{"gene":"RRP1","run_date":"2026-06-10T07:46:28","timeline":{"discoveries":[{"year":1991,"finding":"Drosophila Rrp1 (recombination repair protein 1) possesses apurinic endonuclease activity, double-stranded DNA 3'-exonuclease activity, single-stranded DNA renaturation activity (Mg2+-dependent), and DNA strand transfer activity. The C-terminal 252-aa region (homologous to E. coli exonuclease III and S. pneumoniae exonuclease A) is responsible for the nuclease activities, while the unique N-terminal 427-aa region contributes to strand transfer and ssDNA renaturation.","method":"Protein purification from Drosophila embryo extracts; in vitro enzymatic assays; sequence homology analysis; column chromatography co-migration of activities","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple in vitro enzymatic assays with purified protein, domain dissection, replicated across multiple papers from the same group","pmids":["1713691"],"is_preprint":false},{"year":1991,"finding":"The C-terminal exonuclease domain of Drosophila Rrp1 is required for DNA strand transfer activity in vitro; a C-terminally deleted mutant lacking nuclease activity cannot perform strand transfer, but strand transfer can be restored by providing E. coli exonuclease III in trans, demonstrating that 3'-exonuclease activity is necessary for the strand transfer reaction.","method":"E. coli overexpression of Rrp1 and truncation mutant; in vitro DNA strand transfer assay; complementation with exogenous exonuclease III","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstitution in vitro with deletion mutant and trans-complementation, single lab but multiple orthogonal methods","pmids":["1653418","7678415"],"is_preprint":false},{"year":1993,"finding":"Drosophila Rrp1 is a class II apurinic endonuclease that cleaves the phosphodiester backbone at one position 5' to the apurinic site, leaving a 3'-hydroxyl terminus that supports DNA synthesis. The specific activity is ~1×10^5 units/mg. Cleavage is specific to double-stranded DNA at the abasic site; the complementary strand and single-stranded substrates are not cleaved.","method":"In vitro endonuclease assay with 5'-end-labeled 37-bp oligonucleotide containing a single apurinic site; gel mobility analysis; DNA polymerase extension assay","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — rigorous in vitro reconstitution with defined substrate and mutagenesis controls, single lab","pmids":["7692963"],"is_preprint":false},{"year":1993,"finding":"Expression of Drosophila Rrp1 in repair-deficient E. coli (xth nfo double mutants) confers resistance to oxidative (H2O2, t-BuOOH, bleomycin) and alkylating (MMS, mitomycin C) agents. Complementation requires the C-terminal nuclease domain of Rrp1 but not the N-terminal domain, and is accompanied by up to 12-fold increase in AP endonuclease activity in cell extracts.","method":"Expression of Rrp1 constructs in repair-deficient E. coli strains BW528 and LG101; survival assays with DNA-damaging agents; AP endonuclease activity measurement in extracts","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vivo complementation with domain-deletion constructs plus biochemical activity assays, single lab with multiple orthogonal methods","pmids":["7694234"],"is_preprint":false},{"year":1994,"finding":"Site-directed mutagenesis of conserved residues in the Drosophila Rrp1 nuclease domain identified Glu-461 as essential for AP endonuclease activity; Lys-463 and Thr-462 influence substrate specificity of the nuclease. Mutants T462A, K463Q, and L484P retain protection against MMS but not against oxidative damage, demonstrating distinct specificity for alkylation versus oxidative substrates.","method":"Site-directed mutagenesis; E. coli complementation assays; purification and in vitro enzymatic activity measurements (AP endonuclease, 3'-phosphodiesterase)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — active-site mutagenesis combined with in vitro enzymatic assays and in vivo complementation, single lab","pmids":["7798276"],"is_preprint":false},{"year":1995,"finding":"Drosophila Rrp1 possesses 3'-phosphodiesterase activity (removing 3'-phosphoglycolate termini generated by oxygen radical-induced DNA cleavage) and 3'-phosphatase activity. The 3'-phosphatase activity is at least 25-fold lower than phosphodiesterase or AP endonuclease activity. The phosphodiesterase releases a 3'-hydroxyl terminus. High NaCl reduces exonuclease 25-fold but does not inhibit phosphodiesterase.","method":"In vitro assays with site-specifically damaged oligonucleotide substrates (3'-phosphoglycolate from Fe(II)-bleomycin cleavage); gel mobility shift; DNA synthesis stimulation assay","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple in vitro assays with defined substrates and domain-specific controls, single lab","pmids":["7530050"],"is_preprint":false},{"year":1996,"finding":"Drosophila Rrp1 3'-exonuclease activity exhibits DNA sequence dependence and strand specificity: it is more efficient in purine-rich than pyrimidine-rich regions, with purine-purine and 3'-pyrimidine-5'-purine dinucleotide bonds cleaved faster than 3'-purine-5'-pyrimidine or pyrimidine-pyrimidine bonds.","method":"In vitro dsDNA 3'-exonuclease assays with defined oligonucleotide substrates of varying sequence composition; gel analysis","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — rigorous in vitro biochemical assay, single lab, single study","pmids":["8918793"],"is_preprint":false},{"year":1996,"finding":"Overexpression of wild-type Drosophila Rrp1 from a heat-shock-inducible transgene reduces somatic mutation and recombination frequency induced by oxidative DNA-damaging agents (gamma-rays, bleomycin, paraquat) but not by alkylating agents (MMS, MNU), demonstrating a lesion-specific in vivo role in oxidative DNA damage repair.","method":"Drosophila w/w+ mosaic eye system (loss-of-heterozygosity assay); transgenic overexpression; heat-shock induction; treatment with multiple DNA-damaging agents","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Moderate — defined genetic system in vivo, multiple damage agents tested, transgene-dependent effect confirmed, single lab","pmids":["8643678"],"is_preprint":false},{"year":1998,"finding":"Drosophila Rrp1 has a bipartite domain structure: a highly organized, globular, predominantly alpha-helical C-terminal domain (Rrp1-C274, from Thr-406 onward) and an N-terminal ~399-aa region that is predominantly random coil and asymmetric. Both intact Rrp1 and Rrp1-C274 are monomers. The isolated C-terminal domain retains AP endonuclease activity at wild-type levels but has reduced 3'-exonuclease (210-fold) and 3'-phosphodiesterase (6.8-fold) activities.","method":"Limited proteolysis with endoproteinase Glu-C; biophysical analysis (circular dichroism, frictional coefficients); in vitro enzymatic assays of isolated domains","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — structural and enzymatic characterization of defined domains, single lab, single study","pmids":["9852053"],"is_preprint":false},{"year":1987,"finding":"The yeast (S. cerevisiae) RRP1 gene is required for processing of 27S pre-rRNA to mature 25S and 5.8S rRNAs. The rrp1 mutant also shows hypersensitivity to aminoglycoside antibiotics and a reduced 25S/18S rRNA ratio.","method":"Temperature-sensitive mutant analysis; RNA processing assays; genetic mapping; gene cloning","journal":"Journal of bacteriology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined genetic mutant with specific rRNA processing phenotype, replicated in follow-up studies","pmids":["3549696"],"is_preprint":false},{"year":1990,"finding":"In S. cerevisiae, suppressor gene SRD1 was identified by second-site suppressor screening of rrp1-1 mutants; loss-of-function srd1 alleles suppress the pre-rRNA processing defect, drug sensitivity, and thermolethality of the rrp1-1 point mutation but cannot suppress an rrp1 null allele, suggesting the SRD1 gene product interacts with or regulates the RRP1 product.","method":"Second-site suppressor screen; genetic analysis; allele-specific suppression test with disruption allele","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with suppressor screen, allele specificity confirmed, single lab","pmids":["2179050"],"is_preprint":false},{"year":2004,"finding":"S. cerevisiae Rrp1p is a nucleolar protein associated with several distinct 66S pre-ribosomal particles containing ribosomal proteins plus at least 28 nonribosomal proteins. Inactivation of Rrp1p blocks processing of 27SA3 to 27SBS pre-rRNA and of 27SB pre-rRNA to 7S plus 25.5S pre-rRNA, causing accumulation of 66S particles containing 27SA3 and 27SB(L) pre-rRNAs.","method":"Temperature-sensitive mutant inactivation; proteomic analysis of pre-ribosomal particles; RNA processing assays (Northern blot); subcellular localization (nucleolar)","journal":"RNA (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function with defined pre-rRNA processing blocks and proteomic characterization of associated particles, multiple orthogonal methods","pmids":["15100437"],"is_preprint":false},{"year":1999,"finding":"Human Nop52 (RRP1/NNP-1) is a nucleolar protein that localizes to the granular external domain of the nucleolus, excluded from rRNA transcription sites, and colocalizes with late rRNA-processing factors hPop1 and protein B23. During nucleologenesis at the end of mitosis, Nop52 is recruited at late stages via the prenucleolar body pathway, after fibrillarin and nucleolin.","method":"Immunocytochemistry with human autoantibodies; transfection of cDNA in mammalian cells; cell cycle analysis; colocalization studies with known nucleolar proteins","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct localization by immunocytochemistry and transfection with functional context (late rRNA processing stage), multiple orthogonal observations","pmids":["10341208"],"is_preprint":false},{"year":2011,"finding":"Human p32 (splicing factor 2-associated protein) directly interacts with Nop52 (RRP1/NNP-1). Nop52 competes with fibrillarin (FBL) for binding to p32 in the nucleolus. Knockdown of p32 slows early rRNA processing (47S/45S to 18S and 32S pre-rRNA). p32 is present in pre-ribosomal fractions and associates with 47S/45S and 32S pre-rRNAs, suggesting that the competitive exchange of FBL for Nop52 on p32 drives remodeling from pre-90S to pre-40S and pre-60S particles.","method":"Mass spectrometry-based interactome; immunoblotting; immunocytochemistry; cell fractionation; ultracentrifugation; siRNA knockdown; co-localization analysis","journal":"Molecular & cellular proteomics : MCP","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction by MS and immunoblot, functional knockdown data, single lab with multiple orthogonal methods","pmids":["21536856"],"is_preprint":false},{"year":2015,"finding":"Human RRP1 (Nop52/NNP-1) is required for site 2 cleavage in ITS1 of 47S/45S, 41S, and 36S pre-rRNAs. RRP1 knockdown suppresses site 2 cleavage, and double knockdown of XRN2 and RRP1 shows RRP1 accelerates this cleavage. RRP1 is present in the 90S pre-ribosomal particle and localizes to the dense fibrillar component of the nucleolus in an RNA Pol I transcription-dependent manner.","method":"siRNA knockdown (single and double with XRN2); pre-rRNA processing analysis; subcellular fractionation; immunofluorescence; actinomycin D treatment","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — loss-of-function with specific pre-rRNA cleavage site phenotype, double-knockdown epistasis, localization data, multiple orthogonal methods in single lab","pmids":["25969445"],"is_preprint":false},{"year":2021,"finding":"S. pombe Rrp1 (ortholog of S. cerevisiae Uls1, a Rad5/16-like SWI2/SNF2 translocase) directly interacts with Rad51, removes Rad51 from double-stranded DNA in an ATPase-dependent manner, and possesses E3 ubiquitin ligase activity with Rad51 as a substrate. Rrp1 also binds DNA and has DNA-dependent ATPase activity. These activities restrict genome destabilization caused by excessive Rad51.","method":"Purified protein biochemistry (DNA binding, ATPase assay, translocase assay, ubiquitin ligase assay); pull-down/direct interaction; in vivo overexpression toxicity rescue; centromere ChIP","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of translocase and ubiquitin ligase activities with purified proteins, ATPase-domain mutagenesis, multiple orthogonal methods","pmids":["34157114"],"is_preprint":false},{"year":2013,"finding":"S. pombe Rrp1 and Rrp2 interact with each other and with Swi5 (HR mediator) via yeast two-hybrid. They form co-localizing MMS-induced nuclear foci, suggesting they function as a complex. Epistasis analysis places Rrp1 in the Srs2/Swi5-dependent synthesis-dependent strand annealing HR sub-pathway, independently of Rad57 and Rqh1.","method":"Yeast two-hybrid; microscopy (foci formation); genetic epistasis analysis with HR mutants; recombination frequency measurements","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with multiple mutant combinations plus protein interaction data, single lab","pmids":["23828040"],"is_preprint":false},{"year":2020,"finding":"S. pombe Rrp1 overproduction leads to chromosome instability, growth defects, reduction in global histone levels, and mislocalization of centromere-specific histone Cnp1, phenotypes that depend on the putative DNA translocase activity of Rrp1, indicating Rrp1 modulates nucleosome dynamics at centromeres.","method":"Overexpression studies; chromosome stability assays; histone level analysis (immunoblot); Cnp1 localization by microscopy; domain mutant analysis","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple phenotypic readouts with translocase-domain dependence, single lab","pmids":["31932509"],"is_preprint":false},{"year":2025,"finding":"Human RRP1 acts as an RNA-binding protein that binds nuclear TYMS (thymidylate synthase) transcript and suppresses TYMS expression post-transcriptionally in inflammatory macrophages, thereby reducing folate/one-carbon metabolism and dampening innate inflammatory responses. Myeloid-specific RRP1-deficient mice develop severe experimental arthritis with increased pro-inflammatory cytokines.","method":"Global RNA-protein interactome purification (GRPIp); RNA-binding validation; siRNA knockdown; myeloid-specific knockout mouse model (experimental arthritis); cytokine measurement; TYMS expression analysis","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — novel RNA-binding function with in vivo knockout phenotype and mechanistic link to TYMS post-transcriptional regulation, single lab, multiple orthogonal methods","pmids":["40715096"],"is_preprint":false},{"year":2025,"finding":"In Drosophila, Rrp1 (APE1 homolog) acts as a redox regulator of long-term memory (LTM) in dorsal-anterior-lateral neurons. Rrp1 knockdown impairs LTM formation; overexpression enhances retention. Pharmacological inhibition of Rrp1 redox activity (E3330) suppresses Period and CaMKII expression. Human APE1 redox activity rescues memory deficits in Rrp1-deficient flies and promotes Period synthesis. Rrp1 is required for CREBA-mediated LTM acceleration.","method":"Neuron-specific RNAi knockdown; overexpression; pharmacological inhibition with E3330; behavioral assays (aversive olfactory LTM); transgenic rescue with human APE1; gene expression analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with specific behavioral and molecular readouts, pharmacological inhibition, cross-species rescue, single lab","pmids":["41289397"],"is_preprint":false}],"current_model":"Human RRP1 (Nop52/NNP-1) is a nucleolar RNA-binding protein required for site 2 cleavage in ITS1 of pre-rRNAs during early ribosome biogenesis, where it competes with fibrillarin for binding to p32 (C1QBP) on the 90S pre-ribosome to promote splitting into pre-40S and pre-60S particles; additionally, it functions as an mRNA-binding post-transcriptional suppressor of TYMS expression in macrophages to dampen one-carbon metabolism-driven inflammation, while its Drosophila ortholog (also called Rrp1/APE1-like) is a multifunctional DNA repair enzyme with AP endonuclease, 3'-exonuclease, 3'-phosphodiesterase, and strand transfer activities mediated by its C-terminal exonuclease III-homology domain, and also serves as a redox regulator of long-term memory formation."},"narrative":{"mechanistic_narrative":"The RRP1 symbol in this corpus maps to several distinct, organism-specific proteins, and the timeline fragments accordingly. In human cells, RRP1 (Nop52/NNP-1) is a nucleolar factor of early ribosome biogenesis: it localizes to the granular component and dense fibrillar component of the nucleolus in an RNA Pol I transcription-dependent manner and is recruited late during post-mitotic nucleologenesis [PMID:10341208, PMID:25969445]. It is a component of the 90S pre-ribosomal particle and is required for site 2 cleavage within ITS1 of 47S/45S, 41S, and 36S pre-rRNAs, acting in concert with XRN2 to accelerate this cleavage [PMID:25969445]. RRP1 directly binds p32 (C1QBP) and competes with fibrillarin for this interaction, a competitive exchange that drives remodeling of pre-90S particles into pre-40S and pre-60S [PMID:21536856]. The orthologous yeast RRP1 genes perform analogous roles in large-subunit rRNA maturation: S. cerevisiae Rrp1p is a nucleolar protein of 66S pre-ribosomal particles whose inactivation blocks 27SA3 and 27SB pre-rRNA processing toward mature 25S/5.8S rRNA [PMID:3549696, PMID:15100437]. A separate human function has been defined in inflammatory macrophages, where RRP1 acts as an mRNA-binding post-transcriptional suppressor of TYMS, restraining folate/one-carbon metabolism and innate inflammation; myeloid-specific RRP1 loss produces severe experimental arthritis [PMID:40715096]. The Drosophila protein bearing the Rrp1 name is mechanistically unrelated: it is a class II AP endonuclease with associated 3'-exonuclease, 3'-phosphodiesterase, 3'-phosphatase, and DNA strand transfer activities, all dependent on a C-terminal exonuclease III-homology domain (with Glu-461 essential for catalysis), and it protects against oxidative DNA damage in vivo and serves as a redox regulator of long-term memory [PMID:1713691, PMID:7692963, PMID:7798276, PMID:8643678, PMID:41289397]. The S. pombe Rrp1 is yet another distinct protein — a Rad5/16-like SWI2/SNF2 translocase and Rad51-targeting E3 ubiquitin ligase acting in homologous recombination and centromeric nucleosome dynamics [PMID:34157114, PMID:23828040]. These activities should not be conflated into a single protein; the timeline describes name-sharing factors across species rather than one conserved enzyme.","teleology":[{"year":1987,"claim":"Established that a gene named RRP1 is required for ribosomal RNA maturation, defining the founding ribosome-biogenesis function of the yeast gene.","evidence":"Temperature-sensitive mutant analysis and RNA processing assays in S. cerevisiae","pmids":["3549696"],"confidence":"Medium","gaps":["Did not define the molecular activity of Rrp1p","No physical association with pre-ribosomes shown at this stage"]},{"year":1990,"claim":"Genetic suppressor screening implicated a partner gene (SRD1) functionally interacting with yeast RRP1, framing RRP1 within a regulatable processing pathway.","evidence":"Second-site suppressor screen with allele-specificity test in S. cerevisiae","pmids":["2179050"],"confidence":"Medium","gaps":["No direct physical interaction demonstrated between SRD1 and RRP1 products","Molecular mechanism of suppression unknown"]},{"year":1991,"claim":"Resolved that the Drosophila protein named Rrp1 is a multifunctional DNA repair enzyme, assigning AP endonuclease, 3'-exonuclease, ssDNA renaturation, and strand transfer activities to defined domains.","evidence":"Protein purification from embryo extracts, in vitro enzymatic assays, domain dissection, and trans-complementation with E. coli exonuclease III","pmids":["1713691","1653418","7678415"],"confidence":"High","gaps":["No structure of the full-length protein","Physiological substrate in vivo not yet defined"]},{"year":1993,"claim":"Defined the Drosophila Rrp1 cleavage chemistry and demonstrated it functions in cellular DNA repair, establishing it as a class II AP endonuclease active in vivo.","evidence":"In vitro endonuclease assays with defined abasic substrates plus complementation of repair-deficient E. coli (xth nfo) with damage-survival assays","pmids":["7692963","7694234"],"confidence":"High","gaps":["Endogenous Drosophila phenotype of Rrp1 loss not addressed","Did not distinguish oxidative versus alkylation lesion preference"]},{"year":1994,"claim":"Active-site mutagenesis identified catalytic and specificity-determining residues and uncovered separable handling of alkylation versus oxidative lesions by Drosophila Rrp1.","evidence":"Site-directed mutagenesis (Glu-461, Thr-462, Lys-463) with E. coli complementation and in vitro nuclease assays","pmids":["7798276"],"confidence":"High","gaps":["Structural basis of lesion discrimination not resolved","No in vivo Drosophila validation of residue requirements"]},{"year":1995,"claim":"Extended the Drosophila Rrp1 activity repertoire to 3'-end cleanup, showing it removes oxidative 3'-blocking groups to generate primer-ready termini.","evidence":"In vitro assays with site-specifically damaged oligonucleotides bearing 3'-phosphoglycolate and 3'-phosphate termini","pmids":["7530050"],"confidence":"High","gaps":["Relative in vivo contribution of each activity unknown","No coupling to downstream repair polymerase/ligase demonstrated"]},{"year":1996,"claim":"Demonstrated a lesion-specific in vivo repair role for Drosophila Rrp1 and characterized sequence dependence of its exonuclease, linking biochemistry to genome protection.","evidence":"Drosophila mosaic eye loss-of-heterozygosity assay with inducible transgene overexpression, plus in vitro exonuclease sequence-preference assays","pmids":["8643678","8918793"],"confidence":"High","gaps":["Loss-of-function (rather than overexpression) phenotype not tested","Endogenous expression and regulation not characterized"]},{"year":1998,"claim":"Defined the bipartite architecture of Drosophila Rrp1, mapping catalytic activities to a folded C-terminal exonuclease III-homology domain and assigning a disordered N-terminus.","evidence":"Limited proteolysis, circular dichroism, frictional analysis, and enzymatic assays of isolated domains","pmids":["9852053"],"confidence":"Medium","gaps":["No high-resolution crystal structure","Function of the disordered N-terminal region beyond strand transfer unresolved"]},{"year":1999,"claim":"Identified human RRP1 (Nop52/NNP-1) as a nucleolar protein of late rRNA processing, placing the human gene in ribosome biogenesis rather than DNA repair.","evidence":"Immunocytochemistry with autoantibodies, cDNA transfection, cell-cycle and colocalization analysis with hPop1 and B23 in human cells","pmids":["10341208"],"confidence":"High","gaps":["No direct rRNA-processing function demonstrated yet","Molecular activity of human RRP1 undefined at this stage"]},{"year":2004,"claim":"Established yeast Rrp1p as a 66S pre-ribosomal particle component and pinpointed the specific pre-rRNA processing steps it controls.","evidence":"Temperature-sensitive inactivation, proteomic analysis of pre-ribosomal particles, and Northern blot processing assays in S. cerevisiae","pmids":["15100437"],"confidence":"High","gaps":["Whether Rrp1p has catalytic activity or is a scaffold unresolved","Direct RNA contacts not mapped"]},{"year":2011,"claim":"Provided a molecular mechanism for human RRP1 in pre-ribosome remodeling: competition with fibrillarin for p32 binding to drive particle splitting.","evidence":"Mass-spectrometry interactome, immunoblotting, cell fractionation, ultracentrifugation, and siRNA knockdown in human cells","pmids":["21536856"],"confidence":"Medium","gaps":["Competitive exchange model inferred rather than directly visualized","Structural basis of the p32 interaction unknown"]},{"year":2015,"claim":"Defined the precise pre-rRNA cleavage step controlled by human RRP1, assigning it to ITS1 site 2 cleavage on the 90S particle and showing functional interplay with XRN2.","evidence":"Single and double siRNA knockdown with pre-rRNA processing analysis, fractionation, immunofluorescence, and actinomycin D treatment in human cells","pmids":["25969445"],"confidence":"High","gaps":["Whether RRP1 itself cleaves or recruits a nuclease is unresolved","RNA-binding determinants on RRP1 not mapped"]},{"year":2013,"claim":"Established that the S. pombe protein named Rrp1 functions in homologous recombination, forming a complex with Rrp2 and Swi5 in an SDSA sub-pathway.","evidence":"Yeast two-hybrid, MMS-induced foci microscopy, and genetic epistasis with HR mutants in S. pombe","pmids":["23828040"],"confidence":"Medium","gaps":["Biochemical activity not defined in this study","Direct DNA or Rad51 engagement not yet shown"]},{"year":2020,"claim":"Revealed that S. pombe Rrp1 modulates centromeric nucleosome dynamics, linking its translocase activity to chromosome stability and histone homeostasis.","evidence":"Overexpression, chromosome stability assays, histone immunoblotting, Cnp1 localization microscopy, and translocase-domain mutant analysis","pmids":["31932509"],"confidence":"Medium","gaps":["Effect studied via overproduction rather than physiological levels","Direct nucleosome remodeling not reconstituted"]},{"year":2021,"claim":"Reconstituted the biochemical activities of S. pombe Rrp1 as a Rad51-stripping DNA translocase and Rad51-directed E3 ubiquitin ligase that restrains genome destabilization.","evidence":"Purified-protein DNA binding, ATPase, translocase, and ubiquitin ligase assays plus in vivo overexpression toxicity rescue and centromere ChIP in S. pombe","pmids":["34157114"],"confidence":"High","gaps":["Relationship of these activities to the human/fly proteins of the same name unestablished","Endogenous regulation of the translocase/ligase switch unknown"]},{"year":2025,"claim":"Uncovered a non-ribosomal function for human RRP1 as an mRNA-binding suppressor of TYMS that dampens one-carbon-metabolism-driven inflammation in macrophages.","evidence":"Global RNA-protein interactome purification, RNA-binding validation, siRNA knockdown, and myeloid-specific knockout mouse arthritis model","pmids":["40715096"],"confidence":"Medium","gaps":["Relationship between this cytoplasmic mRNA-regulatory role and the nucleolar rRNA-processing role unresolved","RNA-binding domain on RRP1 not mapped"]},{"year":2025,"claim":"Defined a neuronal redox function for Drosophila Rrp1 in long-term memory, mechanistically tying its APE1-like redox activity to Period and CaMKII expression.","evidence":"Neuron-specific RNAi and overexpression, E3330 pharmacological inhibition, aversive olfactory memory assays, and human APE1 transgenic rescue in Drosophila","pmids":["41289397"],"confidence":"Medium","gaps":["Direct redox targets of Rrp1 in neurons not identified","Connection between DNA-repair and redox-signaling roles unresolved"]},{"year":null,"claim":"It remains unresolved whether the nucleolar rRNA-processing RRP1 and the cytoplasmic TYMS-mRNA-suppressing RRP1 are the same human protein operating in two compartments, and how the species-specific DNA-repair, HR-translocase, and ribosome-biogenesis activities relate at the gene level.","evidence":"No timeline discovery reconciles the divergent activities across human, fly, and yeast proteins sharing the RRP1 name","pmids":[],"confidence":"Low","gaps":["No study bridges the human nucleolar and macrophage functions","Orthology relationships among the species-specific activities are not experimentally established in the corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[13,14,18]},{"term_id":"GO:0140097","term_label":"catalytic activity, acting on DNA","supporting_discovery_ids":[0,2,5]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,2,5,8]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,15]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[15]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[15]}],"localization":[{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[11,12,14]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[12,14,18]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[9,11,13,14]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[0,2,3,7]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[18]}],"complexes":["90S pre-ribosomal particle","66S pre-ribosomal particle"],"partners":["C1QBP","FBL","XRN2","RAD51","RRP2","SWI5","TYMS"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P56182","full_name":"Ribosomal RNA processing protein 1 homolog A","aliases":["Novel nuclear protein 1","NNP-1","Nucleolar protein Nop52","RRP1-like protein"],"length_aa":461,"mass_kda":52.8,"function":"Plays a critical role in the generation of 28S rRNA","subcellular_location":"Nucleus, nucleolus","url":"https://www.uniprot.org/uniprotkb/P56182/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/RRP1","classification":"Common Essential","n_dependent_lines":1043,"n_total_lines":1208,"dependency_fraction":0.8634105960264901},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000160214","cell_line_id":"CID000861","localizations":[{"compartment":"nucleolus_gc","grade":3},{"compartment":"nucleoplasm","grade":1}],"interactors":[{"gene":"DDOST","stoichiometry":0.2},{"gene":"DRG1","stoichiometry":0.2},{"gene":"LMNB1","stoichiometry":0.2},{"gene":"OST4","stoichiometry":0.2},{"gene":"RACK1","stoichiometry":0.2},{"gene":"RPN1","stoichiometry":0.2},{"gene":"RPN2","stoichiometry":0.2},{"gene":"KPNA3","stoichiometry":0.2},{"gene":"NIFK","stoichiometry":0.2},{"gene":"UBE2O","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000861","total_profiled":1310},"omim":[{"mim_id":"610654","title":"RIBOSOMAL RNA-PROCESSING 1B; RRP1B","url":"https://www.omim.org/entry/610654"},{"mim_id":"610653","title":"RIBOSOMAL RNA-PROCESSING 1; RRP1","url":"https://www.omim.org/entry/610653"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoli","reliability":"Enhanced"},{"location":"Mitotic chromosome","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RRP1"},"hgnc":{"alias_symbol":["NNP-1","Nop52","NOP52","RRP1A","D21S2056E"],"prev_symbol":[]},"alphafold":{"accession":"P56182","domains":[{"cath_id":"-","chopping":"186-241_294-371","consensus_level":"medium","plddt":84.277,"start":186,"end":371},{"cath_id":"1.25.40","chopping":"10-167","consensus_level":"high","plddt":95.0324,"start":10,"end":167}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P56182","model_url":"https://alphafold.ebi.ac.uk/files/AF-P56182-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P56182-F1-predicted_aligned_error_v6.png","plddt_mean":75.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RRP1","jax_strain_url":"https://www.jax.org/strain/search?query=RRP1"},"sequence":{"accession":"P56182","fasta_url":"https://rest.uniprot.org/uniprotkb/P56182.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P56182/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P56182"}},"corpus_meta":[{"pmid":"19210621","id":"PMC_19210621","title":"Rrp1, a cyclic-di-GMP-producing response regulator, is an important regulator of Borrelia burgdorferi core cellular functions.","date":"2009","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/19210621","citation_count":113,"is_preprint":false},{"pmid":"15100437","id":"PMC_15100437","title":"Role of the yeast Rrp1 protein in the dynamics of pre-ribosome maturation.","date":"2004","source":"RNA (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/15100437","citation_count":85,"is_preprint":false},{"pmid":"21542866","id":"PMC_21542866","title":"The diguanylate cyclase, Rrp1, regulates critical steps in the enzootic cycle of the Lyme disease spirochetes.","date":"2011","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/21542866","citation_count":82,"is_preprint":false},{"pmid":"1713691","id":"PMC_1713691","title":"Drosophila Rrp1 protein: an apurinic endonuclease with homologous recombination activities.","date":"1991","source":"Proceedings of the 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Isolation of mutants deficient in repair of oxidative DNA damage.","date":"1994","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7798276","citation_count":18,"is_preprint":false},{"pmid":"8918793","id":"PMC_8918793","title":"Drosophila Rrp1 3'-exonuclease: demonstration of DNA sequence dependence and DNA strand specificity.","date":"1996","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/8918793","citation_count":16,"is_preprint":false},{"pmid":"15606508","id":"PMC_15606508","title":"Upregulation of the NNP-1 (novel nuclear protein-1, D21S2056E) gene in keloid tissue determined by cDNA microarray and in situ hybridization.","date":"2004","source":"The British journal of dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/15606508","citation_count":16,"is_preprint":false},{"pmid":"8643678","id":"PMC_8643678","title":"Overexpression of a Rrp1 transgene reduces the somatic mutation and recombination frequency induced by oxidative DNA damage in Drosophila melanogaster.","date":"1996","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/8643678","citation_count":15,"is_preprint":false},{"pmid":"19185548","id":"PMC_19185548","title":"The role of novel genes rrp1(+) and rrp2(+) in the repair of DNA damage in Schizosaccharomyces pombe.","date":"2009","source":"DNA repair","url":"https://pubmed.ncbi.nlm.nih.gov/19185548","citation_count":13,"is_preprint":false},{"pmid":"12209604","id":"PMC_12209604","title":"Novel products of the HUD, HUC, NNP-1 and alpha-internexin genes identified by autologous antibody screening of a pediatric neuroblastoma library.","date":"2002","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/12209604","citation_count":13,"is_preprint":false},{"pmid":"2179050","id":"PMC_2179050","title":"srd1, a Saccharomyces cerevisiae suppressor of the temperature-sensitive pre-rRNA processing defect of rrp1-1.","date":"1990","source":"Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/2179050","citation_count":13,"is_preprint":false},{"pmid":"7692963","id":"PMC_7692963","title":"Characterization of the apurinic endonuclease activity of Drosophila Rrp1.","date":"1993","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7692963","citation_count":13,"is_preprint":false},{"pmid":"9192856","id":"PMC_9192856","title":"The NNP-1 gene (D21S2056E), which encodes a novel nuclear protein, maps in close proximity to the cystatin B gene within the EPM1 and APECED critical region on 21q22.3.","date":"1997","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/9192856","citation_count":11,"is_preprint":false},{"pmid":"34157114","id":"PMC_34157114","title":"Rrp1 translocase and ubiquitin ligase activities restrict the genome destabilising effects of Rad51 in fission yeast.","date":"2021","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/34157114","citation_count":8,"is_preprint":false},{"pmid":"23828040","id":"PMC_23828040","title":"Involvement of Schizosaccharomyces pombe rrp1+ and rrp2+ in the Srs2- and Swi5/Sfr1-dependent pathway in response to DNA damage and replication inhibition.","date":"2013","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/23828040","citation_count":8,"is_preprint":false},{"pmid":"9852053","id":"PMC_9852053","title":"Drosophila Rrp1 domain structure as defined by limited proteolysis and biophysical analyses.","date":"1998","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9852053","citation_count":8,"is_preprint":false},{"pmid":"39775665","id":"PMC_39775665","title":"MCP5, a methyl-accepting chemotaxis protein regulated by both the Hk1-Rrp1 and Rrp2-RpoN-RpoS pathways, is required for the immune evasion of Borrelia burgdorferi.","date":"2024","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/39775665","citation_count":6,"is_preprint":false},{"pmid":"40715096","id":"PMC_40715096","title":"The RNA-binding protein RRP1 brakes macrophage one-carbon metabolism to suppress autoinflammation.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/40715096","citation_count":5,"is_preprint":false},{"pmid":"35716431","id":"PMC_35716431","title":"Rrp1, Rrp2 and Uls1 - Yeast SWI2/SNF2 DNA dependent translocases in genome stability maintenance.","date":"2022","source":"DNA repair","url":"https://pubmed.ncbi.nlm.nih.gov/35716431","citation_count":5,"is_preprint":false},{"pmid":"31932509","id":"PMC_31932509","title":"Schizosaccharomyces pombe DNA translocases Rrp1 and Rrp2 have distinct roles at centromeres and telomeres that ensure genome stability.","date":"2020","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/31932509","citation_count":2,"is_preprint":false},{"pmid":"38915556","id":"PMC_38915556","title":"MCP5, a methyl-accepting chemotaxis protein regulated by both the Hk1-Rrp1 and Rrp2-RpoN-RpoS pathways, is required for the immune evasion of Borrelia burgdorferi.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/38915556","citation_count":2,"is_preprint":false},{"pmid":"38905307","id":"PMC_38905307","title":"Replication stress response in fission yeast differentially depends on maintaining proper levels of Srs2 helicase and Rrp1, Rrp2 DNA translocases.","date":"2024","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/38905307","citation_count":1,"is_preprint":false},{"pmid":"41289397","id":"PMC_41289397","title":"Redox regulation of memory formation by Rrp1 in Drosophila.","date":"2025","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/41289397","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":18054,"output_tokens":5650,"usd":0.069456,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14049,"output_tokens":5520,"usd":0.104123,"stage2_stop_reason":"end_turn"},"total_usd":0.173579,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1991,\n      \"finding\": \"Drosophila Rrp1 (recombination repair protein 1) possesses apurinic endonuclease activity, double-stranded DNA 3'-exonuclease activity, single-stranded DNA renaturation activity (Mg2+-dependent), and DNA strand transfer activity. The C-terminal 252-aa region (homologous to E. coli exonuclease III and S. pneumoniae exonuclease A) is responsible for the nuclease activities, while the unique N-terminal 427-aa region contributes to strand transfer and ssDNA renaturation.\",\n      \"method\": \"Protein purification from Drosophila embryo extracts; in vitro enzymatic assays; sequence homology analysis; column chromatography co-migration of activities\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple in vitro enzymatic assays with purified protein, domain dissection, replicated across multiple papers from the same group\",\n      \"pmids\": [\"1713691\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"The C-terminal exonuclease domain of Drosophila Rrp1 is required for DNA strand transfer activity in vitro; a C-terminally deleted mutant lacking nuclease activity cannot perform strand transfer, but strand transfer can be restored by providing E. coli exonuclease III in trans, demonstrating that 3'-exonuclease activity is necessary for the strand transfer reaction.\",\n      \"method\": \"E. coli overexpression of Rrp1 and truncation mutant; in vitro DNA strand transfer assay; complementation with exogenous exonuclease III\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstitution in vitro with deletion mutant and trans-complementation, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"1653418\", \"7678415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"Drosophila Rrp1 is a class II apurinic endonuclease that cleaves the phosphodiester backbone at one position 5' to the apurinic site, leaving a 3'-hydroxyl terminus that supports DNA synthesis. The specific activity is ~1×10^5 units/mg. Cleavage is specific to double-stranded DNA at the abasic site; the complementary strand and single-stranded substrates are not cleaved.\",\n      \"method\": \"In vitro endonuclease assay with 5'-end-labeled 37-bp oligonucleotide containing a single apurinic site; gel mobility analysis; DNA polymerase extension assay\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — rigorous in vitro reconstitution with defined substrate and mutagenesis controls, single lab\",\n      \"pmids\": [\"7692963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"Expression of Drosophila Rrp1 in repair-deficient E. coli (xth nfo double mutants) confers resistance to oxidative (H2O2, t-BuOOH, bleomycin) and alkylating (MMS, mitomycin C) agents. Complementation requires the C-terminal nuclease domain of Rrp1 but not the N-terminal domain, and is accompanied by up to 12-fold increase in AP endonuclease activity in cell extracts.\",\n      \"method\": \"Expression of Rrp1 constructs in repair-deficient E. coli strains BW528 and LG101; survival assays with DNA-damaging agents; AP endonuclease activity measurement in extracts\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vivo complementation with domain-deletion constructs plus biochemical activity assays, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"7694234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Site-directed mutagenesis of conserved residues in the Drosophila Rrp1 nuclease domain identified Glu-461 as essential for AP endonuclease activity; Lys-463 and Thr-462 influence substrate specificity of the nuclease. Mutants T462A, K463Q, and L484P retain protection against MMS but not against oxidative damage, demonstrating distinct specificity for alkylation versus oxidative substrates.\",\n      \"method\": \"Site-directed mutagenesis; E. coli complementation assays; purification and in vitro enzymatic activity measurements (AP endonuclease, 3'-phosphodiesterase)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — active-site mutagenesis combined with in vitro enzymatic assays and in vivo complementation, single lab\",\n      \"pmids\": [\"7798276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Drosophila Rrp1 possesses 3'-phosphodiesterase activity (removing 3'-phosphoglycolate termini generated by oxygen radical-induced DNA cleavage) and 3'-phosphatase activity. The 3'-phosphatase activity is at least 25-fold lower than phosphodiesterase or AP endonuclease activity. The phosphodiesterase releases a 3'-hydroxyl terminus. High NaCl reduces exonuclease 25-fold but does not inhibit phosphodiesterase.\",\n      \"method\": \"In vitro assays with site-specifically damaged oligonucleotide substrates (3'-phosphoglycolate from Fe(II)-bleomycin cleavage); gel mobility shift; DNA synthesis stimulation assay\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple in vitro assays with defined substrates and domain-specific controls, single lab\",\n      \"pmids\": [\"7530050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Drosophila Rrp1 3'-exonuclease activity exhibits DNA sequence dependence and strand specificity: it is more efficient in purine-rich than pyrimidine-rich regions, with purine-purine and 3'-pyrimidine-5'-purine dinucleotide bonds cleaved faster than 3'-purine-5'-pyrimidine or pyrimidine-pyrimidine bonds.\",\n      \"method\": \"In vitro dsDNA 3'-exonuclease assays with defined oligonucleotide substrates of varying sequence composition; gel analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — rigorous in vitro biochemical assay, single lab, single study\",\n      \"pmids\": [\"8918793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Overexpression of wild-type Drosophila Rrp1 from a heat-shock-inducible transgene reduces somatic mutation and recombination frequency induced by oxidative DNA-damaging agents (gamma-rays, bleomycin, paraquat) but not by alkylating agents (MMS, MNU), demonstrating a lesion-specific in vivo role in oxidative DNA damage repair.\",\n      \"method\": \"Drosophila w/w+ mosaic eye system (loss-of-heterozygosity assay); transgenic overexpression; heat-shock induction; treatment with multiple DNA-damaging agents\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined genetic system in vivo, multiple damage agents tested, transgene-dependent effect confirmed, single lab\",\n      \"pmids\": [\"8643678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Drosophila Rrp1 has a bipartite domain structure: a highly organized, globular, predominantly alpha-helical C-terminal domain (Rrp1-C274, from Thr-406 onward) and an N-terminal ~399-aa region that is predominantly random coil and asymmetric. Both intact Rrp1 and Rrp1-C274 are monomers. The isolated C-terminal domain retains AP endonuclease activity at wild-type levels but has reduced 3'-exonuclease (210-fold) and 3'-phosphodiesterase (6.8-fold) activities.\",\n      \"method\": \"Limited proteolysis with endoproteinase Glu-C; biophysical analysis (circular dichroism, frictional coefficients); in vitro enzymatic assays of isolated domains\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — structural and enzymatic characterization of defined domains, single lab, single study\",\n      \"pmids\": [\"9852053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1987,\n      \"finding\": \"The yeast (S. cerevisiae) RRP1 gene is required for processing of 27S pre-rRNA to mature 25S and 5.8S rRNAs. The rrp1 mutant also shows hypersensitivity to aminoglycoside antibiotics and a reduced 25S/18S rRNA ratio.\",\n      \"method\": \"Temperature-sensitive mutant analysis; RNA processing assays; genetic mapping; gene cloning\",\n      \"journal\": \"Journal of bacteriology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined genetic mutant with specific rRNA processing phenotype, replicated in follow-up studies\",\n      \"pmids\": [\"3549696\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"In S. cerevisiae, suppressor gene SRD1 was identified by second-site suppressor screening of rrp1-1 mutants; loss-of-function srd1 alleles suppress the pre-rRNA processing defect, drug sensitivity, and thermolethality of the rrp1-1 point mutation but cannot suppress an rrp1 null allele, suggesting the SRD1 gene product interacts with or regulates the RRP1 product.\",\n      \"method\": \"Second-site suppressor screen; genetic analysis; allele-specific suppression test with disruption allele\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with suppressor screen, allele specificity confirmed, single lab\",\n      \"pmids\": [\"2179050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"S. cerevisiae Rrp1p is a nucleolar protein associated with several distinct 66S pre-ribosomal particles containing ribosomal proteins plus at least 28 nonribosomal proteins. Inactivation of Rrp1p blocks processing of 27SA3 to 27SBS pre-rRNA and of 27SB pre-rRNA to 7S plus 25.5S pre-rRNA, causing accumulation of 66S particles containing 27SA3 and 27SB(L) pre-rRNAs.\",\n      \"method\": \"Temperature-sensitive mutant inactivation; proteomic analysis of pre-ribosomal particles; RNA processing assays (Northern blot); subcellular localization (nucleolar)\",\n      \"journal\": \"RNA (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function with defined pre-rRNA processing blocks and proteomic characterization of associated particles, multiple orthogonal methods\",\n      \"pmids\": [\"15100437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Human Nop52 (RRP1/NNP-1) is a nucleolar protein that localizes to the granular external domain of the nucleolus, excluded from rRNA transcription sites, and colocalizes with late rRNA-processing factors hPop1 and protein B23. During nucleologenesis at the end of mitosis, Nop52 is recruited at late stages via the prenucleolar body pathway, after fibrillarin and nucleolin.\",\n      \"method\": \"Immunocytochemistry with human autoantibodies; transfection of cDNA in mammalian cells; cell cycle analysis; colocalization studies with known nucleolar proteins\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by immunocytochemistry and transfection with functional context (late rRNA processing stage), multiple orthogonal observations\",\n      \"pmids\": [\"10341208\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Human p32 (splicing factor 2-associated protein) directly interacts with Nop52 (RRP1/NNP-1). Nop52 competes with fibrillarin (FBL) for binding to p32 in the nucleolus. Knockdown of p32 slows early rRNA processing (47S/45S to 18S and 32S pre-rRNA). p32 is present in pre-ribosomal fractions and associates with 47S/45S and 32S pre-rRNAs, suggesting that the competitive exchange of FBL for Nop52 on p32 drives remodeling from pre-90S to pre-40S and pre-60S particles.\",\n      \"method\": \"Mass spectrometry-based interactome; immunoblotting; immunocytochemistry; cell fractionation; ultracentrifugation; siRNA knockdown; co-localization analysis\",\n      \"journal\": \"Molecular & cellular proteomics : MCP\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction by MS and immunoblot, functional knockdown data, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"21536856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Human RRP1 (Nop52/NNP-1) is required for site 2 cleavage in ITS1 of 47S/45S, 41S, and 36S pre-rRNAs. RRP1 knockdown suppresses site 2 cleavage, and double knockdown of XRN2 and RRP1 shows RRP1 accelerates this cleavage. RRP1 is present in the 90S pre-ribosomal particle and localizes to the dense fibrillar component of the nucleolus in an RNA Pol I transcription-dependent manner.\",\n      \"method\": \"siRNA knockdown (single and double with XRN2); pre-rRNA processing analysis; subcellular fractionation; immunofluorescence; actinomycin D treatment\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with specific pre-rRNA cleavage site phenotype, double-knockdown epistasis, localization data, multiple orthogonal methods in single lab\",\n      \"pmids\": [\"25969445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"S. pombe Rrp1 (ortholog of S. cerevisiae Uls1, a Rad5/16-like SWI2/SNF2 translocase) directly interacts with Rad51, removes Rad51 from double-stranded DNA in an ATPase-dependent manner, and possesses E3 ubiquitin ligase activity with Rad51 as a substrate. Rrp1 also binds DNA and has DNA-dependent ATPase activity. These activities restrict genome destabilization caused by excessive Rad51.\",\n      \"method\": \"Purified protein biochemistry (DNA binding, ATPase assay, translocase assay, ubiquitin ligase assay); pull-down/direct interaction; in vivo overexpression toxicity rescue; centromere ChIP\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of translocase and ubiquitin ligase activities with purified proteins, ATPase-domain mutagenesis, multiple orthogonal methods\",\n      \"pmids\": [\"34157114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"S. pombe Rrp1 and Rrp2 interact with each other and with Swi5 (HR mediator) via yeast two-hybrid. They form co-localizing MMS-induced nuclear foci, suggesting they function as a complex. Epistasis analysis places Rrp1 in the Srs2/Swi5-dependent synthesis-dependent strand annealing HR sub-pathway, independently of Rad57 and Rqh1.\",\n      \"method\": \"Yeast two-hybrid; microscopy (foci formation); genetic epistasis analysis with HR mutants; recombination frequency measurements\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with multiple mutant combinations plus protein interaction data, single lab\",\n      \"pmids\": [\"23828040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"S. pombe Rrp1 overproduction leads to chromosome instability, growth defects, reduction in global histone levels, and mislocalization of centromere-specific histone Cnp1, phenotypes that depend on the putative DNA translocase activity of Rrp1, indicating Rrp1 modulates nucleosome dynamics at centromeres.\",\n      \"method\": \"Overexpression studies; chromosome stability assays; histone level analysis (immunoblot); Cnp1 localization by microscopy; domain mutant analysis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple phenotypic readouts with translocase-domain dependence, single lab\",\n      \"pmids\": [\"31932509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Human RRP1 acts as an RNA-binding protein that binds nuclear TYMS (thymidylate synthase) transcript and suppresses TYMS expression post-transcriptionally in inflammatory macrophages, thereby reducing folate/one-carbon metabolism and dampening innate inflammatory responses. Myeloid-specific RRP1-deficient mice develop severe experimental arthritis with increased pro-inflammatory cytokines.\",\n      \"method\": \"Global RNA-protein interactome purification (GRPIp); RNA-binding validation; siRNA knockdown; myeloid-specific knockout mouse model (experimental arthritis); cytokine measurement; TYMS expression analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — novel RNA-binding function with in vivo knockout phenotype and mechanistic link to TYMS post-transcriptional regulation, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"40715096\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In Drosophila, Rrp1 (APE1 homolog) acts as a redox regulator of long-term memory (LTM) in dorsal-anterior-lateral neurons. Rrp1 knockdown impairs LTM formation; overexpression enhances retention. Pharmacological inhibition of Rrp1 redox activity (E3330) suppresses Period and CaMKII expression. Human APE1 redox activity rescues memory deficits in Rrp1-deficient flies and promotes Period synthesis. Rrp1 is required for CREBA-mediated LTM acceleration.\",\n      \"method\": \"Neuron-specific RNAi knockdown; overexpression; pharmacological inhibition with E3330; behavioral assays (aversive olfactory LTM); transgenic rescue with human APE1; gene expression analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with specific behavioral and molecular readouts, pharmacological inhibition, cross-species rescue, single lab\",\n      \"pmids\": [\"41289397\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Human RRP1 (Nop52/NNP-1) is a nucleolar RNA-binding protein required for site 2 cleavage in ITS1 of pre-rRNAs during early ribosome biogenesis, where it competes with fibrillarin for binding to p32 (C1QBP) on the 90S pre-ribosome to promote splitting into pre-40S and pre-60S particles; additionally, it functions as an mRNA-binding post-transcriptional suppressor of TYMS expression in macrophages to dampen one-carbon metabolism-driven inflammation, while its Drosophila ortholog (also called Rrp1/APE1-like) is a multifunctional DNA repair enzyme with AP endonuclease, 3'-exonuclease, 3'-phosphodiesterase, and strand transfer activities mediated by its C-terminal exonuclease III-homology domain, and also serves as a redox regulator of long-term memory formation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"The RRP1 symbol in this corpus maps to several distinct, organism-specific proteins, and the timeline fragments accordingly. In human cells, RRP1 (Nop52/NNP-1) is a nucleolar factor of early ribosome biogenesis: it localizes to the granular component and dense fibrillar component of the nucleolus in an RNA Pol I transcription-dependent manner and is recruited late during post-mitotic nucleologenesis [#12, #14]. It is a component of the 90S pre-ribosomal particle and is required for site 2 cleavage within ITS1 of 47S/45S, 41S, and 36S pre-rRNAs, acting in concert with XRN2 to accelerate this cleavage [#14]. RRP1 directly binds p32 (C1QBP) and competes with fibrillarin for this interaction, a competitive exchange that drives remodeling of pre-90S particles into pre-40S and pre-60S [#13]. The orthologous yeast RRP1 genes perform analogous roles in large-subunit rRNA maturation: S. cerevisiae Rrp1p is a nucleolar protein of 66S pre-ribosomal particles whose inactivation blocks 27SA3 and 27SB pre-rRNA processing toward mature 25S/5.8S rRNA [#9, #11]. A separate human function has been defined in inflammatory macrophages, where RRP1 acts as an mRNA-binding post-transcriptional suppressor of TYMS, restraining folate/one-carbon metabolism and innate inflammation; myeloid-specific RRP1 loss produces severe experimental arthritis [#18]. The Drosophila protein bearing the Rrp1 name is mechanistically unrelated: it is a class II AP endonuclease with associated 3'-exonuclease, 3'-phosphodiesterase, 3'-phosphatase, and DNA strand transfer activities, all dependent on a C-terminal exonuclease III-homology domain (with Glu-461 essential for catalysis), and it protects against oxidative DNA damage in vivo and serves as a redox regulator of long-term memory [#0, #2, #4, #7, #19]. The S. pombe Rrp1 is yet another distinct protein — a Rad5/16-like SWI2/SNF2 translocase and Rad51-targeting E3 ubiquitin ligase acting in homologous recombination and centromeric nucleosome dynamics [#15, #16]. These activities should not be conflated into a single protein; the timeline describes name-sharing factors across species rather than one conserved enzyme.\",\n  \"teleology\": [\n    {\n      \"year\": 1987,\n      \"claim\": \"Established that a gene named RRP1 is required for ribosomal RNA maturation, defining the founding ribosome-biogenesis function of the yeast gene.\",\n      \"evidence\": \"Temperature-sensitive mutant analysis and RNA processing assays in S. cerevisiae\",\n      \"pmids\": [\"3549696\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define the molecular activity of Rrp1p\", \"No physical association with pre-ribosomes shown at this stage\"]\n    },\n    {\n      \"year\": 1990,\n      \"claim\": \"Genetic suppressor screening implicated a partner gene (SRD1) functionally interacting with yeast RRP1, framing RRP1 within a regulatable processing pathway.\",\n      \"evidence\": \"Second-site suppressor screen with allele-specificity test in S. cerevisiae\",\n      \"pmids\": [\"2179050\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct physical interaction demonstrated between SRD1 and RRP1 products\", \"Molecular mechanism of suppression unknown\"]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"Resolved that the Drosophila protein named Rrp1 is a multifunctional DNA repair enzyme, assigning AP endonuclease, 3'-exonuclease, ssDNA renaturation, and strand transfer activities to defined domains.\",\n      \"evidence\": \"Protein purification from embryo extracts, in vitro enzymatic assays, domain dissection, and trans-complementation with E. coli exonuclease III\",\n      \"pmids\": [\"1713691\", \"1653418\", \"7678415\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structure of the full-length protein\", \"Physiological substrate in vivo not yet defined\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Defined the Drosophila Rrp1 cleavage chemistry and demonstrated it functions in cellular DNA repair, establishing it as a class II AP endonuclease active in vivo.\",\n      \"evidence\": \"In vitro endonuclease assays with defined abasic substrates plus complementation of repair-deficient E. coli (xth nfo) with damage-survival assays\",\n      \"pmids\": [\"7692963\", \"7694234\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous Drosophila phenotype of Rrp1 loss not addressed\", \"Did not distinguish oxidative versus alkylation lesion preference\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Active-site mutagenesis identified catalytic and specificity-determining residues and uncovered separable handling of alkylation versus oxidative lesions by Drosophila Rrp1.\",\n      \"evidence\": \"Site-directed mutagenesis (Glu-461, Thr-462, Lys-463) with E. coli complementation and in vitro nuclease assays\",\n      \"pmids\": [\"7798276\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of lesion discrimination not resolved\", \"No in vivo Drosophila validation of residue requirements\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Extended the Drosophila Rrp1 activity repertoire to 3'-end cleanup, showing it removes oxidative 3'-blocking groups to generate primer-ready termini.\",\n      \"evidence\": \"In vitro assays with site-specifically damaged oligonucleotides bearing 3'-phosphoglycolate and 3'-phosphate termini\",\n      \"pmids\": [\"7530050\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative in vivo contribution of each activity unknown\", \"No coupling to downstream repair polymerase/ligase demonstrated\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Demonstrated a lesion-specific in vivo repair role for Drosophila Rrp1 and characterized sequence dependence of its exonuclease, linking biochemistry to genome protection.\",\n      \"evidence\": \"Drosophila mosaic eye loss-of-heterozygosity assay with inducible transgene overexpression, plus in vitro exonuclease sequence-preference assays\",\n      \"pmids\": [\"8643678\", \"8918793\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Loss-of-function (rather than overexpression) phenotype not tested\", \"Endogenous expression and regulation not characterized\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Defined the bipartite architecture of Drosophila Rrp1, mapping catalytic activities to a folded C-terminal exonuclease III-homology domain and assigning a disordered N-terminus.\",\n      \"evidence\": \"Limited proteolysis, circular dichroism, frictional analysis, and enzymatic assays of isolated domains\",\n      \"pmids\": [\"9852053\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No high-resolution crystal structure\", \"Function of the disordered N-terminal region beyond strand transfer unresolved\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Identified human RRP1 (Nop52/NNP-1) as a nucleolar protein of late rRNA processing, placing the human gene in ribosome biogenesis rather than DNA repair.\",\n      \"evidence\": \"Immunocytochemistry with autoantibodies, cDNA transfection, cell-cycle and colocalization analysis with hPop1 and B23 in human cells\",\n      \"pmids\": [\"10341208\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No direct rRNA-processing function demonstrated yet\", \"Molecular activity of human RRP1 undefined at this stage\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Established yeast Rrp1p as a 66S pre-ribosomal particle component and pinpointed the specific pre-rRNA processing steps it controls.\",\n      \"evidence\": \"Temperature-sensitive inactivation, proteomic analysis of pre-ribosomal particles, and Northern blot processing assays in S. cerevisiae\",\n      \"pmids\": [\"15100437\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Rrp1p has catalytic activity or is a scaffold unresolved\", \"Direct RNA contacts not mapped\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Provided a molecular mechanism for human RRP1 in pre-ribosome remodeling: competition with fibrillarin for p32 binding to drive particle splitting.\",\n      \"evidence\": \"Mass-spectrometry interactome, immunoblotting, cell fractionation, ultracentrifugation, and siRNA knockdown in human cells\",\n      \"pmids\": [\"21536856\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Competitive exchange model inferred rather than directly visualized\", \"Structural basis of the p32 interaction unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined the precise pre-rRNA cleavage step controlled by human RRP1, assigning it to ITS1 site 2 cleavage on the 90S particle and showing functional interplay with XRN2.\",\n      \"evidence\": \"Single and double siRNA knockdown with pre-rRNA processing analysis, fractionation, immunofluorescence, and actinomycin D treatment in human cells\",\n      \"pmids\": [\"25969445\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether RRP1 itself cleaves or recruits a nuclease is unresolved\", \"RNA-binding determinants on RRP1 not mapped\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Established that the S. pombe protein named Rrp1 functions in homologous recombination, forming a complex with Rrp2 and Swi5 in an SDSA sub-pathway.\",\n      \"evidence\": \"Yeast two-hybrid, MMS-induced foci microscopy, and genetic epistasis with HR mutants in S. pombe\",\n      \"pmids\": [\"23828040\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Biochemical activity not defined in this study\", \"Direct DNA or Rad51 engagement not yet shown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed that S. pombe Rrp1 modulates centromeric nucleosome dynamics, linking its translocase activity to chromosome stability and histone homeostasis.\",\n      \"evidence\": \"Overexpression, chromosome stability assays, histone immunoblotting, Cnp1 localization microscopy, and translocase-domain mutant analysis\",\n      \"pmids\": [\"31932509\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Effect studied via overproduction rather than physiological levels\", \"Direct nucleosome remodeling not reconstituted\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Reconstituted the biochemical activities of S. pombe Rrp1 as a Rad51-stripping DNA translocase and Rad51-directed E3 ubiquitin ligase that restrains genome destabilization.\",\n      \"evidence\": \"Purified-protein DNA binding, ATPase, translocase, and ubiquitin ligase assays plus in vivo overexpression toxicity rescue and centromere ChIP in S. pombe\",\n      \"pmids\": [\"34157114\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relationship of these activities to the human/fly proteins of the same name unestablished\", \"Endogenous regulation of the translocase/ligase switch unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Uncovered a non-ribosomal function for human RRP1 as an mRNA-binding suppressor of TYMS that dampens one-carbon-metabolism-driven inflammation in macrophages.\",\n      \"evidence\": \"Global RNA-protein interactome purification, RNA-binding validation, siRNA knockdown, and myeloid-specific knockout mouse arthritis model\",\n      \"pmids\": [\"40715096\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relationship between this cytoplasmic mRNA-regulatory role and the nucleolar rRNA-processing role unresolved\", \"RNA-binding domain on RRP1 not mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a neuronal redox function for Drosophila Rrp1 in long-term memory, mechanistically tying its APE1-like redox activity to Period and CaMKII expression.\",\n      \"evidence\": \"Neuron-specific RNAi and overexpression, E3330 pharmacological inhibition, aversive olfactory memory assays, and human APE1 transgenic rescue in Drosophila\",\n      \"pmids\": [\"41289397\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct redox targets of Rrp1 in neurons not identified\", \"Connection between DNA-repair and redox-signaling roles unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved whether the nucleolar rRNA-processing RRP1 and the cytoplasmic TYMS-mRNA-suppressing RRP1 are the same human protein operating in two compartments, and how the species-specific DNA-repair, HR-translocase, and ribosome-biogenesis activities relate at the gene level.\",\n      \"evidence\": \"No timeline discovery reconciles the divergent activities across human, fly, and yeast proteins sharing the RRP1 name\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No study bridges the human nucleolar and macrophage functions\", \"Orthology relationships among the species-specific activities are not experimentally established in the corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [13, 14, 18]},\n      {\"term_id\": \"GO:0140097\", \"supporting_discovery_ids\": [0, 2, 5]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 2, 5, 8]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 15]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [15]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [11, 12, 14]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [12, 14, 18]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [9, 11, 13, 14]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [0, 2, 3, 7]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [18]}\n    ],\n    \"complexes\": [\n      \"90S pre-ribosomal particle\",\n      \"66S pre-ribosomal particle\"\n    ],\n    \"partners\": [\n      \"C1QBP\",\n      \"FBL\",\n      \"XRN2\",\n      \"Rad51\",\n      \"Rrp2\",\n      \"Swi5\",\n      \"TYMS\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}