dsRNAs that escape to the cytosol and activate PKR, triggering type I IFN signaling and proinflammatory cytokine production; this PKR activation accounts for impaired innate immune functions (migration, phagocytosis, ATP synthesis) in SUV3-deficient monocytes, reversible by PKR co-knockdown.","method":"Protein complex identification, siRNA knockdown, fCLIP-qPCR for dsRNA-PKR interaction, TEM for subcellular localization of dsRNAs, cytokine assays, functional assays (migration, phagocytosis, ATP synthesis), rescue by PKR co-knockdown","journal":"Circulation / Rheumatology (Oxford, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (complex identification, fCLIP, TEM, functional rescue); two independent studies; single method per step","pmids":["39973625","40268748"],"is_preprint":false},{"year":2024,"finding":"SUV3 knockdown in hepatocellular carcinoma cells reduces mtDNA copy number, causes mtDNA leakage into the cytoplasm, and elevates PD-L1 expression; TREX1 overexpression in SUV3-knockdown cells reduces cytoplasmic mtDNA and suppresses the PD-L1 induction, establishing that cytoplasmic mtDNA accumulation mediates the PD-L1 upregulation.","method":"siRNA knockdown, subcellular fractionation for mtDNA quantification, qRT-PCR for PD-L1, TREX1 overexpression rescue experiment","journal":"Zhonghua gan zang bing za zhi","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic rescue experiment linking cytoplasmic mtDNA to PD-L1; single lab with mechanistic pathway placement","pmids":["39267568"],"is_preprint":false},{"year":2026,"finding":"Cryo-EM structures of human Suv3 in four functional states (apo, ADP-bound, ssRNA-bound, ssRNA+AMP-PNP-bound) at near-atomic resolution reveal an asymmetric dimeric organization in which only one protomer engages ADP, ssRNA, or both ssRNA and AMP-PNP in initial binding; biochemical analyses confirm that dimerization enhances RNA-binding and unwinding efficiency in an ATP-hydrolysis-dependent manner, establishing the mechanistic basis for processive RNA unwinding.","method":"Cryo-EM structure determination in four functional states, biochemical RNA-binding and unwinding assays with wild-type and mutant Suv3","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — near-atomic-resolution cryo-EM structures in multiple functional states combined with complementary biochemical validation; rigorous multi-method single study","pmids":["41986356"],"is_preprint":false},{"year":2024,"finding":"Depletion of SUV3 helicase triggers formation of distinct mitochondrial RNA granules (termed inhibition granules) that differ from canonical mitochondrial RNA granules; these granules stabilize certain mt-mRNAs and appear to serve a protective function during transcription inhibition.","method":"Single-molecule RNA-FISH after SUV3 depletion, comparison with canonical MRG markers","journal":"bioRxiv (preprint)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single preprint, single method (smRNA-FISH), no complementation or mechanistic dissection of granule formation","pmids":["bio_10.1101_2024.09.25.614902"],"is_preprint":true}],"current_model":"SUPV3L1/SUV3 is a nuclear-encoded, predominantly mitochondria-localized ATP-dependent RNA/DNA helicase of the SF2/DExH-box family that forms the core of the mitochondrial degradosome: as a homodimer (assembled via its C-terminal tail, with an asymmetric active architecture revealed by cryo-EM), it binds PNPase (via residues ~510-514) to form a 330-kDa heteropentamer that degrades structured and double-stranded RNA 3'→5'; it also bridges mtPAP (via residues ~100-104) in a transient trimeric complex that adjusts mt-mRNA poly(A) tail lengths in response to changes in mitochondrial Pi/ATP ratios; in the nucleus SUV3 interacts with BLM, WRN, RPA, and FEN1 and suppresses homologous recombination; SUV3 also works with ELAC2 to degrade mitochondrial circular RNAs (mecciRNAs), and its loss causes accumulation of mitochondrial dsRNAs that escape to the cytosol, activate PKR-mediated innate immune signaling, and induce mtDNA leakage-dependent PD-L1 upregulation; collectively, SUV3 is essential for mitochondrial RNA processing, mtDNA stability, and cellular homeostasis, with haploinsufficiency leading to mtDNA mutations, tumorigenesis, and premature aging in mice."},"narrative":{"mechanistic_narrative":"SUPV3L1 (SUV3) is a nuclear-encoded, ATP-dependent RNA/DNA helicase of the SF2 family that is the central determinant of mitochondrial post-transcriptional RNA metabolism, first defined in yeast where loss-of-function alters splicing and stability of intron-containing mitochondrial transcripts and the protein carries a mitochondrial targeting presequence with conserved helicase motifs [PMID:1379722, PMID:2158076, PMID:8529267]. Crystal and cryo-EM structures define a four-domain architecture — two RecA-like domains, a C-terminal helical domain through which substrate RNA threads, and an external N-terminal domain — that assembles into an asymmetric homodimer via its C-terminal tail, an arrangement required for efficient, ATP-hydrolysis-dependent processive RNA binding and unwinding [PMID:22101826, PMID:35481630, PMID:41986356]. As the catalytic core of the mitochondrial degradosome, the SUV3 dimer binds the PNPase trimer (through SUV3 residues ~510-514) to form a 330-kDa heteropentamer that degrades structured and double-stranded RNA with 3'→5' directionality, a reaction that requires intact helicase activity [PMID:19509288]; the same complex transiently recruits mtPAP (via SUV3 residues ~100-104) to bidirectionally tune mt-mRNA poly(A) tail length in response to mitochondrial Pi/ATP ratios [PMID:24770417]. Through these activities SUV3 controls processing of mitochondrial polycistronic transcripts, mt-mRNA and tRNA maturation, mtDNA copy number and replication, and overall mitochondrial bioenergetic function [PMID:18678873, PMID:21911497, PMID:26152302]. SUV3 also degrades mitochondria-encoded circular RNAs together with ELAC2, and its loss causes accumulation of mitochondrial double-stranded RNAs that escape to the cytosol and activate PKR-mediated innate immune and type I interferon signaling, while mtDNA leakage drives PD-L1 upregulation [PMID:39973625, PMID:40268748, PMID:39267568]. A distinct nuclear/nucleolar pool of SUV3 interacts with the BLM and WRN helicases and with RPA and FEN1 and suppresses homologous recombination, contributing to genome stability [PMID:17961633, PMID:21846330, PMID:28291845]. In vivo, Supv3L1 is essential: conditional disruption causes premature aging and skin barrier failure, and heterozygous mice accumulate maternally transmitted mtDNA mutations with reduced copy number and develop tumors [PMID:19145458, PMID:22562243]. A homozygous truncating SUPV3L1 mutation causes a human mitochondrial RNA-processing disorder with reduced mature ND6 mRNA and dsRNA accumulation, rescued by cDNA complementation [PMID:35023579].","teleology":[{"year":1992,"claim":"Established the molecular identity of SUV3 as a mitochondrial ATP-dependent RNA helicase and linked a point mutation in a conserved helicase motif to mitochondrial RNA defects, defining the gene's biochemical class.","evidence":"Gene cloning, sequencing, and mutant-allele analysis of the SUV3-1 gain-of-function mutation in yeast","pmids":["1379722","2158076"],"confidence":"High","gaps":["Helicase catalytic activity not demonstrated biochemically on purified protein","Direct RNA substrates not defined"]},{"year":1995,"claim":"Showed SUV3 is required for stability and processing of intron-containing mitochondrial transcripts in an intron-number-dependent manner, framing it as a post-transcriptional RNA stability factor rather than a transcriptional regulator.","evidence":"Northern analysis in yeast strains with defined intron combinations plus SUV3 disruption","pmids":["8529267","7736607"],"confidence":"High","gaps":["Mechanism distinguishing direct turnover from indirect effects not resolved","rRNA processing role from single intron background"]},{"year":1999,"claim":"Identified human SUPV3L1 as the conserved orthologue with a mitochondrial leader sequence, extending the yeast function to a candidate human mitochondrial helicase.","evidence":"cDNA cloning, sequencing, Northern and EST analysis","pmids":["10453991"],"confidence":"Medium","gaps":["No functional assay of the human protein","Subcellular localization inferred from sequence only"]},{"year":2007,"claim":"Revealed an unexpected nuclear pool of human SUV3 and its interaction with RecQ helicases BLM and WRN, implicating it in genome stability and HR suppression beyond mitochondria.","evidence":"siRNA knockdown with apoptosis/cell-cycle assays, ELISA binding, and sister chromatid exchange assays in HeLa cells","pmids":["17352692","17961633"],"confidence":"Medium","gaps":["Co-IP/ELISA without structural mapping of interaction interfaces","Whether nuclear effects are direct or secondary to mitochondrial dysfunction unresolved"]},{"year":2008,"claim":"Demonstrated that loss of human SUV3 causes shortened polyadenylated mt-RNAs and broad bioenergetic collapse, establishing its essential role in mammalian mitochondrial RNA metabolism and cell viability.","evidence":"siRNA knockdown with mt-RNA, protein synthesis, ROS, membrane potential, mtDNA copy number, and morphology assays","pmids":["18678873"],"confidence":"High","gaps":["Direct vs. indirect cause of poly(A) shortening not separated","Enzymatic mechanism not addressed"]},{"year":2009,"claim":"Reconstituted the mitochondrial degradosome, showing the SUV3 dimer and PNPase trimer form a 330-kDa heteropentamer that degrades dsRNA 3'→5' in an ATP- and helicase-activity-dependent manner.","evidence":"Purified protein reconstitution, gel filtration sizing, in vitro RNA degradation, and site-directed mutagenesis (residues 510-514)","pmids":["19509288"],"confidence":"High","gaps":["In vivo substrate repertoire not defined","Regulation of complex assembly in cells unknown"]},{"year":2009,"claim":"Showed in vivo that Supv3L1 is organismally essential, with conditional loss causing premature aging and skin barrier failure.","evidence":"Conditional Cre/lox disruption with histology and phenotyping in mice","pmids":["19145458"],"confidence":"High","gaps":["Molecular link between mitochondrial RNA defects and skin phenotype not delineated","Tissue-specific substrate dependencies unknown"]},{"year":2010,"claim":"Resolved the mechanism of SUV3's splicing role as indirect, via degradosome-mediated turnover of excised intron RNPs that recycle a limiting splicing cofactor.","evidence":"Genetic epistasis with suv3-1, Mrs1p overexpression/depletion, and intron RNP analysis in yeast","pmids":["20064926"],"confidence":"High","gaps":["Generality of cofactor-sequestration model to other introns/organisms untested"]},{"year":2011,"claim":"Separated SUV3's mtDNA maintenance function from intron turnover and tied it to active replication origins, requiring ATPase activity and the CC region but not RNA binding.","evidence":"Inducible knockdown with structure-function mutagenesis (K245A, V272L, ΔCC) and ChIP at mtDNA origins in yeast","pmids":["21911497"],"confidence":"High","gaps":["Direct DNA substrate at origins not biochemically defined","How helicase activity supports replication mechanistically unresolved"]},{"year":2011,"claim":"Connected nuclear SUV3 to replication/repair machinery by demonstrating physical and functional interplay with RPA and FEN1.","evidence":"Co-IP of hSuv3 complexes, in vitro helicase assays with RPA vs mtSSB, and FEN1 stimulation assays","pmids":["21846330"],"confidence":"Medium","gaps":["Single Co-IP without reciprocal in-cell validation of functional consequence","No demonstration that SUV3 acts at nuclear replication forks in vivo"]},{"year":2011,"claim":"Provided the first atomic-resolution architecture of human Suv3, defining a four-domain SF2 fold with an RNA-threading C-terminal domain and assigning it to a distinct helicase subfamily.","evidence":"X-ray crystallography with AMPPNP and RNA ligands plus functional validation","pmids":["22101826"],"confidence":"High","gaps":["Oligomeric/dimeric state and its functional role not captured in monomeric structures"]},{"year":2012,"claim":"Established a causal in vivo link between SUV3 dosage and mtDNA integrity, with haploinsufficiency producing maternally transmitted mtDNA mutations, copy-number loss, tumorigenesis, and shortened lifespan.","evidence":"Heterozygous mouse genetics with mtDNA mutation/copy-number analysis, tumor histology, and maternal transmission","pmids":["22562243"],"confidence":"High","gaps":["Mechanistic chain from mtDNA mutation to specific tumor types not defined"]},{"year":2014,"claim":"Defined a regulatory function for the degradosome in adjusting mt-mRNA poly(A) tail length, with SUV3 simultaneously bridging mtPAP and PNPase to sense the mitochondrial Pi/ATP ratio.","evidence":"Reconstitution of the SUV3·PNPase·mtPAP complex, binding-site mutagenesis (residues 100-104), polyadenylation/degradation assays, and cellular Pi manipulation","pmids":["24770417"],"confidence":"High","gaps":["Physiological signals controlling complex switching in vivo not fully mapped","Which mt-mRNAs are preferentially regulated unresolved"]},{"year":2014,"claim":"Characterized cofactor dependence of human Suv3, showing helicase activity requires specific divalent cations and that only ATP supports activity at high nucleotide concentrations, implying sensitivity to local metabolite availability.","evidence":"In vitro helicase and ATPase assays with varied divalent cations and nucleotides","pmids":["25446650"],"confidence":"Medium","gaps":["In vitro biochemistry; physiological relevance of cofactor sensitivity untested","Single method type"]},{"year":2015,"claim":"Extended SUV3 function to metazoan mitochondrial polycistronic transcript processing, showing tRNA maturation and translation defects that occur independently of PNPase.","evidence":"Drosophila loss-of-function genetics with Northern blotting, translation, and respiratory complex assays","pmids":["26152302"],"confidence":"High","gaps":["PNPase-independent processing mechanism not biochemically defined"]},{"year":2017,"claim":"Localized human SUV3 to nucleoli and attributed the growth defect of SUV3 depletion to nuclear rather than mitochondrial function, while excluding it from DNA-repair foci.","evidence":"Fluorescence microscopy with nuclear-targeted constructs and siRNA growth assays in HeLa cells","pmids":["28291845"],"confidence":"Medium","gaps":["Nucleolar substrate/function of SUV3 unidentified","Reconciliation with reported HR/repair-factor interactions unresolved"]},{"year":2022,"claim":"Defined dimerization via the C-terminal tail as mechanistically required for efficient RNA unwinding and PNPase binding, and described the dumbbell-shaped degradosome architecture.","evidence":"CTT mutagenesis, in vitro RNA binding/unwinding assays, crystal structure of Suv3ΔC, and SAXS of dimeric and PNPase-bound complexes","pmids":["35481630"],"confidence":"High","gaps":["High-resolution structure of the full dimeric degradosome not yet resolved at this stage"]},{"year":2022,"claim":"Provided human disease evidence that biallelic SUPV3L1 loss causes a mitochondrial RNA-processing disorder, with cDNA complementation confirming pathogenicity.","evidence":"Patient fibroblast RNA analysis, dsRNA immunostaining, and lentiviral cDNA complementation rescue","pmids":["35023579"],"confidence":"Medium","gaps":["Only two siblings; phenotypic spectrum and genotype-phenotype range undefined","Partial rescue leaves residual mechanism uncertain"]},{"year":2024,"claim":"Linked SUV3 loss to innate immune dysregulation, showing accumulated mitochondrial dsRNA escapes to the cytosol and activates PKR-driven type I IFN signaling, and that mtDNA leakage drives PD-L1 upregulation.","evidence":"siRNA knockdown, fCLIP-qPCR, TEM, cytokine and functional assays with PKR co-knockdown rescue; mtDNA fractionation with TREX1 overexpression rescue","pmids":["39973625","40268748","39267568"],"confidence":"Medium","gaps":["Single lab per pathway arm","Direct mechanism of dsRNA/mtDNA cytosolic escape not fully defined"]},{"year":2026,"claim":"Defined the structural basis of processive unwinding by capturing asymmetric dimeric Suv3 in four functional states, showing only one protomer initially engages nucleotide/RNA in an ATP-hydrolysis-dependent cycle.","evidence":"Cryo-EM in apo, ADP, ssRNA, and ssRNA+AMP-PNP states with biochemical RNA-binding/unwinding validation","pmids":["41986356"],"confidence":"High","gaps":["Structure of the full degradosome engaging substrate not resolved","Coupling of unwinding to PNPase degradation step not visualized"]},{"year":null,"claim":"How the same protein partitions and coordinates its distinct mitochondrial RNA-degradation/processing roles, its nucleolar/HR-related nuclear functions, and its mtDNA-replication role remains unresolved, as does the in vivo substrate map across compartments.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking nuclear and mitochondrial pools","Nucleolar substrate undefined","Full in vivo mt-RNA substrate repertoire incomplete"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[10,17,19,22,26]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[10,15,22,26]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[10,13,18,26]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[10,18]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[14,18]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,5,9,17]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[7,14]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[20]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[9,10,17,19]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[24]},{"term_id":"R-HSA-69306","term_label":"DNA Replication","supporting_discovery_ids":[13]}],"complexes":["mitochondrial degradosome (SUV3-PNPase)","SUV3-PNPase-mtPAP complex","SUPV3L1-ELAC2 complex"],"partners":["PNPT1","MTPAP","ELAC2","BLM","WRN","RPA","FEN1","GRSF1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8IYB8","full_name":"ATP-dependent RNA helicase SUPV3L1, mitochondrial","aliases":["Suppressor of var1 3-like protein 1","SUV3-like protein 1"],"length_aa":786,"mass_kda":88.0,"function":"Major helicase player in mitochondrial RNA metabolism. Component of the mitochondrial degradosome (mtEXO) complex, that degrades 3' overhang double-stranded RNA with a 3'-to-5' directionality in an ATP-dependent manner. Involved in the degradation of non-coding mitochondrial transcripts (MT-ncRNA) and tRNA-like molecules (PubMed:29967381). ATPase and ATP-dependent multisubstrate helicase, able to unwind double-stranded (ds) DNA and RNA, and RNA/DNA heteroduplexes in the 5'-to-3' direction. Plays a role in the RNA surveillance system in mitochondria; regulates the stability of mature mRNAs, the removal of aberrantly formed mRNAs and the rapid degradation of non coding processing intermediates. Also implicated in recombination and chromatin maintenance pathways. May protect cells from apoptosis. Associates with mitochondrial DNA","subcellular_location":"Nucleus; Mitochondrion matrix; Mitochondrion matrix, mitochondrion nucleoid","url":"https://www.uniprot.org/uniprotkb/Q8IYB8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/SUPV3L1","classification":"Common Essential","n_dependent_lines":1120,"n_total_lines":1208,"dependency_fraction":0.9271523178807947},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SUPV3L1","total_profiled":1310},"omim":[{"mim_id":"605122","title":"SUV3-LIKE 1; SUPV3L1","url":"https://www.omim.org/entry/605122"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Mitochondria","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SUPV3L1"},"hgnc":{"alias_symbol":["SUV3"],"prev_symbol":[]},"alphafold":{"accession":"Q8IYB8","domains":[{"cath_id":"1.10.1740.140","chopping":"62-174","consensus_level":"high","plddt":90.2734,"start":62,"end":174},{"cath_id":"3.40.50.300","chopping":"189-345","consensus_level":"high","plddt":96.5459,"start":189,"end":345},{"cath_id":"3.40.50.300","chopping":"352-500","consensus_level":"high","plddt":90.7919,"start":352,"end":500},{"cath_id":"1.20.58.1080","chopping":"555-685","consensus_level":"medium","plddt":94.8844,"start":555,"end":685}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IYB8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IYB8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IYB8-F1-predicted_aligned_error_v6.png","plddt_mean":83.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SUPV3L1","jax_strain_url":"https://www.jax.org/strain/search?query=SUPV3L1"},"sequence":{"accession":"Q8IYB8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IYB8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IYB8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IYB8"}},"corpus_meta":[{"pmid":"1379722","id":"PMC_1379722","title":"The yeast nuclear gene suv3 affecting mitochondrial post-transcriptional processes encodes a putative ATP-dependent RNA helicase.","date":"1992","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/1379722","citation_count":91,"is_preprint":false},{"pmid":"19509288","id":"PMC_19509288","title":"Human mitochondrial SUV3 and polynucleotide phosphorylase form a 330-kDa heteropentamer to cooperatively degrade double-stranded RNA with a 3'-to-5' directionality.","date":"2009","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19509288","citation_count":88,"is_preprint":false},{"pmid":"2158076","id":"PMC_2158076","title":"The nuclear SUV3-1 mutation affects a variety of post-transcriptional processes in yeast mitochondria.","date":"1990","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/2158076","citation_count":59,"is_preprint":false},{"pmid":"18678873","id":"PMC_18678873","title":"Role of SUV3 helicase in maintaining mitochondrial homeostasis in human cells.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18678873","citation_count":48,"is_preprint":false},{"pmid":"10453991","id":"PMC_10453991","title":"A human putative Suv3-like RNA helicase is conserved between Rhodobacter and all eukaryotes.","date":"1999","source":"Acta biochimica Polonica","url":"https://pubmed.ncbi.nlm.nih.gov/10453991","citation_count":41,"is_preprint":false},{"pmid":"8529267","id":"PMC_8529267","title":"The S. cerevisiae nuclear gene SUV3 encoding a putative RNA helicase is necessary for the stability of mitochondrial transcripts containing multiple introns.","date":"1995","source":"Current genetics","url":"https://pubmed.ncbi.nlm.nih.gov/8529267","citation_count":41,"is_preprint":false},{"pmid":"22562243","id":"PMC_22562243","title":"Mitochondrial genome instability resulting from SUV3 haploinsufficiency leads to tumorigenesis and shortened lifespan.","date":"2012","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/22562243","citation_count":32,"is_preprint":false},{"pmid":"17352692","id":"PMC_17352692","title":"Down-regulation of human RNA/DNA helicase SUV3 induces apoptosis by a caspase- and AIF-dependent pathway.","date":"2007","source":"Biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/17352692","citation_count":31,"is_preprint":false},{"pmid":"24770417","id":"PMC_24770417","title":"Helicase SUV3, polynucleotide phosphorylase, and mitochondrial polyadenylation polymerase form a transient complex to modulate mitochondrial mRNA polyadenylated tail lengths in response to energetic changes.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24770417","citation_count":29,"is_preprint":false},{"pmid":"17961633","id":"PMC_17961633","title":"Interaction of human SUV3 RNA/DNA helicase with BLM helicase; loss of the SUV3 gene results in mouse embryonic lethality.","date":"2007","source":"Mechanisms of ageing and development","url":"https://pubmed.ncbi.nlm.nih.gov/17961633","citation_count":27,"is_preprint":false},{"pmid":"7736607","id":"PMC_7736607","title":"The suv3 nuclear gene product is required for the in vivo processing of the yeast mitochondrial 21s rRNA transcripts containing the r1 intron.","date":"1995","source":"Current genetics","url":"https://pubmed.ncbi.nlm.nih.gov/7736607","citation_count":26,"is_preprint":false},{"pmid":"26152302","id":"PMC_26152302","title":"SUV3 helicase is required for correct processing of mitochondrial transcripts.","date":"2015","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/26152302","citation_count":22,"is_preprint":false},{"pmid":"10397341","id":"PMC_10397341","title":"Yeast nuclear PET127 gene can suppress deletions of the SUV3 or DSS1 genes: an indication of a functional interaction between 3' and 5' ends of mitochondrial mRNAs.","date":"1998","source":"Acta biochimica Polonica","url":"https://pubmed.ncbi.nlm.nih.gov/10397341","citation_count":20,"is_preprint":false},{"pmid":"20064926","id":"PMC_20064926","title":"Splicing of yeast aI5beta group I intron requires SUV3 to recycle MRS1 via mitochondrial degradosome-promoted decay of excised intron ribonucleoprotein (RNP).","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20064926","citation_count":20,"is_preprint":false},{"pmid":"39973625","id":"PMC_39973625","title":"Fast Degradation of MecciRNAs by SUPV3L1/ELAC2 Provides a Novel Opportunity to Tackle Heart Failure With Exogenous MecciRNA.","date":"2025","source":"Circulation","url":"https://pubmed.ncbi.nlm.nih.gov/39973625","citation_count":19,"is_preprint":false},{"pmid":"21911497","id":"PMC_21911497","title":"Uncoupling the roles of the SUV3 helicase in maintenance of mitochondrial genome stability and RNA degradation.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21911497","citation_count":19,"is_preprint":false},{"pmid":"30525095","id":"PMC_30525095","title":"Controlling the mitochondrial antisense - role of the SUV3-PNPase complex and its co-factor GRSF1 in mitochondrial RNA surveillance.","date":"2018","source":"Molecular & cellular oncology","url":"https://pubmed.ncbi.nlm.nih.gov/30525095","citation_count":19,"is_preprint":false},{"pmid":"12402239","id":"PMC_12402239","title":"Overexpressed yeast mitochondrial putative RNA helicase Mss116 partially restores proper mtRNA metabolism in strains lacking the Suv3 mtRNA helicase.","date":"2002","source":"Yeast (Chichester, England)","url":"https://pubmed.ncbi.nlm.nih.gov/12402239","citation_count":19,"is_preprint":false},{"pmid":"21846330","id":"PMC_21846330","title":"The human Suv3 helicase interacts with replication protein A and flap endonuclease 1 in the nucleus.","date":"2011","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/21846330","citation_count":18,"is_preprint":false},{"pmid":"19145458","id":"PMC_19145458","title":"Disruption of Supv3L1 damages the skin and causes sarcopenia, loss of fat, and death.","date":"2009","source":"Mammalian genome : official journal of the International Mammalian Genome Society","url":"https://pubmed.ncbi.nlm.nih.gov/19145458","citation_count":17,"is_preprint":false},{"pmid":"22101826","id":"PMC_22101826","title":"Human Suv3 protein reveals unique features among SF2 helicases.","date":"2011","source":"Acta crystallographica. Section D, Biological crystallography","url":"https://pubmed.ncbi.nlm.nih.gov/22101826","citation_count":13,"is_preprint":false},{"pmid":"35023579","id":"PMC_35023579","title":"Mitochondrial RNA processing defect caused by a SUPV3L1 mutation in two siblings with a novel neurodegenerative syndrome.","date":"2022","source":"Journal of inherited metabolic disease","url":"https://pubmed.ncbi.nlm.nih.gov/35023579","citation_count":12,"is_preprint":false},{"pmid":"35481630","id":"PMC_35481630","title":"Dimeric assembly of human Suv3 helicase promotes its RNA unwinding function in mitochondrial RNA degradosome for RNA decay.","date":"2022","source":"Protein science : a publication of the Protein Society","url":"https://pubmed.ncbi.nlm.nih.gov/35481630","citation_count":11,"is_preprint":false},{"pmid":"25311683","id":"PMC_25311683","title":"Rice SUV3 is a bidirectional helicase that binds both DNA and RNA.","date":"2014","source":"BMC plant biology","url":"https://pubmed.ncbi.nlm.nih.gov/25311683","citation_count":8,"is_preprint":false},{"pmid":"14734028","id":"PMC_14734028","title":"The SUV3 gene from Saccharomyces douglasii is a functional equivalent of its Saccharomyces cerevisiae orthologue and is essential for respiratory growth.","date":"2004","source":"FEMS yeast research","url":"https://pubmed.ncbi.nlm.nih.gov/14734028","citation_count":7,"is_preprint":false},{"pmid":"25303666","id":"PMC_25303666","title":"Salt tolerant SUV3 overexpressing transgenic rice plants conserve physicochemical properties and microbial communities of rhizosphere.","date":"2014","source":"Chemosphere","url":"https://pubmed.ncbi.nlm.nih.gov/25303666","citation_count":6,"is_preprint":false},{"pmid":"27586643","id":"PMC_27586643","title":"Overexpression of PDH45 or SUV3 helicases in rice leads to delayed leaf senescence-associated events.","date":"2016","source":"Protoplasma","url":"https://pubmed.ncbi.nlm.nih.gov/27586643","citation_count":4,"is_preprint":false},{"pmid":"19937380","id":"PMC_19937380","title":"Widespread expression of the Supv3L1 mitochondrial RNA helicase in the mouse.","date":"2009","source":"Transgenic research","url":"https://pubmed.ncbi.nlm.nih.gov/19937380","citation_count":3,"is_preprint":false},{"pmid":"37298184","id":"PMC_37298184","title":"SUV3 Helicase and Mitochondrial Homeostasis.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37298184","citation_count":2,"is_preprint":false},{"pmid":"28291845","id":"PMC_28291845","title":"Human SUV3 helicase regulates growth rate of the HeLa cells and can localize in the nucleoli.","date":"2017","source":"Acta biochimica Polonica","url":"https://pubmed.ncbi.nlm.nih.gov/28291845","citation_count":2,"is_preprint":false},{"pmid":"40268748","id":"PMC_40268748","title":"Diminished SUV3 expression and its functional implications in the IFN-enriched monocyte subset of childhood Sjögren's disease.","date":"2025","source":"Rheumatology (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/40268748","citation_count":1,"is_preprint":false},{"pmid":"25446650","id":"PMC_25446650","title":"Regulation of the human Suv3 helicase on DNA by inorganic cofactors.","date":"2014","source":"Biochimie","url":"https://pubmed.ncbi.nlm.nih.gov/25446650","citation_count":1,"is_preprint":false},{"pmid":"39596606","id":"PMC_39596606","title":"A New Case of Mitochondrial RNA Helicase SUPV3L1-Associated Neurodegenerative Disease: Ataxia, Spasticity, Optic Atrophy, and Skin Hypopigmentation (ASOASH).","date":"2024","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/39596606","citation_count":1,"is_preprint":false},{"pmid":"39267568","id":"PMC_39267568","title":"[SUV3 knockdown inhibits proliferation, migration, and invasion of hepatocellular carcinoma cells and induces PD-L1 expression].","date":"2024","source":"Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/39267568","citation_count":0,"is_preprint":false},{"pmid":"41986356","id":"PMC_41986356","title":"Asymmetric dimeric assembly of Suv3 helicase facilitates processive RNA unwinding.","date":"2026","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/41986356","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.09.25.614902","title":"Transcription arrest induces formation of protective RNA granules in mitochondria","date":"2024-09-26","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.25.614902","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":18487,"output_tokens":7230,"usd":0.081956,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":16589,"output_tokens":6190,"usd":0.118847,"stage2_stop_reason":"end_turn"},"total_usd":0.200803,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1992,\n      \"finding\": \"The yeast SUV3 gene encodes an 84-kDa protein with a mitochondrial targeting presequence and conserved sequence motifs of ATP-dependent RNA helicases; the SUV3-1 gain-of-function mutation is a Val→Leu substitution in a conserved helicase motif block, causing accumulation of excised group I introns in mitochondria.\",\n      \"method\": \"Gene cloning by colony Northern hybridization, sequence analysis, and mutant allele identification\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct cloning and sequencing with mutant allele identification; foundational paper replicated by subsequent studies\",\n      \"pmids\": [\"1379722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"The SUV3-1 mutation causes over-accumulation of excised group I intron RNAs, lowers levels of cob and cox1 mRNAs, and blocks dodecamer cleavage in yeast mitochondria, establishing SUV3 as a key regulator of mitochondrial post-transcriptional processes including RNA stability and splicing.\",\n      \"method\": \"Northern hybridization survey of mitochondrial RNAs in SUV3-1 and suv3 deletion strains\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic Northern blotting across multiple mitochondrial genes; replicated and extended by later studies\",\n      \"pmids\": [\"2158076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"SUV3 is required for stability of intron-containing mitochondrial transcripts in a cumulative manner depending on intron number; loss of SUV3 decreases mRNA levels without accumulating high-molecular-weight precursors or affecting transcription.\",\n      \"method\": \"Northern hybridization of mitochondrial RNAs in strains with defined combinations of cytb and cox1 introns combined with SUV3 gene disruption\",\n      \"journal\": \"Current genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic genetic epistasis with controlled mitochondrial genome backgrounds; replicated across multiple intron combinations\",\n      \"pmids\": [\"8529267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"The suv3 protein is required for proper processing of r1 intron-containing 21S rRNA transcripts; in its absence, the excised r1 intron pattern is altered and mature 21S rRNA is ~50-fold reduced.\",\n      \"method\": \"Northern analysis of mitochondrial RNA in suv3 disruption strain carrying r1-only intron genome\",\n      \"journal\": \"Current genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — single lab, clean genetic system with Northern analysis, one defined intron background\",\n      \"pmids\": [\"7736607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The PET127 gene (involved in 5'-end processing of mitochondrial mRNAs) can suppress SUV3 or DSS1 gene disruptions, suggesting functional coupling between 5' and 3' ends of mitochondrial mRNAs and placing SUV3/DSS1 degradosome activity in a pathway coordinated with 5'-end processing.\",\n      \"method\": \"Genetic suppression by PET127 on low- and high-copy vectors in SUV3/DSS1 disruption strains\",\n      \"journal\": \"Acta biochimica Polonica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean epistasis by genetic suppression; single lab, single method\",\n      \"pmids\": [\"10397341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Human SUPV3L1 (hSUV3) encodes a protein with a mitochondrial leader sequence that is the human homologue of yeast Suv3 helicase, conserved across eukaryotes and Rhodobacter sphaeroides.\",\n      \"method\": \"cDNA cloning, sequencing, Northern blot, and EST database analysis\",\n      \"journal\": \"Acta biochimica Polonica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct cDNA cloning with sequence and expression analysis; single lab\",\n      \"pmids\": [\"10453991\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Overexpression of the yeast mitochondrial helicase Mss116 can partially suppress the loss of SUV3, restoring respiratory competence and normalizing COB and ATP6/8 mRNA levels, indicating functional overlap between these two distinct RNA helicase classes in mitochondrial RNA metabolism.\",\n      \"method\": \"Multicopy plasmid suppression, respiratory growth assays, and Northern blotting in SUV3-deleted strains\",\n      \"journal\": \"Yeast (Chichester, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic suppression with molecular readouts; single lab\",\n      \"pmids\": [\"12402239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Human SUV3 localizes not only to mitochondria but also to the nucleus; siRNA-mediated knockdown in HeLa cells causes cell cycle perturbations, p53 induction, and both AIF-dependent and caspase-dependent apoptosis.\",\n      \"method\": \"siRNA knockdown, cell cycle analysis, apoptosis assays (AIF and caspase pathway), subcellular fractionation/localization\",\n      \"journal\": \"Biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with defined cellular phenotypes and pathway placement; single lab\",\n      \"pmids\": [\"17352692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Human SUV3 protein physically interacts with BLM helicase (Kd ~0.5 nM) and WRN helicase (Kd ~5 nM) as measured by ELISA binding assay; SUV3 knockdown in HeLa cells elevates sister chromatid exchange frequency, indicating a role in homologous recombination suppression.\",\n      \"method\": \"ELISA binding assay for protein-protein interaction, sister chromatid exchange assay after siRNA knockdown\",\n      \"journal\": \"Mechanisms of ageing and development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assay with Kd measurement plus functional SCE assay; single lab, two orthogonal methods\",\n      \"pmids\": [\"17961633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Knockdown of hSUV3 in mammalian cells causes accumulation of shortened polyadenylated mitochondrial RNA species, impaired mitochondrial protein synthesis, increased reactive oxygen species, decreased membrane potential and ATP production, reduced mtDNA copy number, and shift of mitochondrial morphology from tubular to granular, leading to senescence or cell death.\",\n      \"method\": \"siRNA knockdown, mitochondrial RNA analysis, protein synthesis assay, ROS measurement, membrane potential assay, mtDNA copy number quantification, fluorescence microscopy of mitochondrial morphology\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods in a single study with defined molecular and cellular phenotypes; broadly consistent with yeast and subsequent human studies\",\n      \"pmids\": [\"18678873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Purified human SUV3 dimer and PNPase trimer form a 330-kDa heteropentamer (2 SUV3 + 3 PNPase) that degrades double-stranded RNA with 3'-to-5' directionality and preference for substrates with 3' overhang, in an ATP-dependent manner; deletion of SUV3 residues 510-514 abolishes stable complex formation and dsRNA degradation but not helicase activity; ATPase-dead or RNA-binding-dead SUV3 mutants can still bind PNPase but the resulting complexes fail to degrade dsRNA, establishing that intact helicase activity is essential for degradosome function.\",\n      \"method\": \"Purified protein reconstitution, gel filtration molecular sizing, in vitro RNA degradation assays, site-directed mutagenesis, biochemical interaction assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with purified components, mutagenesis, molecular sizing, and directional RNA degradation assays in a single rigorous study\",\n      \"pmids\": [\"19509288\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Conditional disruption of Supv3L1 in the mouse (using Mx1-Cre or tamoxifen-inducible Esr1/Cre) causes postnatal growth delay, loss of adipose tissue and muscle mass, severe skin abnormalities (ichthyosis, epidermal thickening, dermal atrophy), premature aging, and death; keratinocyte-specific ablation confirms atrophic skin changes, establishing Supv3L1 as essential for skin barrier maintenance.\",\n      \"method\": \"Conditional gene disruption (Cre/lox), histology, and phenotypic analysis in mice\",\n      \"journal\": \"Mammalian genome : official journal of the International Mammalian Genome Society\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean conditional KO in multiple tissue contexts with defined phenotypic readouts; replicated with two independent Cre drivers\",\n      \"pmids\": [\"19145458\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Yeast Suv3p acts indirectly through the degradosome (with Dss1p) to promote splicing of the aI5beta group I intron by degrading excised aI5beta ribonucleoprotein (RNP), thereby recycling the limiting splicing cofactor Mrs1p; sequestration of Mrs1p in stable excised intron RNPs accounts for reduced splicing in suv3 mutants.\",\n      \"method\": \"Genetic epistasis using suv3-1 allele (retains stable mtDNA), overexpression/depletion of Mrs1p, intron RNP analysis, and RNA metabolic assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic and biochemical approaches including epistasis, overexpression rescue, and RNP analysis; provides mechanistic model for indirect splicing role\",\n      \"pmids\": [\"20064926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SUV3 ATPase-dead (K245A) and CC-region deletion (ΔCC, residues ~511-518) mutants lose both degradosome activity and mtDNA maintenance; V272L (RNA-binding mutant) loses degradosome activity but retains mtDNA maintenance under intronless background; wild-type SUV3 and V272L, but not K245A or ΔCC, associate with active mtDNA replication origins and facilitate mtDNA replication, establishing a direct role for SUV3 in mtDNA maintenance independent of intron turnover that requires intact ATPase activity and the CC region.\",\n      \"method\": \"Inducible knockdown with structure-function mutagenesis in yeast, intronless mtDNA genetic backgrounds, chromatin immunoprecipitation at mtDNA replication origins\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic mutagenesis with genetic epistasis across multiple alleles and defined mtDNA backgrounds; multiple orthogonal methods\",\n      \"pmids\": [\"21911497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Human hSuv3 physically interacts with RPA (replication protein A) and FEN1 (flap endonuclease 1) in the nucleus; low amounts of RPA inhibit hSuv3 helicase activity on forked substrates in vitro (while mitochondrial SSB does not, indicating specificity); hSuv3 stimulates FEN1 flap endonuclease activity in vitro independently of flap length.\",\n      \"method\": \"Co-immunoprecipitation of hSuv3 complexes, in vitro helicase activity assays with RPA or mtSSB, in vitro FEN1 endonuclease stimulation assay\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus in vitro functional assays; single lab, two orthogonal methods\",\n      \"pmids\": [\"21846330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"X-ray crystal structures of human Suv3 in complex with the non-hydrolysable ATP analog AMPPNP (2.08 Å) and with a 5-nucleotide RNA strand (2.9 Å) reveal a four-domain architecture: two RecA-like domains (typical of SF2 helicases) forming a ring with a C-terminal all-helical domain through which the nucleotide strand threads, and an N-terminal helical domain positioned externally; unique structural features suggest Suv3 constitutes a separate helicase subfamily.\",\n      \"method\": \"X-ray crystallography with functional validation\",\n      \"journal\": \"Acta crystallographica. Section D, Biological crystallography\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — two independent crystal structures at near-atomic resolution with AMPPNP and RNA ligands\",\n      \"pmids\": [\"22101826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Heterozygous mSuv3+/− mice accumulate increased mitochondrial DNA mutations and have decreased mtDNA copy numbers, leading to tumor development at multiple sites and shortened lifespan; these phenotypes are transmitted maternally, demonstrating a causative mitochondrial etiology.\",\n      \"method\": \"Mouse genetics (heterozygous knockout), mtDNA mutation analysis, mtDNA copy number quantification, tumor histology, maternal transmission analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo animal model with multiple orthogonal readouts (mtDNA mutation, copy number, tumorigenesis, lifespan, maternal transmission)\",\n      \"pmids\": [\"22562243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SUV3·PNPase complex interacts with mitochondrial polyadenylation polymerase (mtPAP) under low inorganic phosphate (Pi) conditions; SUV3 bridges mtPAP (via SUV3 N-terminal residues ~100-104) and PNPase (via SUV3 C-terminal residues ~510-514) simultaneously; SUV3 enhances mtPAP polyadenylation activity through its ssRNA binding domain; the reconstituted SUV3·PNPase·mtPAP complex (SUV3 dimer + mtPAP dimer + PNPase trimer) can lengthen or shorten mt-mRNA poly(A) tails depending on Pi/ATP ratios; poly(A) tail lengths in cells are modulated by altering mitochondrial matrix Pi via selective inhibition of respiratory chain or ATP synthase.\",\n      \"method\": \"Purified protein reconstitution, in vitro binding assays with defined SUV3 mutants, molecular sizing, in vitro polyadenylation and RNA degradation assays, cellular Pi manipulation with respiratory chain inhibitors\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with mutagenesis to map binding sites, multiple functional assays, and cellular validation; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"24770417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Human hSuv3 helicase and ATPase activities are strictly dependent on specific divalent cations; multiple NTPs and dNTPs can support helicase activity at low concentrations (cofactor-dependent), but only ATP supports helicase activity at higher nucleotide concentrations, suggesting that hSuv3 DNA unwinding capacity is sensitive to local inorganic cofactor availability.\",\n      \"method\": \"In vitro biochemical helicase and ATPase assays with varied divalent cations and nucleotide cofactors\",\n      \"journal\": \"Biochimie\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro biochemical characterization; single lab, single method type\",\n      \"pmids\": [\"25446650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Loss of dmsuv3 (Drosophila SUV3) causes accumulation of mitochondrial mRNAs without increasing rRNA levels, severe decrease in mitochondrial tRNAs with accumulation of unprocessed polycistronic precursor transcripts, reduced mitochondrial translation, respiratory chain complex deficiency, and pupal lethality; these processing defects occur independently of PNPase, establishing SUV3 as predominantly required for processing of mitochondrial polycistronic transcripts in metazoans.\",\n      \"method\": \"Drosophila loss-of-function genetics, Northern blotting, mitochondrial translation assay, respiratory chain complex activity measurement\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic model in Drosophila with multiple orthogonal molecular readouts; extends function to metazoan context\",\n      \"pmids\": [\"26152302\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Human SUV3 helicase localizes to HeLa cell nucleoli (in addition to mitochondria); nuclear-targeted SUV3 constructs establish that the cell growth rate impairment upon SUV3 depletion is due to nuclear (not mitochondrial) SUV3 function; SUV3 is not detectable in DNA-repair foci.\",\n      \"method\": \"Fluorescence microscopy with nuclear-targeted SUV3 constructs, siRNA knockdown with cell growth assays, co-localization with nucleolar markers\",\n      \"journal\": \"Acta biochimica Polonica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization with nuclear-targeted constructs to dissect nuclear vs. mitochondrial function; single lab, moderate follow-up\",\n      \"pmids\": [\"28291845\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The mitochondrial degradosome (SUV3·PNPase) together with the G-quadruplex-melting protein GRSF1 restricts mitochondrial antisense RNAs, including those forming G-quadruplex structures.\",\n      \"method\": \"Molecular and biochemical characterization of SUV3-PNPase-GRSF1 complex activity on antisense mt-RNAs\",\n      \"journal\": \"Molecular & cellular oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — abstract provides limited methodological detail; single lab report\",\n      \"pmids\": [\"30525095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Dimeric assembly of human Suv3 via its C-terminal tail (CTT) is required for efficient RNA unwinding: CTT-truncated monomeric Suv3 (Suv3ΔC) has ~6-7-fold lower RNA binding and unwinding activities, cannot bind RNA independently of ATP/ADP, and fails to interact with PNPase; crystal structure of apo-Suv3ΔC and SAXS structures of dimeric Suv3 and PNPase-Suv3 complex show dimeric Suv3 caps on top of PNPase via S1 domain interactions forming a dumbbell-shaped degradosome.\",\n      \"method\": \"Mutagenesis of CTT domain, in vitro RNA binding and unwinding assays, crystal structure of truncation mutant, SAXS of native complexes, PNPase binding assay\",\n      \"journal\": \"Protein science : a publication of the Protein Society\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure + SAXS + mutagenesis + multiple in vitro functional assays in one study; rigorous multi-method approach\",\n      \"pmids\": [\"35481630\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A homozygous truncating SUPV3L1 mutation in two siblings causes mitochondrial RNA processing defects including reduction of mature ND6 mRNA and accumulation of double-stranded RNA in patient fibroblasts; lentiviral complementation with full-length SUPV3L1 cDNA partly restores these RNA phenotypes, confirming pathogenicity.\",\n      \"method\": \"Patient fibroblast analysis, RT-PCR/Northern blot for mt-RNA processing, dsRNA immunostaining, lentiviral cDNA complementation\",\n      \"journal\": \"Journal of inherited metabolic disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic disease model with complementation rescue; multiple RNA readouts, single lab\",\n      \"pmids\": [\"35023579\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SUPV3L1 and endoribonuclease ELAC2 form a conserved complex that rapidly degrades mitochondria-encoded circular RNAs (mecciRNAs); SUV3 knockdown leads to accumulation of mitochondrial dsRNAs that escape to the cytosol and activate PKR, triggering type I IFN signaling and proinflammatory cytokine production; this PKR activation accounts for impaired innate immune functions (migration, phagocytosis, ATP synthesis) in SUV3-deficient monocytes, reversible by PKR co-knockdown.\",\n      \"method\": \"Protein complex identification, siRNA knockdown, fCLIP-qPCR for dsRNA-PKR interaction, TEM for subcellular localization of dsRNAs, cytokine assays, functional assays (migration, phagocytosis, ATP synthesis), rescue by PKR co-knockdown\",\n      \"journal\": \"Circulation / Rheumatology (Oxford, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (complex identification, fCLIP, TEM, functional rescue); two independent studies; single method per step\",\n      \"pmids\": [\"39973625\", \"40268748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SUV3 knockdown in hepatocellular carcinoma cells reduces mtDNA copy number, causes mtDNA leakage into the cytoplasm, and elevates PD-L1 expression; TREX1 overexpression in SUV3-knockdown cells reduces cytoplasmic mtDNA and suppresses the PD-L1 induction, establishing that cytoplasmic mtDNA accumulation mediates the PD-L1 upregulation.\",\n      \"method\": \"siRNA knockdown, subcellular fractionation for mtDNA quantification, qRT-PCR for PD-L1, TREX1 overexpression rescue experiment\",\n      \"journal\": \"Zhonghua gan zang bing za zhi\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic rescue experiment linking cytoplasmic mtDNA to PD-L1; single lab with mechanistic pathway placement\",\n      \"pmids\": [\"39267568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Cryo-EM structures of human Suv3 in four functional states (apo, ADP-bound, ssRNA-bound, ssRNA+AMP-PNP-bound) at near-atomic resolution reveal an asymmetric dimeric organization in which only one protomer engages ADP, ssRNA, or both ssRNA and AMP-PNP in initial binding; biochemical analyses confirm that dimerization enhances RNA-binding and unwinding efficiency in an ATP-hydrolysis-dependent manner, establishing the mechanistic basis for processive RNA unwinding.\",\n      \"method\": \"Cryo-EM structure determination in four functional states, biochemical RNA-binding and unwinding assays with wild-type and mutant Suv3\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — near-atomic-resolution cryo-EM structures in multiple functional states combined with complementary biochemical validation; rigorous multi-method single study\",\n      \"pmids\": [\"41986356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Depletion of SUV3 helicase triggers formation of distinct mitochondrial RNA granules (termed inhibition granules) that differ from canonical mitochondrial RNA granules; these granules stabilize certain mt-mRNAs and appear to serve a protective function during transcription inhibition.\",\n      \"method\": \"Single-molecule RNA-FISH after SUV3 depletion, comparison with canonical MRG markers\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single preprint, single method (smRNA-FISH), no complementation or mechanistic dissection of granule formation\",\n      \"pmids\": [\"bio_10.1101_2024.09.25.614902\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"SUPV3L1/SUV3 is a nuclear-encoded, predominantly mitochondria-localized ATP-dependent RNA/DNA helicase of the SF2/DExH-box family that forms the core of the mitochondrial degradosome: as a homodimer (assembled via its C-terminal tail, with an asymmetric active architecture revealed by cryo-EM), it binds PNPase (via residues ~510-514) to form a 330-kDa heteropentamer that degrades structured and double-stranded RNA 3'→5'; it also bridges mtPAP (via residues ~100-104) in a transient trimeric complex that adjusts mt-mRNA poly(A) tail lengths in response to changes in mitochondrial Pi/ATP ratios; in the nucleus SUV3 interacts with BLM, WRN, RPA, and FEN1 and suppresses homologous recombination; SUV3 also works with ELAC2 to degrade mitochondrial circular RNAs (mecciRNAs), and its loss causes accumulation of mitochondrial dsRNAs that escape to the cytosol, activate PKR-mediated innate immune signaling, and induce mtDNA leakage-dependent PD-L1 upregulation; collectively, SUV3 is essential for mitochondrial RNA processing, mtDNA stability, and cellular homeostasis, with haploinsufficiency leading to mtDNA mutations, tumorigenesis, and premature aging in mice.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SUPV3L1 (SUV3) is a nuclear-encoded, ATP-dependent RNA/DNA helicase of the SF2 family that is the central determinant of mitochondrial post-transcriptional RNA metabolism, first defined in yeast where loss-of-function alters splicing and stability of intron-containing mitochondrial transcripts and the protein carries a mitochondrial targeting presequence with conserved helicase motifs [#0, #1, #2]. Crystal and cryo-EM structures define a four-domain architecture — two RecA-like domains, a C-terminal helical domain through which substrate RNA threads, and an external N-terminal domain — that assembles into an asymmetric homodimer via its C-terminal tail, an arrangement required for efficient, ATP-hydrolysis-dependent processive RNA binding and unwinding [#15, #22, #26]. As the catalytic core of the mitochondrial degradosome, the SUV3 dimer binds the PNPase trimer (through SUV3 residues ~510-514) to form a 330-kDa heteropentamer that degrades structured and double-stranded RNA with 3'→5' directionality, a reaction that requires intact helicase activity [#10]; the same complex transiently recruits mtPAP (via SUV3 residues ~100-104) to bidirectionally tune mt-mRNA poly(A) tail length in response to mitochondrial Pi/ATP ratios [#17]. Through these activities SUV3 controls processing of mitochondrial polycistronic transcripts, mt-mRNA and tRNA maturation, mtDNA copy number and replication, and overall mitochondrial bioenergetic function [#9, #13, #19]. SUV3 also degrades mitochondria-encoded circular RNAs together with ELAC2, and its loss causes accumulation of mitochondrial double-stranded RNAs that escape to the cytosol and activate PKR-mediated innate immune and type I interferon signaling, while mtDNA leakage drives PD-L1 upregulation [#24, #25]. A distinct nuclear/nucleolar pool of SUV3 interacts with the BLM and WRN helicases and with RPA and FEN1 and suppresses homologous recombination, contributing to genome stability [#8, #14, #20]. In vivo, Supv3L1 is essential: conditional disruption causes premature aging and skin barrier failure, and heterozygous mice accumulate maternally transmitted mtDNA mutations with reduced copy number and develop tumors [#11, #16]. A homozygous truncating SUPV3L1 mutation causes a human mitochondrial RNA-processing disorder with reduced mature ND6 mRNA and dsRNA accumulation, rescued by cDNA complementation [#23].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Established the molecular identity of SUV3 as a mitochondrial ATP-dependent RNA helicase and linked a point mutation in a conserved helicase motif to mitochondrial RNA defects, defining the gene's biochemical class.\",\n      \"evidence\": \"Gene cloning, sequencing, and mutant-allele analysis of the SUV3-1 gain-of-function mutation in yeast\",\n      \"pmids\": [\"1379722\", \"2158076\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Helicase catalytic activity not demonstrated biochemically on purified protein\", \"Direct RNA substrates not defined\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Showed SUV3 is required for stability and processing of intron-containing mitochondrial transcripts in an intron-number-dependent manner, framing it as a post-transcriptional RNA stability factor rather than a transcriptional regulator.\",\n      \"evidence\": \"Northern analysis in yeast strains with defined intron combinations plus SUV3 disruption\",\n      \"pmids\": [\"8529267\", \"7736607\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism distinguishing direct turnover from indirect effects not resolved\", \"rRNA processing role from single intron background\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Identified human SUPV3L1 as the conserved orthologue with a mitochondrial leader sequence, extending the yeast function to a candidate human mitochondrial helicase.\",\n      \"evidence\": \"cDNA cloning, sequencing, Northern and EST analysis\",\n      \"pmids\": [\"10453991\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional assay of the human protein\", \"Subcellular localization inferred from sequence only\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Revealed an unexpected nuclear pool of human SUV3 and its interaction with RecQ helicases BLM and WRN, implicating it in genome stability and HR suppression beyond mitochondria.\",\n      \"evidence\": \"siRNA knockdown with apoptosis/cell-cycle assays, ELISA binding, and sister chromatid exchange assays in HeLa cells\",\n      \"pmids\": [\"17352692\", \"17961633\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Co-IP/ELISA without structural mapping of interaction interfaces\", \"Whether nuclear effects are direct or secondary to mitochondrial dysfunction unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrated that loss of human SUV3 causes shortened polyadenylated mt-RNAs and broad bioenergetic collapse, establishing its essential role in mammalian mitochondrial RNA metabolism and cell viability.\",\n      \"evidence\": \"siRNA knockdown with mt-RNA, protein synthesis, ROS, membrane potential, mtDNA copy number, and morphology assays\",\n      \"pmids\": [\"18678873\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs. indirect cause of poly(A) shortening not separated\", \"Enzymatic mechanism not addressed\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Reconstituted the mitochondrial degradosome, showing the SUV3 dimer and PNPase trimer form a 330-kDa heteropentamer that degrades dsRNA 3'→5' in an ATP- and helicase-activity-dependent manner.\",\n      \"evidence\": \"Purified protein reconstitution, gel filtration sizing, in vitro RNA degradation, and site-directed mutagenesis (residues 510-514)\",\n      \"pmids\": [\"19509288\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo substrate repertoire not defined\", \"Regulation of complex assembly in cells unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed in vivo that Supv3L1 is organismally essential, with conditional loss causing premature aging and skin barrier failure.\",\n      \"evidence\": \"Conditional Cre/lox disruption with histology and phenotyping in mice\",\n      \"pmids\": [\"19145458\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between mitochondrial RNA defects and skin phenotype not delineated\", \"Tissue-specific substrate dependencies unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Resolved the mechanism of SUV3's splicing role as indirect, via degradosome-mediated turnover of excised intron RNPs that recycle a limiting splicing cofactor.\",\n      \"evidence\": \"Genetic epistasis with suv3-1, Mrs1p overexpression/depletion, and intron RNP analysis in yeast\",\n      \"pmids\": [\"20064926\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of cofactor-sequestration model to other introns/organisms untested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Separated SUV3's mtDNA maintenance function from intron turnover and tied it to active replication origins, requiring ATPase activity and the CC region but not RNA binding.\",\n      \"evidence\": \"Inducible knockdown with structure-function mutagenesis (K245A, V272L, ΔCC) and ChIP at mtDNA origins in yeast\",\n      \"pmids\": [\"21911497\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct DNA substrate at origins not biochemically defined\", \"How helicase activity supports replication mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Connected nuclear SUV3 to replication/repair machinery by demonstrating physical and functional interplay with RPA and FEN1.\",\n      \"evidence\": \"Co-IP of hSuv3 complexes, in vitro helicase assays with RPA vs mtSSB, and FEN1 stimulation assays\",\n      \"pmids\": [\"21846330\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single Co-IP without reciprocal in-cell validation of functional consequence\", \"No demonstration that SUV3 acts at nuclear replication forks in vivo\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Provided the first atomic-resolution architecture of human Suv3, defining a four-domain SF2 fold with an RNA-threading C-terminal domain and assigning it to a distinct helicase subfamily.\",\n      \"evidence\": \"X-ray crystallography with AMPPNP and RNA ligands plus functional validation\",\n      \"pmids\": [\"22101826\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Oligomeric/dimeric state and its functional role not captured in monomeric structures\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Established a causal in vivo link between SUV3 dosage and mtDNA integrity, with haploinsufficiency producing maternally transmitted mtDNA mutations, copy-number loss, tumorigenesis, and shortened lifespan.\",\n      \"evidence\": \"Heterozygous mouse genetics with mtDNA mutation/copy-number analysis, tumor histology, and maternal transmission\",\n      \"pmids\": [\"22562243\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic chain from mtDNA mutation to specific tumor types not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined a regulatory function for the degradosome in adjusting mt-mRNA poly(A) tail length, with SUV3 simultaneously bridging mtPAP and PNPase to sense the mitochondrial Pi/ATP ratio.\",\n      \"evidence\": \"Reconstitution of the SUV3·PNPase·mtPAP complex, binding-site mutagenesis (residues 100-104), polyadenylation/degradation assays, and cellular Pi manipulation\",\n      \"pmids\": [\"24770417\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological signals controlling complex switching in vivo not fully mapped\", \"Which mt-mRNAs are preferentially regulated unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Characterized cofactor dependence of human Suv3, showing helicase activity requires specific divalent cations and that only ATP supports activity at high nucleotide concentrations, implying sensitivity to local metabolite availability.\",\n      \"evidence\": \"In vitro helicase and ATPase assays with varied divalent cations and nucleotides\",\n      \"pmids\": [\"25446650\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vitro biochemistry; physiological relevance of cofactor sensitivity untested\", \"Single method type\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Extended SUV3 function to metazoan mitochondrial polycistronic transcript processing, showing tRNA maturation and translation defects that occur independently of PNPase.\",\n      \"evidence\": \"Drosophila loss-of-function genetics with Northern blotting, translation, and respiratory complex assays\",\n      \"pmids\": [\"26152302\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"PNPase-independent processing mechanism not biochemically defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Localized human SUV3 to nucleoli and attributed the growth defect of SUV3 depletion to nuclear rather than mitochondrial function, while excluding it from DNA-repair foci.\",\n      \"evidence\": \"Fluorescence microscopy with nuclear-targeted constructs and siRNA growth assays in HeLa cells\",\n      \"pmids\": [\"28291845\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Nucleolar substrate/function of SUV3 unidentified\", \"Reconciliation with reported HR/repair-factor interactions unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined dimerization via the C-terminal tail as mechanistically required for efficient RNA unwinding and PNPase binding, and described the dumbbell-shaped degradosome architecture.\",\n      \"evidence\": \"CTT mutagenesis, in vitro RNA binding/unwinding assays, crystal structure of Suv3ΔC, and SAXS of dimeric and PNPase-bound complexes\",\n      \"pmids\": [\"35481630\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"High-resolution structure of the full dimeric degradosome not yet resolved at this stage\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Provided human disease evidence that biallelic SUPV3L1 loss causes a mitochondrial RNA-processing disorder, with cDNA complementation confirming pathogenicity.\",\n      \"evidence\": \"Patient fibroblast RNA analysis, dsRNA immunostaining, and lentiviral cDNA complementation rescue\",\n      \"pmids\": [\"35023579\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Only two siblings; phenotypic spectrum and genotype-phenotype range undefined\", \"Partial rescue leaves residual mechanism uncertain\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked SUV3 loss to innate immune dysregulation, showing accumulated mitochondrial dsRNA escapes to the cytosol and activates PKR-driven type I IFN signaling, and that mtDNA leakage drives PD-L1 upregulation.\",\n      \"evidence\": \"siRNA knockdown, fCLIP-qPCR, TEM, cytokine and functional assays with PKR co-knockdown rescue; mtDNA fractionation with TREX1 overexpression rescue\",\n      \"pmids\": [\"39973625\", \"40268748\", \"39267568\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab per pathway arm\", \"Direct mechanism of dsRNA/mtDNA cytosolic escape not fully defined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined the structural basis of processive unwinding by capturing asymmetric dimeric Suv3 in four functional states, showing only one protomer initially engages nucleotide/RNA in an ATP-hydrolysis-dependent cycle.\",\n      \"evidence\": \"Cryo-EM in apo, ADP, ssRNA, and ssRNA+AMP-PNP states with biochemical RNA-binding/unwinding validation\",\n      \"pmids\": [\"41986356\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the full degradosome engaging substrate not resolved\", \"Coupling of unwinding to PNPase degradation step not visualized\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the same protein partitions and coordinates its distinct mitochondrial RNA-degradation/processing roles, its nucleolar/HR-related nuclear functions, and its mtDNA-replication role remains unresolved, as does the in vivo substrate map across compartments.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking nuclear and mitochondrial pools\", \"Nucleolar substrate undefined\", \"Full in vivo mt-RNA substrate repertoire incomplete\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [10, 17, 19, 22, 26]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [10, 15, 22, 26]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [10, 13, 18, 26]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [10, 18]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [14, 18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 5, 9, 17]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [7, 14]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [20]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [9, 10, 17, 19]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [24]},\n      {\"term_id\": \"R-HSA-69306\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"complexes\": [\n      \"mitochondrial degradosome (SUV3-PNPase)\",\n      \"SUV3-PNPase-mtPAP complex\",\n      \"SUPV3L1-ELAC2 complex\"\n    ],\n    \"partners\": [\n      \"PNPT1\",\n      \"MTPAP\",\n      \"ELAC2\",\n      \"BLM\",\n      \"WRN\",\n      \"RPA\",\n      \"FEN1\",\n      \"GRSF1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}