{"gene":"EXOSC10","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":1999,"finding":"EXOSC10 (PM-Scl100/Rrp6p) is exclusively present in the nuclear form of the exosome complex but absent from the cytoplasmic form, as demonstrated by biochemical fractionation and indirect immunofluorescence in both yeast and human cells. The human PM-Scl complex and yeast exosome are functionally equivalent, with the Rrp4p subunit confirmed as shared between both complexes.","method":"Biochemical fractionation, indirect immunofluorescence, genetic complementation","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (fractionation, immunofluorescence, complementation), replicated across yeast and human systems","pmids":["10465791"],"is_preprint":false},{"year":1998,"finding":"Yeast Rrp6p (homolog of human PM-Scl100/EXOSC10) is a 3'-5' exoribonuclease (homologous to RNase D) required for 5.8S rRNA 3' end formation; loss-of-function mutations cause accumulation of a 5.8S* processing intermediate retaining ~30 nucleotides of ITS2, with pulse-chase demonstrating a precursor-product relationship between 5.8S* and mature 5.8S rRNA.","method":"Genetic selection, molecular cloning, pulse-chase RNA analysis, sequence homology to RNase D","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic and biochemical characterization with pulse-chase kinetics, foundational mechanistic study","pmids":["9582370"],"is_preprint":false},{"year":2006,"finding":"Crystal structure of yeast Rrp6p reveals a conserved RNase D core with a flanking HRDC domain in an unusual conformation. Complexes with AMP and UMP show how the protein specifically recognizes ribonucleotides. In vivo mutagenesis of conserved active-site residues and the HRDC domain demonstrates that the HRDC domain conformation is important for the processing (but not degradation) function, revealing independent control of processing vs. degradation activities.","method":"X-ray crystallography, in vivo mutagenesis, RNA processing assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with active-site mutagenesis and functional validation in vivo","pmids":["16882719"],"is_preprint":false},{"year":2003,"finding":"Mutation of conserved active-site residues predicted to coordinate metal ions in Rrp6p (yeast homolog of EXOSC10) abolishes in vitro and in vivo exoribonuclease activity, confirming a two-metal ion mechanism. The HRDC domain point mutation results in nuclear-localized Rrp6p that retains degradation activity but loses 5.8S rRNA and snoRNA 3'-end processing activity, demonstrating domain-specific functional separation.","method":"Site-directed mutagenesis, in vitro exonuclease assays, in vivo RNA processing assays","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted in vitro activity combined with mutagenesis and in vivo functional validation","pmids":["12923258"],"is_preprint":false},{"year":2007,"finding":"Human EXOSC10 (PM/Scl-100) co-localizes with C1D and hMtr4p in nucleoli. C1D binds directly to PM/Scl-100 (EXOSC10), and C1D, MPP6, and PM/Scl-100 form a stable trimeric complex in vitro. The nucleolar accumulation of C1D is dependent on PM/Scl-100. RNAi knockdown of C1D, MPP6, or hMtr4p causes accumulation of 3'-extended 5.8S rRNA precursors, demonstrating these cofactors are required for EXOSC10-dependent rRNA processing.","method":"Co-immunoprecipitation, subcellular localization, in vitro reconstitution, RNAi knockdown, Northern blotting","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal interaction studies, in vitro complex reconstitution, functional RNAi knockdown with specific RNA processing readout","pmids":["17412707"],"is_preprint":false},{"year":2007,"finding":"The PMC2NT domain at the N-terminus of Rrp6p (EXOSC10 homolog) is the binding interface for Rrp47p cofactor, as shown by pull-down assays. Rrp47p binds structured nucleic acids and promotes Rrp6p activity. Strains expressing Rrp6p lacking the N-terminal PMC2NT domain fail to accumulate Rrp47p at normal levels and exhibit RNA processing defects consistent with loss of Rrp47p function.","method":"Recombinant protein pull-down, nucleic acid binding assays, in vivo mutagenesis, RNA processing assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — pull-down mapping of interaction domain combined with in vivo functional validation, single lab but multiple orthogonal methods","pmids":["17704127"],"is_preprint":false},{"year":2008,"finding":"Rrp6p (EXOSC10 yeast homolog) can perform some RNA 3'-end processing functions (5.8S rRNA, snoRNAs) and degrade specific substrates independently of physical association with the nine-subunit core exosome, as shown by a C-terminal truncation that abolishes core exosome co-purification but retains these activities. However, combined activities of Rrp6p and Dis3p/core exosome are required for efficient degradation of certain poly(A)+ rRNA processing products.","method":"Affinity purification, RNA processing assays, genetic epistasis (double depletion), Northern blotting","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — domain truncation combined with biochemical purification and genetic epistasis, multiple orthogonal approaches in single lab","pmids":["18940861"],"is_preprint":false},{"year":2009,"finding":"The TRAMP complex directly enhances the 3'-5' exoribonuclease activity of purified Rrp6p (EXOSC10 yeast homolog) ~10-fold in vitro, independently of TRAMP's poly(A) polymerase (Trf4) and helicase (Mtr4) activities. Enhancement requires a key catalytic residue in Rrp6p's active site; TRAMP cannot stimulate a catalytically inactive Rrp6p mutant, confirming the effect is on Rrp6p hydrolytic activity specifically.","method":"In vitro exonuclease assay with purified recombinant proteins, active-site mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstituted in vitro activity assay with purified components and mutagenesis validation, single lab","pmids":["19955569"],"is_preprint":false},{"year":2011,"finding":"Human RRP6 (EXOSC10/PM-Scl-100) exhibits distributive 3'-to-5' exoribonuclease activity and is inhibited by stable RNA secondary structure. X-ray crystal structure of the human RRP6 exoribonuclease+HRDC domain construct shows a more exposed active site compared to yeast Rrp6, which correlates with human RRP6's greater ability to degrade structured RNA substrates in vitro.","method":"X-ray crystallography, in vitro exonuclease assays, comparison of human and yeast constructs","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure of human protein combined with in vitro activity assays, single lab with multiple orthogonal methods","pmids":["21705430"],"is_preprint":false},{"year":2012,"finding":"Human EXOSC10 (Rrp6/PM-Scl-100) functions with Microprocessor, Setx, and Xrn2 to induce RNAPII pausing and premature transcription termination at the HIV-1 promoter. EXOSC10 further processes Microprocessor cleavage products to generate small RNAs that mediate transcriptional repression and chromatin remodeling. ChIP-seq identified cellular gene targets modulated by this pathway.","method":"ChIP-seq, RNAi knockdown, transcription termination assays, chromatin remodeling assays","journal":"Cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple genomic and functional approaches in single lab; pathway placement supported by combinatorial depletion experiments","pmids":["22980978"],"is_preprint":false},{"year":2012,"finding":"The nuclear exosome subunit Rrp6p (EXOSC10 homolog) counteracts poly(A) tail extension by Trf4p in vitro and in vivo, and controls PABP loading: Rrp6p interacts with Nab2p and displaces it from poly(A) tails, potentially directing RNAs to turnover. This defines a nuclear mRNP surveillance step involving Rrp6p targeting of Nab2p-bound poly(A)-tailed RNPs.","method":"In vitro polyadenylation assay, co-immunoprecipitation, RNA-seq, genetic analysis","journal":"Molecular cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro reconstitution with purified proteins plus in vivo validation, single lab","pmids":["22683267"],"is_preprint":false},{"year":2014,"finding":"Crystal structure of a ten-subunit yeast RNA exosome (Exo9 core + Rrp6) bound to poly(A) RNA at 3.3 Å resolution shows the Rrp6 catalytic domain resting on top of the Exo9 S1/KH ring above the central channel, with the RNA 3' end anchored in the Rrp6 active site. RNA traverses the S1/KH ring in the opposite orientation to Rrp44-bound complexes. Solution studies with human and yeast exosomes confirm the RNA path to Rrp6 is conserved and dependent on S1/KH ring integrity.","method":"X-ray crystallography (3.3 Å), solution biochemistry, cross-species validation with human RRP6","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structure with functional validation, confirmed in both yeast and human exosome complexes","pmids":["25043052"],"is_preprint":false},{"year":2014,"finding":"The N-terminal domains of Rrp6 and Rrp47 form a highly intertwined structural unit (crystallographic analysis) that creates a composite conserved surface groove binding the N-terminus of Mtr4 helicase. Mtr4 binding to the exosome core (Exo-10) in vitro requires both Rrp6 and Rrp47. Mutation of conserved residues at the Rrp6–Mtr4 interface disrupts their interaction and inhibits yeast growth.","method":"X-ray crystallography, in vitro binding assays, site-directed mutagenesis, yeast growth assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with mutagenesis and in vitro binding validation, multiple orthogonal methods","pmids":["25319414"],"is_preprint":false},{"year":2015,"finding":"RRP6/EXOSC10 is recruited to DNA double-strand breaks (DSBs) in Drosophila S2 cells (RRP6) and human HeLa cells (EXOSC10). Depletion of RRP6/EXOSC10 impairs RAD51 recruitment to DSBs without affecting H2AX phosphorylation. Catalytically inactive RRP6-Y361A mutant also inhibits RAD51 recruitment, demonstrating that ribonucleolytic activity is required. RRP6/EXOSC10 co-immunoprecipitates with RAD51, placing it in the homologous recombination pathway.","method":"Immunofluorescence, RNAi depletion, co-immunoprecipitation, catalytic mutant overexpression, radiation sensitivity assay","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, catalytic mutant, and KD with specific HR phenotype; validated in both Drosophila and human cells","pmids":["25632158"],"is_preprint":false},{"year":2016,"finding":"The Rrp6 C-terminal 'lasso' domain (highly basic tail) binds RNA and stimulates ribonuclease activities of both Rrp44 and Rrp6 within the 11-subunit nuclear exosome. Stimulation is dependent on the Exo9 central channel. The lasso contributes to degradation and processing of exosome substrates in vitro and in vivo, and is proposed to be a conserved feature.","method":"In vitro exonuclease assays, RNA binding assays, truncation mutants, in vivo RNA processing assays","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro reconstitution and in vivo validation, single lab with multiple orthogonal approaches","pmids":["27899565"],"is_preprint":false},{"year":2016,"finding":"EXOSC10 is SUMOylated (conjugated with SUMO1) in response to cellular cooling in human cells and in vivo. The major SUMOylation sites in EXOSC10 were identified by mutagenesis. Overexpression of SUMO1 alone is sufficient to suppress EXOSC10 abundance. RNAi depletion of EXOSC10 causes 3' pre-rRNA processing defects and reduces the 40S:60S ribosomal subunit ratio, demonstrating that SUMOylation-mediated reduction of EXOSC10 downregulates ribosome biogenesis.","method":"RNAi knockdown, site-directed mutagenesis of SUMOylation sites, ribosome profiling, in vivo cooling model","journal":"RNA (New York, N.Y.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis of modification sites combined with functional knockdown readout, single lab with multiple approaches","pmids":["26857222"],"is_preprint":false},{"year":2018,"finding":"EXOSC10 (RRP6) processes 3'-extended forms of human telomerase RNA (hTR) precursor in two steps: longer forms are first trimmed by RRP6 and shorter forms are then processed by PARN. H/ACA RNP assembly on hTR actively promotes RRP6-dependent processing and disrupts tertiary RNA interactions (triplex) in longer precursors that would otherwise favor degradation over productive processing.","method":"In vitro processing assays, RNAi knockdown, RNA structure analysis, RNP reconstitution","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro processing assays combined with cell-based knockdown, single lab with multiple complementary approaches","pmids":["30575725"],"is_preprint":false},{"year":2019,"finding":"Depletion of EXOSC10 in human cells leads to increased damage-induced lncRNA (dilncRNA) and DNA-RNA hybrid levels at DNA double-strand breaks. EXOSC10 depletion impairs RPA targeting to damage sites and causes hyper-stimulated DNA end resection. RNase H1 overexpression rescues the RPA recruitment defect, demonstrating that EXOSC10-mediated RNA clearance of dilncRNAs is required for RPA assembly and controlled DNA end resection in homologous recombination.","method":"RNAi depletion, immunofluorescence, DNA-RNA hybrid detection (DRIP), DNA end resection assays, RNase H1 rescue","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods, rescue experiment with RNase H1 confirms mechanism, functional molecular phenotype established","pmids":["31086179"],"is_preprint":false},{"year":2019,"finding":"Rapid depletion of EXOSC10 in human cells reveals that its primary substrates are short 3'-extended ribosomal RNAs and small nucleolar RNAs (snoRNAs), distinct from DIS3 substrates (enhancer RNAs, PROMPTs, PCPA products). Enhancer RNAs and PROMPTs are unaffected by EXOSC10 loss, demonstrating substrate specificity within the nuclear exosome.","method":"Auxin-inducible degron rapid depletion, direct EXOSC10 binding substrate mapping, RNA-seq","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — rapid depletion system (acute loss-of-function) with direct substrate binding assays and genome-wide RNA-seq, distinguishes EXOSC10 from DIS3 substrates rigorously","pmids":["30840897"],"is_preprint":false},{"year":2020,"finding":"Oocyte-specific conditional knockout of Exosc10 in mice causes female subfertility due to delayed germinal vesicle breakdown (GVBD). Single-oocyte RNA-seq reveals dysregulation of mRNAs encoding endomembrane trafficking proteins and meiotic cell cycle regulators. EXOSC10-depleted oocytes show CDK1 activation failure (with persistent WEE1 activity), impaired lamina phosphorylation/disassembly, rRNA processing defects, and endomembrane organelle abnormalities.","method":"CRISPR/Cas9 conditional knockout, single oocyte RNA-seq, immunofluorescence, rRNA processing analysis","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific genetic knockout with multiple molecular phenotypes validated by orthogonal methods","pmids":["32313933"],"is_preprint":false},{"year":2017,"finding":"EXOSC10 is post-translationally regulated in male germ cells; the protein becomes unstable at later stages of gamete development. EXOSC10 localizes to nucleoli and cytoplasm of mitotic and meiotic germ cells and transiently associates with the XY body (a meiotic sex chromosome inactivation structure). Germ cell-specific knockout using Stra8-Cre or Ddx4/Vasa-Cre results in small testes, impaired germ cell differentiation, and subfertility.","method":"Cre-mediated conditional knockout, immunofluorescence, subcellular localization, protein stability analysis","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — two independent Cre drivers for conditional KO, localization studies, and protein stability assays, single lab with multiple approaches","pmids":["29118343"],"is_preprint":false},{"year":2023,"finding":"The nucleolar ubiquitin-specific protease USP36 directly interacts with EXOSC10 in the nucleolus and acts as a SUMO ligase mediating EXOSC10 SUMOylation at lysine 583. Mutation of K583 impairs EXOSC10 binding to pre-rRNAs. K583R mutant EXOSC10 fails to rescue rRNA processing defects and cell growth inhibition caused by knockdown of endogenous EXOSC10, demonstrating that K583 SUMOylation is functionally required for nucleolar RNA exosome activity in ribosome biogenesis.","method":"Co-immunoprecipitation, SUMOylation assays, site-directed mutagenesis (K583R), CLIP/binding assays for pre-rRNA interaction, RNAi rescue experiments","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct interaction mapping, mutagenesis of modification site, functional rescue experiment, multiple orthogonal methods in single lab","pmids":["36912080"],"is_preprint":false},{"year":1999,"finding":"PM-Scl100/EXOSC10 localizes to prenucleolar bodies (PNBs) that are translocated to the nucleolus later than fibrillarin-containing PNBs at mitosis/interphase transition. Microinjection of anti-PM-Scl100 antibodies during mitosis inhibits targeting of PM-Scl100 to the nucleolus without affecting fibrillarin or protein B23 nucleolar assembly, suggesting an ordered pathway for nucleolar reassembly in which EXOSC10 participates in late events.","method":"Antibody microinjection, indirect immunofluorescence time-course, subcellular localization during mitosis","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct localization experiment with functional antibody perturbation, but single lab and limited mechanistic depth","pmids":["10471330"],"is_preprint":false},{"year":1992,"finding":"The cDNA encoding the PM-Scl 100-kD protein (EXOSC10) was cloned; affinity-purified antibody against the clone product stained nucleoli of HEp-2 cells and immunoprecipitated the PM-Scl protein complex, establishing nuclear/nucleolar localization. The predicted protein sequence (98,088 Da) contains a mixed-charge cluster. No sequence homology was found with PM-Scl 75-kD protein.","method":"cDNA cloning, immunoblot, indirect immunofluorescence, immunoprecipitation","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — initial molecular cloning with subcellular localization confirmed by immunofluorescence and immunoprecipitation; replicated across multiple subsequent studies","pmids":["1644924"],"is_preprint":false},{"year":2009,"finding":"Drosophila dRrp6 (EXOSC10 ortholog) is required for cell proliferation and error-free mitosis in S2 cells independently of the core exosome (depletion of core subunit Rrp40 does not cause the same mitotic defects). dRrp6 dynamically redistributes during mitosis, accumulating predominantly on condensed chromosomes, while core exosome subunits localize to microtubules. Depletion causes defects in chromosome congression, separation, and segregation.","method":"RNAi depletion, microarray analysis, immunofluorescence during mitosis, FACS analysis, spindle checkpoint assays","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi knockdown with specific mitotic phenotypes and dynamic localization by direct imaging; Drosophila model but ortholog well-established; single lab","pmids":["19225159"],"is_preprint":false}],"current_model":"EXOSC10 (PM-Scl100/RRP6) is the nuclear-specific distributive 3'-to-5' exoribonuclease subunit of the RNA exosome that processes the 3' ends of pre-rRNAs (especially 5.8S rRNA), snoRNAs, and other nuclear RNAs via a two-metal-ion RNase D-type catalytic mechanism; it is exclusively nuclear (anchored to the exosome core through its N-terminal PMC2NT domain that also recruits Rrp47/Rrp6 cofactors, and positions its active site above the Exo9 S1/KH ring channel as revealed by crystal structure); its activity is stimulated by the TRAMP complex and regulated post-translationally by SUMO1 conjugation at K583 (mediated by USP36, promoting pre-rRNA binding and ribosome biogenesis) and by cooling-induced SUMOylation; beyond RNA surveillance it is recruited to DNA double-strand breaks where its ribonucleolytic activity clears damage-induced lncRNAs and DNA-RNA hybrids to enable RPA loading and controlled DNA end resection for homologous recombination; and it plays essential roles in gametogenesis and oocyte-to-embryo transition by sculpting the transcriptome during meiotic maturation."},"narrative":{"mechanistic_narrative":"EXOSC10 (PM-Scl100/Rrp6) is the nuclear-specific, distributive 3'-to-5' exoribonuclease subunit of the RNA exosome that surveils and matures nuclear RNAs, and it is biochemically restricted to the nuclear form of the complex while absent from the cytoplasmic form [PMID:10465791, PMID:1644924]. It is an RNase D-type enzyme that uses a two-metal-ion catalytic mechanism: mutation of conserved metal-coordinating active-site residues abolishes both in vitro and in vivo exonuclease activity, and its flanking HRDC domain selectively governs processing (5.8S rRNA, snoRNA 3'-end maturation) independently of bulk degradation [PMID:9582370, PMID:16882719, PMID:12923258]. Acute depletion defines its principal physiological substrates as short 3'-extended ribosomal RNAs and snoRNAs, distinguishing it from the DIS3 catalytic subunit, which acts on enhancer RNAs and PROMPTs [PMID:30840897]. Within the holoenzyme, EXOSC10 rests atop the Exo9 S1/KH ring with the substrate 3' end threaded into its active site, and its catalytic output is tuned by partner proteins and an internal basic 'lasso' tail [PMID:25043052, PMID:27899565]. Through its N-terminal PMC2NT domain it forms an intertwined unit with Rrp47/C1D and recruits the Mtr4/TRAMP machinery, which directly stimulates its hydrolytic activity ~10-fold; together these cofactors are required for efficient pre-rRNA 3'-end processing [PMID:17412707, PMID:17704127, PMID:19955569, PMID:25319414]. EXOSC10 activity is post-translationally controlled by SUMO1 conjugation, including a cooling-responsive modification and USP36-mediated SUMOylation at lysine 583 that promotes pre-rRNA binding and ribosome biogenesis [PMID:26857222, PMID:36912080]. Beyond RNA surveillance, EXOSC10 is recruited to DNA double-strand breaks where its ribonucleolytic activity clears damage-induced lncRNAs and DNA-RNA hybrids to enable RPA loading, RAD51 recruitment, and controlled end resection for homologous recombination [PMID:25632158, PMID:31086179]. Genetic ablation in mouse germ cells and oocytes establishes essential roles in gametogenesis and meiotic maturation, where it sculpts the transcriptome to permit CDK1 activation, germinal vesicle breakdown, and proper germ cell differentiation [PMID:32313933, PMID:29118343].","teleology":[{"year":1992,"claim":"Molecular identification of the PM-Scl 100-kD autoantigen as a distinct nuclear protein established the gene product and its nucleolar localization, providing the entry point for all later mechanistic work.","evidence":"cDNA cloning with affinity-purified antibody immunofluorescence and immunoprecipitation in HEp-2 cells","pmids":["1644924"],"confidence":"Medium","gaps":["No enzymatic activity assigned","No exosome association established at this stage"]},{"year":1998,"claim":"Identifying yeast Rrp6 as an RNase D-homologous 3'-5' exoribonuclease required for 5.8S rRNA 3'-end formation defined the core catalytic function of the gene family.","evidence":"Genetic selection, cloning, and pulse-chase RNA analysis in yeast","pmids":["9582370"],"confidence":"High","gaps":["Catalytic mechanism not yet resolved at atomic level","Human ortholog activity not yet demonstrated"]},{"year":1999,"claim":"Demonstrating that EXOSC10 is present only in the nuclear exosome and not the cytoplasmic form, and that it joins the nucleolus late during mitotic reassembly, anchored its compartment-specific role in nuclear RNA metabolism.","evidence":"Biochemical fractionation, immunofluorescence, and antibody microinjection time-course in yeast and human cells","pmids":["10465791","10471330"],"confidence":"High","gaps":["Mechanism of nuclear retention not defined","Order of nucleolar targeting cues unresolved"]},{"year":2006,"claim":"Crystallography and active-site mutagenesis established the two-metal-ion catalytic mechanism and showed the HRDC domain conformation specifically controls processing versus degradation, revealing independently regulated activities.","evidence":"X-ray crystallography of yeast Rrp6 with AMP/UMP plus in vivo and in vitro mutagenesis","pmids":["16882719","12923258"],"confidence":"High","gaps":["Structural basis of HRDC conformational switching not defined","Human enzyme structure not yet solved"]},{"year":2007,"claim":"Mapping of cofactor interfaces showed EXOSC10 binds C1D/Rrp47 and MPP6 and engages Mtr4 through its N-terminal PMC2NT domain, with these cofactors required for efficient rRNA processing, defining the recruitment architecture.","evidence":"Co-IP, in vitro reconstitution, pull-down domain mapping, and RNAi in human and yeast systems","pmids":["17412707","17704127"],"confidence":"High","gaps":["Quantitative contribution of each cofactor to catalysis not separated","Substrate handoff dynamics unresolved"]},{"year":2008,"claim":"Showing that a core-exosome-untethered Rrp6 retains certain processing and degradation activities while others require the core established that EXOSC10 has both exosome-dependent and -independent functions.","evidence":"C-terminal truncation, affinity purification, and genetic epistasis in yeast","pmids":["18940861"],"confidence":"High","gaps":["Which substrates strictly require core association not fully enumerated","In vivo relevance of free Rrp6 pool unclear"]},{"year":2009,"claim":"Demonstrating TRAMP directly stimulates Rrp6 hydrolytic activity ~10-fold independently of its polymerase/helicase activities revealed allosteric activation of the catalytic subunit by its recruitment machinery.","evidence":"In vitro exonuclease assays with purified components and active-site mutagenesis","pmids":["19955569"],"confidence":"High","gaps":["Structural basis of stimulation not resolved","Whether human TRAMP confers identical stimulation untested here"]},{"year":2009,"claim":"Drosophila dRrp6's requirement for error-free mitosis independently of the core exosome, with chromosome-associated redistribution, indicated a function beyond canonical RNA processing.","evidence":"RNAi depletion, mitotic imaging, FACS, and spindle checkpoint assays in S2 cells","pmids":["19225159"],"confidence":"Medium","gaps":["RNA substrate underlying the mitotic role not identified","Conservation to mammalian mitosis not established"]},{"year":2011,"claim":"The human RRP6 crystal structure showed a more exposed active site than yeast, correlating with enhanced ability to degrade structured RNA, distinguishing the human enzyme's substrate range.","evidence":"X-ray crystallography of human RRP6 exo+HRDC construct and comparative in vitro assays","pmids":["21705430"],"confidence":"High","gaps":["Full-length human enzyme structure not solved","Cellular consequence of structured-RNA preference not mapped"]},{"year":2012,"claim":"Linking EXOSC10 to Microprocessor/Setx/Xrn2-driven transcription termination and to nuclear mRNP surveillance via Nab2/PABP displacement expanded its role into co-transcriptional regulation and poly(A) control.","evidence":"ChIP-seq, RNAi, transcription termination assays (HIV-1 promoter) and in vitro polyadenylation/Co-IP in yeast","pmids":["22980978","22683267"],"confidence":"Medium","gaps":["Generality beyond the HIV-1 model promoter unclear","Direct vs indirect role in termination not fully separated"]},{"year":2014,"claim":"High-resolution structures placed Rrp6 atop the Exo9 S1/KH ring with RNA threaded through the channel and defined the intertwined Rrp6-Rrp47 surface that captures Mtr4, establishing the structural logic of substrate channeling and helicase recruitment.","evidence":"X-ray crystallography (3.3 Å ten-subunit exosome; Rrp6-Rrp47-Mtr4 interface) with solution biochemistry and mutagenesis","pmids":["25043052","25319414"],"confidence":"High","gaps":["Conformational changes during catalytic cycling not captured","Dynamics of channel threading not time-resolved"]},{"year":2015,"claim":"Recruitment of RRP6/EXOSC10 to DNA double-strand breaks and the catalytic requirement for RAD51 loading placed its ribonucleolytic activity directly in the homologous recombination pathway.","evidence":"Immunofluorescence, RNAi, reciprocal Co-IP, and catalytic-mutant rescue in Drosophila and human cells","pmids":["25632158"],"confidence":"High","gaps":["RNA species cleared at breaks not yet identified in this study","Recruitment mechanism to DSBs undefined"]},{"year":2016,"claim":"Identifying SUMO1 conjugation of EXOSC10 (cooling-induced, suppressing abundance) and the stimulatory basic C-terminal lasso established post-translational and intramolecular tuning of its ribosome-biogenesis output.","evidence":"RNAi, SUMO-site mutagenesis, ribosome profiling, and in vitro truncation/RNA-binding assays","pmids":["26857222","27899565"],"confidence":"Medium","gaps":["SUMO ligase for cooling-induced modification not identified here","Physiological trigger range beyond cooling unknown"]},{"year":2018,"claim":"Showing two-step trimming of telomerase RNA precursor by RRP6 then PARN, promoted by H/ACA RNP assembly, extended EXOSC10's processing role to a specific non-coding RNA maturation pathway.","evidence":"In vitro processing assays, RNAi, RNA structure analysis, and RNP reconstitution","pmids":["30575725"],"confidence":"Medium","gaps":["In vivo contribution to functional telomerase levels not quantified","Determinants directing processing vs degradation only partly mapped"]},{"year":2019,"claim":"Acute degron depletion defined EXOSC10's primary substrates as short 3'-extended rRNAs and snoRNAs, and DSB studies showed it clears dilncRNAs/DNA-RNA hybrids to enable RPA loading and controlled end resection, sharpening both its surveillance specificity and its genome-stability function.","evidence":"Auxin-inducible degron with substrate-binding mapping and RNA-seq; plus RNAi, DRIP, resection assays, and RNase H1 rescue in human cells","pmids":["30840897","31086179"],"confidence":"High","gaps":["How substrate selectivity is enforced mechanistically not defined","Coupling between rRNA-processing and DSB roles unresolved"]},{"year":2020,"claim":"Germ-cell and oocyte-specific knockouts established EXOSC10 as essential for gametogenesis and meiotic maturation, sculpting the transcriptome to permit CDK1 activation, germinal vesicle breakdown, and germ cell differentiation.","evidence":"Conditional Cre/CRISPR knockouts in mouse testis and oocytes with single-oocyte RNA-seq, immunofluorescence, and rRNA processing analysis","pmids":["32313933","29118343"],"confidence":"High","gaps":["Direct vs indirect targets driving meiotic phenotypes not fully separated","Whether developmental defects stem chiefly from rRNA vs mRNA roles unclear"]},{"year":2023,"claim":"Identifying USP36 as a nucleolar SUMO ligase that SUMOylates EXOSC10 at K583 to promote pre-rRNA binding established a specific functional modification required for ribosome biogenesis.","evidence":"Co-IP, SUMOylation and CLIP/binding assays, K583R mutagenesis, and RNAi rescue in human cells","pmids":["36912080"],"confidence":"High","gaps":["Structural effect of K583 SUMOylation on pre-rRNA engagement undefined","Crosstalk with cooling-induced SUMOylation not addressed"]},{"year":null,"claim":"How EXOSC10 selectively partitions among its distinct roles—nucleolar rRNA/snoRNA maturation, DSB RNA clearance, and meiotic transcriptome sculpting—and how its modifications and cofactors switch between these programs remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No unified model of substrate/role partitioning","Recruitment determinants to DSBs vs nucleolus undefined","Regulatory hierarchy of SUMOylation events unmapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[1,2,3,8,18]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[1,3,7]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[8,14,21]}],"localization":[{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[4,22,23]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,3,23]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[1,4,18]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[13,17]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[19,20]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[15,21]}],"complexes":["nuclear RNA exosome","TRAMP complex (functional partner)"],"partners":["C1D","MPP6","MTR4","RRP47","RAD51","USP36","NAB2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q01780","full_name":"Exosome complex component 10","aliases":["Autoantigen 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Regulates levels of damage-induced RNAs in order to prevent DNA-RNA hybrid formation at DNA double-strand breaks and limit DNA end resection after damage (PubMed:31086179). Plays a role in oocyte development, maturation and survival (By similarity). Required for normal testis development and mitotic division of spermatogonia (By similarity). Plays a role in proper embryo development (By similarity). Required for global protein translation (PubMed:26857222, PubMed:36912080). Required for cell proliferation (PubMed:36912080). 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procapsids: function of size responsiveness mutations.","date":"2012","source":"Journal of structural biology","url":"https://pubmed.ncbi.nlm.nih.gov/22508104","citation_count":22,"is_preprint":false},{"pmid":"36912080","id":"PMC_36912080","title":"The ubiquitin-specific protease USP36 SUMOylates EXOSC10 and promotes the nucleolar RNA exosome function in rRNA processing.","date":"2023","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/36912080","citation_count":21,"is_preprint":false},{"pmid":"20346932","id":"PMC_20346932","title":"Anti-PM/Scl-100 and anti-RNA-polymerase III antibodies in scleroderma.","date":"2010","source":"Clinica chimica acta; international journal of clinical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20346932","citation_count":21,"is_preprint":false},{"pmid":"33485966","id":"PMC_33485966","title":"Aminoglycerophospholipid flipping and P4-ATPases in Toxoplasma gondii.","date":"2021","source":"The Journal of biological 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Location of the P4 origin.","date":"1985","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/2989532","citation_count":19,"is_preprint":false},{"pmid":"19220816","id":"PMC_19220816","title":"Interdependent nucleocytoplasmic trafficking and interactions of Dis3 with Rrp6, the core exosome and importin-alpha3.","date":"2009","source":"Traffic (Copenhagen, Denmark)","url":"https://pubmed.ncbi.nlm.nih.gov/19220816","citation_count":18,"is_preprint":false},{"pmid":"23143101","id":"PMC_23143101","title":"Genetic interactions suggest multiple distinct roles of the arch and core helicase domains of Mtr4 in Rrp6 and exosome function.","date":"2012","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/23143101","citation_count":18,"is_preprint":false},{"pmid":"22652674","id":"PMC_22652674","title":"P4 down-regulates Jagged2 and Notch1 expression during primordial folliculogenesis.","date":"2012","source":"Frontiers in bioscience (Elite edition)","url":"https://pubmed.ncbi.nlm.nih.gov/22652674","citation_count":18,"is_preprint":false},{"pmid":"33822217","id":"PMC_33822217","title":"Dynamic membranes: the multiple roles of P4 and P5 ATPases.","date":"2021","source":"Plant physiology","url":"https://pubmed.ncbi.nlm.nih.gov/33822217","citation_count":18,"is_preprint":false},{"pmid":"17931675","id":"PMC_17931675","title":"Incorporation of scaffolding protein gpO in bacteriophages P2 and P4.","date":"2007","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/17931675","citation_count":18,"is_preprint":false},{"pmid":"22123738","id":"PMC_22123738","title":"The PolyA tail length of yeast histone mRNAs varies during the cell cycle and is influenced by Sen1p and Rrp6p.","date":"2011","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/22123738","citation_count":17,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":47985,"output_tokens":6961,"usd":0.124185,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15876,"output_tokens":5544,"usd":0.10899,"stage2_stop_reason":"end_turn"},"total_usd":0.233175,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1999,\n      \"finding\": \"EXOSC10 (PM-Scl100/Rrp6p) is exclusively present in the nuclear form of the exosome complex but absent from the cytoplasmic form, as demonstrated by biochemical fractionation and indirect immunofluorescence in both yeast and human cells. The human PM-Scl complex and yeast exosome are functionally equivalent, with the Rrp4p subunit confirmed as shared between both complexes.\",\n      \"method\": \"Biochemical fractionation, indirect immunofluorescence, genetic complementation\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (fractionation, immunofluorescence, complementation), replicated across yeast and human systems\",\n      \"pmids\": [\"10465791\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Yeast Rrp6p (homolog of human PM-Scl100/EXOSC10) is a 3'-5' exoribonuclease (homologous to RNase D) required for 5.8S rRNA 3' end formation; loss-of-function mutations cause accumulation of a 5.8S* processing intermediate retaining ~30 nucleotides of ITS2, with pulse-chase demonstrating a precursor-product relationship between 5.8S* and mature 5.8S rRNA.\",\n      \"method\": \"Genetic selection, molecular cloning, pulse-chase RNA analysis, sequence homology to RNase D\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic and biochemical characterization with pulse-chase kinetics, foundational mechanistic study\",\n      \"pmids\": [\"9582370\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Crystal structure of yeast Rrp6p reveals a conserved RNase D core with a flanking HRDC domain in an unusual conformation. Complexes with AMP and UMP show how the protein specifically recognizes ribonucleotides. In vivo mutagenesis of conserved active-site residues and the HRDC domain demonstrates that the HRDC domain conformation is important for the processing (but not degradation) function, revealing independent control of processing vs. degradation activities.\",\n      \"method\": \"X-ray crystallography, in vivo mutagenesis, RNA processing assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with active-site mutagenesis and functional validation in vivo\",\n      \"pmids\": [\"16882719\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Mutation of conserved active-site residues predicted to coordinate metal ions in Rrp6p (yeast homolog of EXOSC10) abolishes in vitro and in vivo exoribonuclease activity, confirming a two-metal ion mechanism. The HRDC domain point mutation results in nuclear-localized Rrp6p that retains degradation activity but loses 5.8S rRNA and snoRNA 3'-end processing activity, demonstrating domain-specific functional separation.\",\n      \"method\": \"Site-directed mutagenesis, in vitro exonuclease assays, in vivo RNA processing assays\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted in vitro activity combined with mutagenesis and in vivo functional validation\",\n      \"pmids\": [\"12923258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Human EXOSC10 (PM/Scl-100) co-localizes with C1D and hMtr4p in nucleoli. C1D binds directly to PM/Scl-100 (EXOSC10), and C1D, MPP6, and PM/Scl-100 form a stable trimeric complex in vitro. The nucleolar accumulation of C1D is dependent on PM/Scl-100. RNAi knockdown of C1D, MPP6, or hMtr4p causes accumulation of 3'-extended 5.8S rRNA precursors, demonstrating these cofactors are required for EXOSC10-dependent rRNA processing.\",\n      \"method\": \"Co-immunoprecipitation, subcellular localization, in vitro reconstitution, RNAi knockdown, Northern blotting\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal interaction studies, in vitro complex reconstitution, functional RNAi knockdown with specific RNA processing readout\",\n      \"pmids\": [\"17412707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The PMC2NT domain at the N-terminus of Rrp6p (EXOSC10 homolog) is the binding interface for Rrp47p cofactor, as shown by pull-down assays. Rrp47p binds structured nucleic acids and promotes Rrp6p activity. Strains expressing Rrp6p lacking the N-terminal PMC2NT domain fail to accumulate Rrp47p at normal levels and exhibit RNA processing defects consistent with loss of Rrp47p function.\",\n      \"method\": \"Recombinant protein pull-down, nucleic acid binding assays, in vivo mutagenesis, RNA processing assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pull-down mapping of interaction domain combined with in vivo functional validation, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"17704127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Rrp6p (EXOSC10 yeast homolog) can perform some RNA 3'-end processing functions (5.8S rRNA, snoRNAs) and degrade specific substrates independently of physical association with the nine-subunit core exosome, as shown by a C-terminal truncation that abolishes core exosome co-purification but retains these activities. However, combined activities of Rrp6p and Dis3p/core exosome are required for efficient degradation of certain poly(A)+ rRNA processing products.\",\n      \"method\": \"Affinity purification, RNA processing assays, genetic epistasis (double depletion), Northern blotting\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain truncation combined with biochemical purification and genetic epistasis, multiple orthogonal approaches in single lab\",\n      \"pmids\": [\"18940861\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The TRAMP complex directly enhances the 3'-5' exoribonuclease activity of purified Rrp6p (EXOSC10 yeast homolog) ~10-fold in vitro, independently of TRAMP's poly(A) polymerase (Trf4) and helicase (Mtr4) activities. Enhancement requires a key catalytic residue in Rrp6p's active site; TRAMP cannot stimulate a catalytically inactive Rrp6p mutant, confirming the effect is on Rrp6p hydrolytic activity specifically.\",\n      \"method\": \"In vitro exonuclease assay with purified recombinant proteins, active-site mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted in vitro activity assay with purified components and mutagenesis validation, single lab\",\n      \"pmids\": [\"19955569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Human RRP6 (EXOSC10/PM-Scl-100) exhibits distributive 3'-to-5' exoribonuclease activity and is inhibited by stable RNA secondary structure. X-ray crystal structure of the human RRP6 exoribonuclease+HRDC domain construct shows a more exposed active site compared to yeast Rrp6, which correlates with human RRP6's greater ability to degrade structured RNA substrates in vitro.\",\n      \"method\": \"X-ray crystallography, in vitro exonuclease assays, comparison of human and yeast constructs\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure of human protein combined with in vitro activity assays, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"21705430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Human EXOSC10 (Rrp6/PM-Scl-100) functions with Microprocessor, Setx, and Xrn2 to induce RNAPII pausing and premature transcription termination at the HIV-1 promoter. EXOSC10 further processes Microprocessor cleavage products to generate small RNAs that mediate transcriptional repression and chromatin remodeling. ChIP-seq identified cellular gene targets modulated by this pathway.\",\n      \"method\": \"ChIP-seq, RNAi knockdown, transcription termination assays, chromatin remodeling assays\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple genomic and functional approaches in single lab; pathway placement supported by combinatorial depletion experiments\",\n      \"pmids\": [\"22980978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The nuclear exosome subunit Rrp6p (EXOSC10 homolog) counteracts poly(A) tail extension by Trf4p in vitro and in vivo, and controls PABP loading: Rrp6p interacts with Nab2p and displaces it from poly(A) tails, potentially directing RNAs to turnover. This defines a nuclear mRNP surveillance step involving Rrp6p targeting of Nab2p-bound poly(A)-tailed RNPs.\",\n      \"method\": \"In vitro polyadenylation assay, co-immunoprecipitation, RNA-seq, genetic analysis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro reconstitution with purified proteins plus in vivo validation, single lab\",\n      \"pmids\": [\"22683267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Crystal structure of a ten-subunit yeast RNA exosome (Exo9 core + Rrp6) bound to poly(A) RNA at 3.3 Å resolution shows the Rrp6 catalytic domain resting on top of the Exo9 S1/KH ring above the central channel, with the RNA 3' end anchored in the Rrp6 active site. RNA traverses the S1/KH ring in the opposite orientation to Rrp44-bound complexes. Solution studies with human and yeast exosomes confirm the RNA path to Rrp6 is conserved and dependent on S1/KH ring integrity.\",\n      \"method\": \"X-ray crystallography (3.3 Å), solution biochemistry, cross-species validation with human RRP6\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structure with functional validation, confirmed in both yeast and human exosome complexes\",\n      \"pmids\": [\"25043052\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The N-terminal domains of Rrp6 and Rrp47 form a highly intertwined structural unit (crystallographic analysis) that creates a composite conserved surface groove binding the N-terminus of Mtr4 helicase. Mtr4 binding to the exosome core (Exo-10) in vitro requires both Rrp6 and Rrp47. Mutation of conserved residues at the Rrp6–Mtr4 interface disrupts their interaction and inhibits yeast growth.\",\n      \"method\": \"X-ray crystallography, in vitro binding assays, site-directed mutagenesis, yeast growth assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with mutagenesis and in vitro binding validation, multiple orthogonal methods\",\n      \"pmids\": [\"25319414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RRP6/EXOSC10 is recruited to DNA double-strand breaks (DSBs) in Drosophila S2 cells (RRP6) and human HeLa cells (EXOSC10). Depletion of RRP6/EXOSC10 impairs RAD51 recruitment to DSBs without affecting H2AX phosphorylation. Catalytically inactive RRP6-Y361A mutant also inhibits RAD51 recruitment, demonstrating that ribonucleolytic activity is required. RRP6/EXOSC10 co-immunoprecipitates with RAD51, placing it in the homologous recombination pathway.\",\n      \"method\": \"Immunofluorescence, RNAi depletion, co-immunoprecipitation, catalytic mutant overexpression, radiation sensitivity assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, catalytic mutant, and KD with specific HR phenotype; validated in both Drosophila and human cells\",\n      \"pmids\": [\"25632158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The Rrp6 C-terminal 'lasso' domain (highly basic tail) binds RNA and stimulates ribonuclease activities of both Rrp44 and Rrp6 within the 11-subunit nuclear exosome. Stimulation is dependent on the Exo9 central channel. The lasso contributes to degradation and processing of exosome substrates in vitro and in vivo, and is proposed to be a conserved feature.\",\n      \"method\": \"In vitro exonuclease assays, RNA binding assays, truncation mutants, in vivo RNA processing assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro reconstitution and in vivo validation, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"27899565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"EXOSC10 is SUMOylated (conjugated with SUMO1) in response to cellular cooling in human cells and in vivo. The major SUMOylation sites in EXOSC10 were identified by mutagenesis. Overexpression of SUMO1 alone is sufficient to suppress EXOSC10 abundance. RNAi depletion of EXOSC10 causes 3' pre-rRNA processing defects and reduces the 40S:60S ribosomal subunit ratio, demonstrating that SUMOylation-mediated reduction of EXOSC10 downregulates ribosome biogenesis.\",\n      \"method\": \"RNAi knockdown, site-directed mutagenesis of SUMOylation sites, ribosome profiling, in vivo cooling model\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis of modification sites combined with functional knockdown readout, single lab with multiple approaches\",\n      \"pmids\": [\"26857222\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"EXOSC10 (RRP6) processes 3'-extended forms of human telomerase RNA (hTR) precursor in two steps: longer forms are first trimmed by RRP6 and shorter forms are then processed by PARN. H/ACA RNP assembly on hTR actively promotes RRP6-dependent processing and disrupts tertiary RNA interactions (triplex) in longer precursors that would otherwise favor degradation over productive processing.\",\n      \"method\": \"In vitro processing assays, RNAi knockdown, RNA structure analysis, RNP reconstitution\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro processing assays combined with cell-based knockdown, single lab with multiple complementary approaches\",\n      \"pmids\": [\"30575725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Depletion of EXOSC10 in human cells leads to increased damage-induced lncRNA (dilncRNA) and DNA-RNA hybrid levels at DNA double-strand breaks. EXOSC10 depletion impairs RPA targeting to damage sites and causes hyper-stimulated DNA end resection. RNase H1 overexpression rescues the RPA recruitment defect, demonstrating that EXOSC10-mediated RNA clearance of dilncRNAs is required for RPA assembly and controlled DNA end resection in homologous recombination.\",\n      \"method\": \"RNAi depletion, immunofluorescence, DNA-RNA hybrid detection (DRIP), DNA end resection assays, RNase H1 rescue\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods, rescue experiment with RNase H1 confirms mechanism, functional molecular phenotype established\",\n      \"pmids\": [\"31086179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Rapid depletion of EXOSC10 in human cells reveals that its primary substrates are short 3'-extended ribosomal RNAs and small nucleolar RNAs (snoRNAs), distinct from DIS3 substrates (enhancer RNAs, PROMPTs, PCPA products). Enhancer RNAs and PROMPTs are unaffected by EXOSC10 loss, demonstrating substrate specificity within the nuclear exosome.\",\n      \"method\": \"Auxin-inducible degron rapid depletion, direct EXOSC10 binding substrate mapping, RNA-seq\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — rapid depletion system (acute loss-of-function) with direct substrate binding assays and genome-wide RNA-seq, distinguishes EXOSC10 from DIS3 substrates rigorously\",\n      \"pmids\": [\"30840897\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Oocyte-specific conditional knockout of Exosc10 in mice causes female subfertility due to delayed germinal vesicle breakdown (GVBD). Single-oocyte RNA-seq reveals dysregulation of mRNAs encoding endomembrane trafficking proteins and meiotic cell cycle regulators. EXOSC10-depleted oocytes show CDK1 activation failure (with persistent WEE1 activity), impaired lamina phosphorylation/disassembly, rRNA processing defects, and endomembrane organelle abnormalities.\",\n      \"method\": \"CRISPR/Cas9 conditional knockout, single oocyte RNA-seq, immunofluorescence, rRNA processing analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific genetic knockout with multiple molecular phenotypes validated by orthogonal methods\",\n      \"pmids\": [\"32313933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"EXOSC10 is post-translationally regulated in male germ cells; the protein becomes unstable at later stages of gamete development. EXOSC10 localizes to nucleoli and cytoplasm of mitotic and meiotic germ cells and transiently associates with the XY body (a meiotic sex chromosome inactivation structure). Germ cell-specific knockout using Stra8-Cre or Ddx4/Vasa-Cre results in small testes, impaired germ cell differentiation, and subfertility.\",\n      \"method\": \"Cre-mediated conditional knockout, immunofluorescence, subcellular localization, protein stability analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two independent Cre drivers for conditional KO, localization studies, and protein stability assays, single lab with multiple approaches\",\n      \"pmids\": [\"29118343\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The nucleolar ubiquitin-specific protease USP36 directly interacts with EXOSC10 in the nucleolus and acts as a SUMO ligase mediating EXOSC10 SUMOylation at lysine 583. Mutation of K583 impairs EXOSC10 binding to pre-rRNAs. K583R mutant EXOSC10 fails to rescue rRNA processing defects and cell growth inhibition caused by knockdown of endogenous EXOSC10, demonstrating that K583 SUMOylation is functionally required for nucleolar RNA exosome activity in ribosome biogenesis.\",\n      \"method\": \"Co-immunoprecipitation, SUMOylation assays, site-directed mutagenesis (K583R), CLIP/binding assays for pre-rRNA interaction, RNAi rescue experiments\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct interaction mapping, mutagenesis of modification site, functional rescue experiment, multiple orthogonal methods in single lab\",\n      \"pmids\": [\"36912080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"PM-Scl100/EXOSC10 localizes to prenucleolar bodies (PNBs) that are translocated to the nucleolus later than fibrillarin-containing PNBs at mitosis/interphase transition. Microinjection of anti-PM-Scl100 antibodies during mitosis inhibits targeting of PM-Scl100 to the nucleolus without affecting fibrillarin or protein B23 nucleolar assembly, suggesting an ordered pathway for nucleolar reassembly in which EXOSC10 participates in late events.\",\n      \"method\": \"Antibody microinjection, indirect immunofluorescence time-course, subcellular localization during mitosis\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct localization experiment with functional antibody perturbation, but single lab and limited mechanistic depth\",\n      \"pmids\": [\"10471330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"The cDNA encoding the PM-Scl 100-kD protein (EXOSC10) was cloned; affinity-purified antibody against the clone product stained nucleoli of HEp-2 cells and immunoprecipitated the PM-Scl protein complex, establishing nuclear/nucleolar localization. The predicted protein sequence (98,088 Da) contains a mixed-charge cluster. No sequence homology was found with PM-Scl 75-kD protein.\",\n      \"method\": \"cDNA cloning, immunoblot, indirect immunofluorescence, immunoprecipitation\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — initial molecular cloning with subcellular localization confirmed by immunofluorescence and immunoprecipitation; replicated across multiple subsequent studies\",\n      \"pmids\": [\"1644924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Drosophila dRrp6 (EXOSC10 ortholog) is required for cell proliferation and error-free mitosis in S2 cells independently of the core exosome (depletion of core subunit Rrp40 does not cause the same mitotic defects). dRrp6 dynamically redistributes during mitosis, accumulating predominantly on condensed chromosomes, while core exosome subunits localize to microtubules. Depletion causes defects in chromosome congression, separation, and segregation.\",\n      \"method\": \"RNAi depletion, microarray analysis, immunofluorescence during mitosis, FACS analysis, spindle checkpoint assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi knockdown with specific mitotic phenotypes and dynamic localization by direct imaging; Drosophila model but ortholog well-established; single lab\",\n      \"pmids\": [\"19225159\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EXOSC10 (PM-Scl100/RRP6) is the nuclear-specific distributive 3'-to-5' exoribonuclease subunit of the RNA exosome that processes the 3' ends of pre-rRNAs (especially 5.8S rRNA), snoRNAs, and other nuclear RNAs via a two-metal-ion RNase D-type catalytic mechanism; it is exclusively nuclear (anchored to the exosome core through its N-terminal PMC2NT domain that also recruits Rrp47/Rrp6 cofactors, and positions its active site above the Exo9 S1/KH ring channel as revealed by crystal structure); its activity is stimulated by the TRAMP complex and regulated post-translationally by SUMO1 conjugation at K583 (mediated by USP36, promoting pre-rRNA binding and ribosome biogenesis) and by cooling-induced SUMOylation; beyond RNA surveillance it is recruited to DNA double-strand breaks where its ribonucleolytic activity clears damage-induced lncRNAs and DNA-RNA hybrids to enable RPA loading and controlled DNA end resection for homologous recombination; and it plays essential roles in gametogenesis and oocyte-to-embryo transition by sculpting the transcriptome during meiotic maturation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"EXOSC10 (PM-Scl100/Rrp6) is the nuclear-specific, distributive 3'-to-5' exoribonuclease subunit of the RNA exosome that surveils and matures nuclear RNAs, and it is biochemically restricted to the nuclear form of the complex while absent from the cytoplasmic form [#0, #23]. It is an RNase D-type enzyme that uses a two-metal-ion catalytic mechanism: mutation of conserved metal-coordinating active-site residues abolishes both in vitro and in vivo exonuclease activity, and its flanking HRDC domain selectively governs processing (5.8S rRNA, snoRNA 3'-end maturation) independently of bulk degradation [#1, #2, #3]. Acute depletion defines its principal physiological substrates as short 3'-extended ribosomal RNAs and snoRNAs, distinguishing it from the DIS3 catalytic subunit, which acts on enhancer RNAs and PROMPTs [#18]. Within the holoenzyme, EXOSC10 rests atop the Exo9 S1/KH ring with the substrate 3' end threaded into its active site, and its catalytic output is tuned by partner proteins and an internal basic 'lasso' tail [#11, #14]. Through its N-terminal PMC2NT domain it forms an intertwined unit with Rrp47/C1D and recruits the Mtr4/TRAMP machinery, which directly stimulates its hydrolytic activity ~10-fold; together these cofactors are required for efficient pre-rRNA 3'-end processing [#4, #5, #7, #12]. EXOSC10 activity is post-translationally controlled by SUMO1 conjugation, including a cooling-responsive modification and USP36-mediated SUMOylation at lysine 583 that promotes pre-rRNA binding and ribosome biogenesis [#15, #21]. Beyond RNA surveillance, EXOSC10 is recruited to DNA double-strand breaks where its ribonucleolytic activity clears damage-induced lncRNAs and DNA-RNA hybrids to enable RPA loading, RAD51 recruitment, and controlled end resection for homologous recombination [#13, #17]. Genetic ablation in mouse germ cells and oocytes establishes essential roles in gametogenesis and meiotic maturation, where it sculpts the transcriptome to permit CDK1 activation, germinal vesicle breakdown, and proper germ cell differentiation [#19, #20].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Molecular identification of the PM-Scl 100-kD autoantigen as a distinct nuclear protein established the gene product and its nucleolar localization, providing the entry point for all later mechanistic work.\",\n      \"evidence\": \"cDNA cloning with affinity-purified antibody immunofluorescence and immunoprecipitation in HEp-2 cells\",\n      \"pmids\": [\"1644924\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No enzymatic activity assigned\", \"No exosome association established at this stage\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Identifying yeast Rrp6 as an RNase D-homologous 3'-5' exoribonuclease required for 5.8S rRNA 3'-end formation defined the core catalytic function of the gene family.\",\n      \"evidence\": \"Genetic selection, cloning, and pulse-chase RNA analysis in yeast\",\n      \"pmids\": [\"9582370\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Catalytic mechanism not yet resolved at atomic level\", \"Human ortholog activity not yet demonstrated\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Demonstrating that EXOSC10 is present only in the nuclear exosome and not the cytoplasmic form, and that it joins the nucleolus late during mitotic reassembly, anchored its compartment-specific role in nuclear RNA metabolism.\",\n      \"evidence\": \"Biochemical fractionation, immunofluorescence, and antibody microinjection time-course in yeast and human cells\",\n      \"pmids\": [\"10465791\", \"10471330\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of nuclear retention not defined\", \"Order of nucleolar targeting cues unresolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Crystallography and active-site mutagenesis established the two-metal-ion catalytic mechanism and showed the HRDC domain conformation specifically controls processing versus degradation, revealing independently regulated activities.\",\n      \"evidence\": \"X-ray crystallography of yeast Rrp6 with AMP/UMP plus in vivo and in vitro mutagenesis\",\n      \"pmids\": [\"16882719\", \"12923258\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of HRDC conformational switching not defined\", \"Human enzyme structure not yet solved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Mapping of cofactor interfaces showed EXOSC10 binds C1D/Rrp47 and MPP6 and engages Mtr4 through its N-terminal PMC2NT domain, with these cofactors required for efficient rRNA processing, defining the recruitment architecture.\",\n      \"evidence\": \"Co-IP, in vitro reconstitution, pull-down domain mapping, and RNAi in human and yeast systems\",\n      \"pmids\": [\"17412707\", \"17704127\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative contribution of each cofactor to catalysis not separated\", \"Substrate handoff dynamics unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showing that a core-exosome-untethered Rrp6 retains certain processing and degradation activities while others require the core established that EXOSC10 has both exosome-dependent and -independent functions.\",\n      \"evidence\": \"C-terminal truncation, affinity purification, and genetic epistasis in yeast\",\n      \"pmids\": [\"18940861\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which substrates strictly require core association not fully enumerated\", \"In vivo relevance of free Rrp6 pool unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrating TRAMP directly stimulates Rrp6 hydrolytic activity ~10-fold independently of its polymerase/helicase activities revealed allosteric activation of the catalytic subunit by its recruitment machinery.\",\n      \"evidence\": \"In vitro exonuclease assays with purified components and active-site mutagenesis\",\n      \"pmids\": [\"19955569\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of stimulation not resolved\", \"Whether human TRAMP confers identical stimulation untested here\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Drosophila dRrp6's requirement for error-free mitosis independently of the core exosome, with chromosome-associated redistribution, indicated a function beyond canonical RNA processing.\",\n      \"evidence\": \"RNAi depletion, mitotic imaging, FACS, and spindle checkpoint assays in S2 cells\",\n      \"pmids\": [\"19225159\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RNA substrate underlying the mitotic role not identified\", \"Conservation to mammalian mitosis not established\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"The human RRP6 crystal structure showed a more exposed active site than yeast, correlating with enhanced ability to degrade structured RNA, distinguishing the human enzyme's substrate range.\",\n      \"evidence\": \"X-ray crystallography of human RRP6 exo+HRDC construct and comparative in vitro assays\",\n      \"pmids\": [\"21705430\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length human enzyme structure not solved\", \"Cellular consequence of structured-RNA preference not mapped\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Linking EXOSC10 to Microprocessor/Setx/Xrn2-driven transcription termination and to nuclear mRNP surveillance via Nab2/PABP displacement expanded its role into co-transcriptional regulation and poly(A) control.\",\n      \"evidence\": \"ChIP-seq, RNAi, transcription termination assays (HIV-1 promoter) and in vitro polyadenylation/Co-IP in yeast\",\n      \"pmids\": [\"22980978\", \"22683267\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generality beyond the HIV-1 model promoter unclear\", \"Direct vs indirect role in termination not fully separated\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"High-resolution structures placed Rrp6 atop the Exo9 S1/KH ring with RNA threaded through the channel and defined the intertwined Rrp6-Rrp47 surface that captures Mtr4, establishing the structural logic of substrate channeling and helicase recruitment.\",\n      \"evidence\": \"X-ray crystallography (3.3 Å ten-subunit exosome; Rrp6-Rrp47-Mtr4 interface) with solution biochemistry and mutagenesis\",\n      \"pmids\": [\"25043052\", \"25319414\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conformational changes during catalytic cycling not captured\", \"Dynamics of channel threading not time-resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Recruitment of RRP6/EXOSC10 to DNA double-strand breaks and the catalytic requirement for RAD51 loading placed its ribonucleolytic activity directly in the homologous recombination pathway.\",\n      \"evidence\": \"Immunofluorescence, RNAi, reciprocal Co-IP, and catalytic-mutant rescue in Drosophila and human cells\",\n      \"pmids\": [\"25632158\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"RNA species cleared at breaks not yet identified in this study\", \"Recruitment mechanism to DSBs undefined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identifying SUMO1 conjugation of EXOSC10 (cooling-induced, suppressing abundance) and the stimulatory basic C-terminal lasso established post-translational and intramolecular tuning of its ribosome-biogenesis output.\",\n      \"evidence\": \"RNAi, SUMO-site mutagenesis, ribosome profiling, and in vitro truncation/RNA-binding assays\",\n      \"pmids\": [\"26857222\", \"27899565\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"SUMO ligase for cooling-induced modification not identified here\", \"Physiological trigger range beyond cooling unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showing two-step trimming of telomerase RNA precursor by RRP6 then PARN, promoted by H/ACA RNP assembly, extended EXOSC10's processing role to a specific non-coding RNA maturation pathway.\",\n      \"evidence\": \"In vitro processing assays, RNAi, RNA structure analysis, and RNP reconstitution\",\n      \"pmids\": [\"30575725\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo contribution to functional telomerase levels not quantified\", \"Determinants directing processing vs degradation only partly mapped\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Acute degron depletion defined EXOSC10's primary substrates as short 3'-extended rRNAs and snoRNAs, and DSB studies showed it clears dilncRNAs/DNA-RNA hybrids to enable RPA loading and controlled end resection, sharpening both its surveillance specificity and its genome-stability function.\",\n      \"evidence\": \"Auxin-inducible degron with substrate-binding mapping and RNA-seq; plus RNAi, DRIP, resection assays, and RNase H1 rescue in human cells\",\n      \"pmids\": [\"30840897\", \"31086179\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How substrate selectivity is enforced mechanistically not defined\", \"Coupling between rRNA-processing and DSB roles unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Germ-cell and oocyte-specific knockouts established EXOSC10 as essential for gametogenesis and meiotic maturation, sculpting the transcriptome to permit CDK1 activation, germinal vesicle breakdown, and germ cell differentiation.\",\n      \"evidence\": \"Conditional Cre/CRISPR knockouts in mouse testis and oocytes with single-oocyte RNA-seq, immunofluorescence, and rRNA processing analysis\",\n      \"pmids\": [\"32313933\", \"29118343\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect targets driving meiotic phenotypes not fully separated\", \"Whether developmental defects stem chiefly from rRNA vs mRNA roles unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identifying USP36 as a nucleolar SUMO ligase that SUMOylates EXOSC10 at K583 to promote pre-rRNA binding established a specific functional modification required for ribosome biogenesis.\",\n      \"evidence\": \"Co-IP, SUMOylation and CLIP/binding assays, K583R mutagenesis, and RNAi rescue in human cells\",\n      \"pmids\": [\"36912080\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural effect of K583 SUMOylation on pre-rRNA engagement undefined\", \"Crosstalk with cooling-induced SUMOylation not addressed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How EXOSC10 selectively partitions among its distinct roles—nucleolar rRNA/snoRNA maturation, DSB RNA clearance, and meiotic transcriptome sculpting—and how its modifications and cofactors switch between these programs remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No unified model of substrate/role partitioning\", \"Recruitment determinants to DSBs vs nucleolus undefined\", \"Regulatory hierarchy of SUMOylation events unmapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [1, 2, 3, 8, 18]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [1, 3, 7]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [8, 14, 21]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [4, 22, 23]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 3, 23]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [1, 4, 18]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [13, 17]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [19, 20]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [15, 21]}\n    ],\n    \"complexes\": [\n      \"nuclear RNA exosome\",\n      \"TRAMP complex (functional partner)\"\n    ],\n    \"partners\": [\n      \"C1D\",\n      \"MPP6\",\n      \"MTR4\",\n      \"RRP47\",\n      \"RAD51\",\n      \"USP36\",\n      \"NAB2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}