{"gene":"RRM1","run_date":"2026-04-28T20:42:06","timeline":{"discoveries":[{"year":2003,"finding":"Overexpression of RRM1 in human and mouse lung cancer cell lines induced PTEN expression, reduced phosphorylation of focal adhesion kinase (FAK), and suppressed migration, invasion, and metastasis formation. Increased PTEN expression was required for RRM1-induced suppression of cell motility and FAK phosphorylation, establishing RRM1 as a metastasis suppressor gene acting through PTEN induction.","method":"Overexpression in cancer cell lines, in vivo animal model, functional migration/invasion assays, PTEN knockdown epistasis","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — clean gain-of-function with defined cellular phenotype, epistasis via PTEN knockdown, replicated in human and mouse lines with in vivo validation","pmids":["12687015"],"is_preprint":false},{"year":2006,"finding":"In genetically engineered lung and breast cancer cell lines spanning a 15-fold RRM1 expression range, the gemcitabine IC50 showed a 100-fold range (highest with high RRM1 expression), while cisplatin/carboplatin IC50 showed only a 2-fold range, demonstrating that RRM1 level is the principal determinant of gemcitabine resistance.","method":"Genetically modified cell lines with increased/decreased RRM1 expression, IC50 determination by cytotoxicity assay","journal":"Journal of clinical oncology","confidence":"High","confidence_rationale":"Tier 1-2 — dose-response over engineered 15-fold expression range, strong quantitative mechanistic relationship established","pmids":["16966686"],"is_preprint":false},{"year":1995,"finding":"The TATA-less promoter of human RRM1 contains a minimal region (nt -195 to +3) sufficient for maximal reporter gene expression; EMSA and supershift assays identified Sp1 as a transcription factor that binds this promoter region in a sequence-specific manner, implicating Sp1 in RRM1 transcriptional regulation.","method":"Reporter gene transfection, electrophoretic mobility shift assay (EMSA), antibody supershift","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 — direct binding demonstrated by EMSA with supershift confirmation, single study","pmids":["7557993"],"is_preprint":false},{"year":2015,"finding":"A conserved tryptophan residue in RRM1 (mouse Rrm1-W688G equivalent) is essential for RRM1 binding to RRM2; homozygous Rrm1(WG/WG) mice are not viable even at earliest embryonic stages, demonstrating that RRM1-RRM2 interaction is essential for mammalian development. Proteomic analyses confirmed the mutation prevents RRM1-RRM2 complex formation.","method":"Mouse knock-in genetics, proteomics/mass spectrometry interaction analysis, embryonic viability assay","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 — in vivo genetic loss-of-function with defined lethality phenotype, proteomic validation of abolished RRM1-RRM2 interaction","pmids":["26077802"],"is_preprint":false},{"year":2020,"finding":"RRM1 is phosphorylated at Ser559 by CDK2/cyclin A during S/G2 phase; this phosphorylation enhances RNR enzymatic activity and is required for maintaining sufficient dNTPs during normal DNA replication. Loss of S559 phosphorylation causes DNA replication stress, double-strand breaks, and genomic instability. Combined targeting of RRM1 S559 phosphorylation and ATR kinase triggers lethal replication stress.","method":"Cell-cycle phosphorylation mapping, CDK2/cyclin A kinase assay, phosphomutant cell lines, dNTP pool measurement, DNA damage markers (γH2AX), ATR inhibitor epistasis","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 — identified writer (CDK2/cyclin A), functional consequence demonstrated by enzymatic activity assay and dNTP measurement, phosphomutant phenotype with multiple orthogonal readouts","pmids":["32712628"],"is_preprint":false},{"year":2022,"finding":"RRM1 loss-of-function variants (dominant catalytic site variant p.N427K and recessive variants at p.R381) cause mitochondrial DNA depletion syndrome (MDDS) by impairing de novo nucleotide synthesis. Patient fibroblasts showed mtDNA depletion under cycling conditions, aberrant nucleoside diphosphate and dNTP pools, and mtDNA ribonucleotide incorporation.","method":"Human genetics (variant identification), molecular dynamics simulations, cultured primary patient fibroblasts, mtDNA copy number, dNTP pool analysis","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1-2 — human loss-of-function variants with functional validation in primary patient cells using multiple biochemical readouts","pmids":["35617047"],"is_preprint":false},{"year":2015,"finding":"MEK1/2 inhibitor pimasertib reduces RRM1 protein levels via MDM2-mediated Lys48-linked polyubiquitination and proteasomal degradation; immunoprecipitation demonstrated enhanced MDM2-RRM1 interaction and polyubiquitination following pimasertib treatment, with AKT partially mediating this effect. Proteasome inhibitor MG132 blocked RRM1 reduction.","method":"Immunoprecipitation, immunoblotting, MG132 proteasome inhibition, ubiquitination assay, in vivo orthotopic pancreatic cancer model","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal Co-IP with ubiquitination linkage determination, proteasome inhibitor validation, single lab","pmids":["26228206"],"is_preprint":false},{"year":2014,"finding":"RRM1 depletion (siRNA) induces cell-cycle arrest at replication phase along with severe DNA damage and centrosomal amplification. CHK1 depletion synergistically increased RRM1-depletion-induced centrosomal amplification; CHK1 was delocalized from the centrosome by RRM1 depletion during hydroxyurea treatment, and CDK1 was found essential for RRM1-depletion-induced centrosomal amplification, establishing a RRM1-CHK1-CDK1 axis maintaining centrosomal integrity.","method":"RNAi knockdown, hydroxyurea replication stress, centrosome counting, CHK1/CDK1 double knockdown epistasis","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 — siRNA loss-of-function with epistasis experiments, single lab","pmids":["24434653"],"is_preprint":false},{"year":2013,"finding":"A synthetic lethality kinase screen identified CHK1 as the kinase with the most significant interaction with RRM1-dependent gemcitabine resistance. Synergism between CHK1 inhibition (AZD7762) and gemcitabine was observed specifically in cells with high RRM1 levels, while antagonism occurred in low RRM1 cells. In tumor specimens, CHK1 and RRM1 in situ protein levels were significantly and inversely correlated.","method":"siRNA kinome screen (87 kinases), cell viability assays, small-molecule CHK1 inhibitor (AZD7762), correlation analysis in 187 patient tumor specimens","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 — systematic screen with small-molecule validation, supported by patient correlative data, single lab","pmids":["23483975"],"is_preprint":false},{"year":2015,"finding":"RRM1 protein (non-enzymatically, as its RR-inactive Y738F mutant behaves identically) upregulates PTEN transactivation to inhibit colorectal cancer cell migration and invasion, reducing Akt phosphorylation and increasing E-cadherin expression; these effects were blocked by PTEN knockdown. Clinical specimens showed RRM1 protein level (but not RR enzymatic activity) correlated with PTEN expression and inversely with invasion/metastasis at stage T4.","method":"Wild-type and RR-inactive Y738F mutant overexpression, PTEN siRNA knockdown epistasis, RR activity assay, migration/invasion assays, clinical specimen analysis","journal":"Tumour biology","confidence":"Medium","confidence_rationale":"Tier 2 — enzymatic-dead mutant dissects non-enzymatic function, PTEN epistasis confirmed, single lab","pmids":["25638032"],"is_preprint":false},{"year":2021,"finding":"RRM1 expression is increased in pancreatic cancer cells within 24 hours of gemcitabine exposure, with induction occurring predominantly in the cytoplasm; cytoplasmic RRM1 activation was related to cancer cell viability after gemcitabine treatment. Cancer cells lacking cytoplasmic RRM1 activation showed severe DNA damage. Histone acetyltransferase inhibition suppressed gemcitabine-induced RRM1 upregulation.","method":"Subcellular fractionation, immunohistochemistry, siRNA knockdown, HAT inhibitor treatment, cell viability assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2-3 — localization experiment with functional consequence, HAT inhibitor mechanistic link, single lab","pmids":["34111175"],"is_preprint":false},{"year":2022,"finding":"Knockdown of RRM1 promotes ferroptosis by increasing ROS and lipid peroxidation through regulation of GPX4 activity/expression. RRM1 controls p53 stability by regulating the deubiquitinating enzyme USP11 and ubiquitinating enzyme MDM2, affecting p53 ubiquitination; unstable p53 inhibits GPX4 via p21, providing a RRM1-USP11/MDM2-p53-p21-GPX4 signaling axis.","method":"siRNA knockdown, ROS/lipid peroxidation assays, ubiquitination assays, GPX4 activity measurement, western blotting for pathway components","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2-3 — pathway placed by loss-of-function with multiple downstream readouts, single lab","pmids":["35915092"],"is_preprint":false},{"year":2024,"finding":"RRM1 interacts with USP11 in the cytoplasm; ionizing radiation-induced recruitment of RRM1 to LaminB1 facilitates USP11 binding to the nuclear pore complex (NPC) and promotes USP11 nuclear entry. Nuclear USP11 binds E2F1 and inhibits its ubiquitin-mediated degradation, enhancing transcription of the HR factor RAD51AP1. A RRM1 deletion mutant lacking amino acids 731-793 (required for USP11 interaction and LaminB1 recruitment) acts as dominant negative and abolishes this pathway.","method":"Co-immunoprecipitation, nuclear fractionation, ubiquitination assay, domain deletion mutagenesis, HR reporter assay, RAD51AP1 transcription analysis","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP interaction, domain mutagenesis, mechanistic epistasis across multiple steps, single lab","pmids":["39695160"],"is_preprint":false},{"year":2020,"finding":"RRM1 knockdown in multiple myeloma cells triggered DNA damage response activation (γ-H2A.X, ATM, ATR, Chk1, Chk2, RAD51, 53BP1, BRCA1, BRCA2 upregulation/activation) and apoptosis via p53/p21/Noxa/Puma pathway in p53 wild-type cells; tumor growth of RRM1-knockdown cells was significantly reduced in murine xenograft model.","method":"siRNA knockdown, gene expression profiling, immunoblotting, in vivo xenograft model","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — siRNA KD with defined molecular phenotype (DNA damage response activation), in vivo validation, single lab","pmids":["28442502"],"is_preprint":false},{"year":2020,"finding":"LINC02535 cooperates with PCBP2 (which binds RRM1 mRNA) to enhance RRM1 mRNA stability in the cytoplasm; co-localization of LINC02535 and PCBP2 was confirmed, and their cooperation was required for RRM1-mediated DNA damage repair and EMT promotion in cervical cancer cells.","method":"RNA immunoprecipitation, mRNA stability assay, subcellular co-localization, siRNA knockdown, in vivo xenograft","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 3 — RNA-protein interaction with mRNA stability readout, functional epistasis, single lab","pmids":["32324262"],"is_preprint":false},{"year":2024,"finding":"YBX1 induces LRP1 transcription by binding to the LRP1 promoter, which alters β-catenin concentration and distribution; through TCF3, β-catenin then binds the RRM1 promoter to upregulate RRM1 expression, conferring gemcitabine resistance in pancreatic cancer cells.","method":"ChIP assay (YBX1 binding to LRP1 promoter, β-catenin/TCF3 binding to RRM1 promoter), β-catenin localization, in vitro and in vivo gemcitabine resistance assays","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP demonstrates direct promoter binding at multiple steps, in vivo validation, single lab","pmids":["39216548"],"is_preprint":false},{"year":2023,"finding":"Reversible demethylation of the PDGFD promoter in gemcitabine-resistant pancreatic cancer cells leads to PDGFD upregulation, which activates STAT3 signaling in autocrine and paracrine manners to upregulate RRM1 expression, contributing to gemcitabine resistance.","method":"Whole genome reduced representation bisulfite sequencing, STAT3 inhibition, PDGFD knockdown/overexpression, RRM1 protein level measurement, in vitro and in vivo resistance models","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic pathway placed by multiple orthogonal approaches including epigenomic sequencing and signal inhibition, single lab","pmids":["37321532"],"is_preprint":false},{"year":2024,"finding":"Diphthamide modification of eEF2 modulates RRM1 mRNA translation via -1 frameshifting; loss of diphthamide in DPH-deficient mammalian cells reduces RRM1 protein levels and causally elevates DNA replication stress.","method":"Quantitative proteomics, computational profiling, -1 frameshifting reporter assay, DPH-deficient cell lines, DNA replication stress markers","journal":"ACS central science","confidence":"Medium","confidence_rationale":"Tier 2 — frameshifting mechanism identified biochemically with causal link to replication stress via RRM1, single lab","pmids":["39463834"],"is_preprint":false}],"current_model":"RRM1 (ribonucleotide reductase large subunit M1) is the catalytic subunit of the RNR complex that reduces ribonucleotides to deoxyribonucleotides; it heterodimerizes with RRM2 (via a conserved tryptophan interaction essential for mammalian viability), is cell-cycle regulated through CDK2/cyclin A-mediated phosphorylation at Ser559 to enhance RNR activity during S/G2 phase, and, beyond its enzymatic role, functions as a metastasis suppressor by inducing PTEN expression and suppressing FAK phosphorylation, promotes homologous recombination repair via cytoplasmic interaction with USP11/LaminB1 and subsequent nuclear E2F1 stabilization and RAD51AP1 transcription, and is subject to MDM2-mediated Lys48-linked polyubiquitination for proteasomal degradation; loss-of-function variants cause mitochondrial DNA depletion syndrome through impaired de novo nucleotide synthesis."},"narrative":{"teleology":[{"year":1995,"claim":"Identification of the RRM1 promoter architecture revealed how this housekeeping gene is transcriptionally regulated: a TATA-less minimal promoter driven by Sp1 binding.","evidence":"Reporter gene assays, EMSA, and antibody supershift in human cells","pmids":["7557993"],"confidence":"Medium","gaps":["No in vivo chromatin validation (ChIP)","Other transcription factors contributing to cell-cycle-dependent regulation not identified"]},{"year":2003,"claim":"RRM1 was established as a metastasis suppressor acting through PTEN induction and FAK dephosphorylation, revealing a non-enzymatic tumor-suppressive function beyond nucleotide synthesis.","evidence":"Overexpression in human/mouse lung cancer cell lines, in vivo metastasis model, PTEN knockdown epistasis","pmids":["12687015"],"confidence":"High","gaps":["Mechanism by which RRM1 transactivates PTEN unknown","Whether this function operates in normal physiology vs. cancer overexpression context unclear"]},{"year":2006,"claim":"Quantitative titration of RRM1 expression demonstrated it is the principal determinant of gemcitabine resistance, establishing the pharmacogenomic basis for gemcitabine response prediction.","evidence":"Engineered cell lines spanning 15-fold RRM1 expression range, IC50 dose-response for gemcitabine vs. platinum agents","pmids":["16966686"],"confidence":"High","gaps":["In vivo dose-response relationship not established in this study","Resistance mechanism beyond competitive substrate binding not dissected"]},{"year":2013,"claim":"A kinome-wide synthetic lethality screen identified CHK1 as the kinase whose inhibition most potently synergizes with gemcitabine in high-RRM1 cells, revealing a replication checkpoint dependency.","evidence":"siRNA kinome screen (87 kinases), CHK1 inhibitor AZD7762 validation, inverse correlation of CHK1/RRM1 in 187 patient tumors","pmids":["23483975"],"confidence":"Medium","gaps":["Direct physical interaction between RRM1 and CHK1 not demonstrated","Mechanism of inverse correlation in patient specimens not established"]},{"year":2014,"claim":"RRM1 depletion was shown to cause centrosomal amplification through CHK1 delocalization and CDK1 dependency, establishing a RRM1–CHK1–CDK1 axis in centrosome integrity maintenance.","evidence":"siRNA knockdown, hydroxyurea replication stress, CHK1/CDK1 double knockdown epistasis, centrosome counting","pmids":["24434653"],"confidence":"Medium","gaps":["Whether centrosomal phenotype is direct or secondary to nucleotide depletion not resolved","Single lab without independent replication"]},{"year":2015,"claim":"Two key advances: (1) a conserved tryptophan in RRM1 was shown to be essential for RRM2 binding and mammalian viability, and (2) the PTEN-induction metastasis suppressor function was demonstrated to be independent of RNR catalytic activity using an enzymatically dead mutant.","evidence":"Mouse Rrm1-W688G knock-in (embryonic lethality, proteomic confirmation of lost RRM2 interaction); Y738F catalytic-dead RRM1 mutant overexpression with PTEN epistasis in colorectal cancer cells","pmids":["26077802","25638032"],"confidence":"High","gaps":["Structural basis of how RRM1 protein (non-enzymatically) induces PTEN transcription unknown","Whether the W688 interaction surface has additional regulatory roles beyond heterodimerization not tested"]},{"year":2015,"claim":"MDM2 was identified as the E3 ligase for RRM1, mediating Lys48-linked polyubiquitination and proteasomal degradation, providing a regulated turnover mechanism downstream of MEK-AKT signaling.","evidence":"Co-immunoprecipitation, ubiquitination linkage assay, MG132 proteasome inhibition, pimasertib treatment in pancreatic cancer cells","pmids":["26228206"],"confidence":"Medium","gaps":["Ubiquitination sites on RRM1 not mapped","Whether MDM2-mediated degradation operates under physiological conditions beyond drug treatment unclear"]},{"year":2020,"claim":"CDK2/cyclin A was identified as the kinase phosphorylating RRM1 at Ser559 during S/G2 phase, directly enhancing RNR enzymatic activity; loss of this modification causes replication stress and synergizes with ATR inhibition.","evidence":"Phosphorylation mapping, in vitro kinase assay, phosphomutant cell lines, dNTP pool measurement, γH2AX, ATR inhibitor epistasis","pmids":["32712628"],"confidence":"High","gaps":["Whether additional phosphorylation sites regulate RRM1 activity not addressed","Structural mechanism by which S559 phosphorylation enhances catalysis not determined"]},{"year":2022,"claim":"Human loss-of-function variants in RRM1 were shown to cause mitochondrial DNA depletion syndrome, establishing RRM1 as a disease gene through impaired de novo nucleotide synthesis demonstrated in patient cells.","evidence":"Patient variant identification (p.N427K dominant, p.R381 recessive), mtDNA copy number in fibroblasts, dNTP pool analysis, molecular dynamics","pmids":["35617047"],"confidence":"High","gaps":["Tissue-specific manifestations (why mitochondria are preferentially affected) not mechanistically explained","No rescue experiment with wild-type RRM1 in patient cells reported"]},{"year":2022,"claim":"RRM1 was linked to ferroptosis regulation through a USP11/MDM2–p53–p21–GPX4 signaling axis, where RRM1 depletion destabilizes p53 and reduces GPX4, promoting lipid peroxidation.","evidence":"siRNA knockdown, ROS and lipid peroxidation assays, ubiquitination assay for p53, GPX4 activity measurement","pmids":["35915092"],"confidence":"Medium","gaps":["Direct physical interaction between RRM1 and USP11/MDM2 for p53 regulation not firmly established with reciprocal IP","Whether ferroptosis sensitivity is secondary to nucleotide depletion not excluded"]},{"year":2024,"claim":"A non-enzymatic DNA repair function was mechanistically delineated: RRM1 interacts with USP11 in the cytoplasm and, upon irradiation, is recruited to LaminB1 at the nuclear pore to facilitate USP11 nuclear entry, where USP11 deubiquitinates E2F1 to drive RAD51AP1 transcription and homologous recombination.","evidence":"Co-IP, nuclear fractionation, deletion mutagenesis (aa 731-793), HR reporter assay, RAD51AP1 transcription analysis","pmids":["39695160"],"confidence":"Medium","gaps":["Single lab; domain deletion dominant-negative phenotype needs independent confirmation","Whether RRM1-USP11 interaction is regulated by post-translational modifications not tested","Stoichiometry and structural basis of RRM1–USP11–LaminB1 complex undefined"]},{"year":2024,"claim":"Translational control of RRM1 was revealed through diphthamide-dependent modulation of eEF2, where loss of diphthamide increases -1 frameshifting on RRM1 mRNA, reducing RRM1 protein and causing replication stress.","evidence":"Quantitative proteomics, -1 frameshifting reporter assay, DPH-deficient mammalian cell lines, replication stress markers","pmids":["39463834"],"confidence":"Medium","gaps":["Specific frameshifting-prone sequences in RRM1 mRNA not mapped","Whether this translational regulation is physiologically modulated unknown"]},{"year":null,"claim":"Major unresolved questions include: the structural/molecular mechanism by which RRM1 protein (independent of catalysis) activates PTEN transcription; how RRM1's enzymatic and non-enzymatic functions are coordinated in different cellular contexts; and the full spectrum of post-translational modifications regulating RRM1 stability, localization, and protein interactions.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of RRM1 non-enzymatic signaling complexes","Tissue-specific roles of RRM1 beyond cancer cell lines poorly characterized","Integration of enzymatic vs. scaffolding functions in normal physiology vs. disease not resolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[3,4,5]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,9,12]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[10,12]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[12]}],"pathway":[{"term_id":"R-HSA-69306","term_label":"DNA Replication","supporting_discovery_ids":[4,5,17]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[7,12,13]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[4,7]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[3,4,5]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[5]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[11,13]}],"complexes":["Ribonucleotide reductase (RNR)"],"partners":["RRM2","USP11","MDM2","PTEN","CDK2","CHK1","LMNB1"],"other_free_text":[]},"mechanistic_narrative":"RRM1 encodes the catalytic large subunit of ribonucleotide reductase (RNR), which converts ribonucleotides to deoxyribonucleotides essential for DNA replication and repair; a conserved tryptophan residue mediates obligate heterodimerization with RRM2, and disruption of this interaction is embryonic lethal [PMID:26077802]. CDK2/cyclin A phosphorylates RRM1 at Ser559 during S/G2 phase to enhance RNR activity and maintain dNTP pools, and loss of this phosphorylation causes replication stress and genomic instability [PMID:32712628]. Independent of its reductase activity, RRM1 functions as a metastasis suppressor by transactivating PTEN to inhibit FAK signaling and cell migration [PMID:12687015, PMID:25638032], and promotes homologous recombination repair by chaperoning USP11 into the nucleus to stabilize E2F1 and upregulate RAD51AP1 transcription [PMID:39695160]. Loss-of-function variants in RRM1 cause mitochondrial DNA depletion syndrome through impaired de novo nucleotide synthesis [PMID:35617047]."},"prefetch_data":{"uniprot":{"accession":"P23921","full_name":"Ribonucleoside-diphosphate reductase large subunit","aliases":["Ribonucleoside-diphosphate reductase subunit M1","Ribonucleotide reductase large subunit"],"length_aa":792,"mass_kda":90.1,"function":"Provides the precursors necessary for DNA synthesis. Catalyzes the biosynthesis of deoxyribonucleotides from the corresponding ribonucleotides","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P23921/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/RRM1","classification":"Common Essential","n_dependent_lines":1208,"n_total_lines":1208,"dependency_fraction":1.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PARP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/RRM1","total_profiled":1310},"omim":[{"mim_id":"621055","title":"POLYADENYLATE-BINDING PROTEIN, CYTOPLASMIC, 1-LIKE; PABPC1L","url":"https://www.omim.org/entry/621055"},{"mim_id":"620647","title":"PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA WITH MITOCHONDRIAL DNA DELETIONS, AUTOSOMAL RECESSIVE 6; PEOB6","url":"https://www.omim.org/entry/620647"},{"mim_id":"615920","title":"PROLINE-RICH PROTEIN 11; PRR11","url":"https://www.omim.org/entry/615920"},{"mim_id":"613171","title":"RNA-BINDING MOTIF PROTEIN 20; RBM20","url":"https://www.omim.org/entry/613171"},{"mim_id":"612960","title":"EPITHELIAL SPLICING REGULATORY PROTEIN 2; ESRP2","url":"https://www.omim.org/entry/612960"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Plasma membrane","reliability":"Additional"},{"location":"Centriolar satellite","reliability":"Additional"},{"location":"Basal body","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RRM1"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P23921","domains":[{"cath_id":"-","chopping":"92-195","consensus_level":"medium","plddt":96.3426,"start":92,"end":195},{"cath_id":"3.20.70.20","chopping":"219-414","consensus_level":"medium","plddt":95.0808,"start":219,"end":414},{"cath_id":"-","chopping":"623-682","consensus_level":"medium","plddt":87.4137,"start":623,"end":682},{"cath_id":"1.10.8","chopping":"2-90","consensus_level":"medium","plddt":88.1655,"start":2,"end":90}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P23921","model_url":"https://alphafold.ebi.ac.uk/files/AF-P23921-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P23921-F1-predicted_aligned_error_v6.png","plddt_mean":92.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RRM1","jax_strain_url":"https://www.jax.org/strain/search?query=RRM1"},"sequence":{"accession":"P23921","fasta_url":"https://rest.uniprot.org/uniprotkb/P23921.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P23921/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P23921"}},"corpus_meta":[{"pmid":"17314339","id":"PMC_17314339","title":"DNA synthesis and repair genes RRM1 and ERCC1 in lung cancer.","date":"2007","source":"The New England journal of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/17314339","citation_count":400,"is_preprint":false},{"pmid":"16966686","id":"PMC_16966686","title":"RRM1 modulated in vitro and in vivo efficacy of gemcitabine and platinum in non-small-cell lung cancer.","date":"2006","source":"Journal of clinical oncology : official journal of the American Society of Clinical Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/16966686","citation_count":286,"is_preprint":false},{"pmid":"24464995","id":"PMC_24464995","title":"The crystal structure of TDP-43 RRM1-DNA complex reveals the specific recognition for UG- and TG-rich nucleic acids.","date":"2014","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/24464995","citation_count":148,"is_preprint":false},{"pmid":"21163702","id":"PMC_21163702","title":"The ribonucleotide reductase large subunit (RRM1) as a predictive factor in patients with cancer.","date":"2010","source":"The Lancet. Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/21163702","citation_count":145,"is_preprint":false},{"pmid":"19884554","id":"PMC_19884554","title":"Randomized phase III trial of gemcitabine-based chemotherapy with in situ RRM1 and ERCC1 protein levels for response prediction in non-small-cell lung cancer.","date":"2009","source":"Journal of clinical oncology : official journal of the American Society of Clinical Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/19884554","citation_count":144,"is_preprint":false},{"pmid":"12687015","id":"PMC_12687015","title":"RRM1-induced metastasis suppression through PTEN-regulated pathways.","date":"2003","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/12687015","citation_count":127,"is_preprint":false},{"pmid":"23690416","id":"PMC_23690416","title":"Randomized international phase III trial of ERCC1 and RRM1 expression-based chemotherapy versus gemcitabine/carboplatin in advanced non-small-cell lung 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science","url":"https://pubmed.ncbi.nlm.nih.gov/39463834","citation_count":7,"is_preprint":false},{"pmid":"25078585","id":"PMC_25078585","title":"Predictive role of RRM1 and BRCA1 mRNA expression on the clinical outcome of advanced non-small cell lung cancer.","date":"2014","source":"Genetics and molecular research : GMR","url":"https://pubmed.ncbi.nlm.nih.gov/25078585","citation_count":7,"is_preprint":false},{"pmid":"34353292","id":"PMC_34353292","title":"RRM1 and ERCC1 as biomarkers in patients with locally advanced and metastatic malignant pleural mesothelioma treated with continuous infusion of low-dose gemcitabine plus cisplatin.","date":"2021","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/34353292","citation_count":6,"is_preprint":false},{"pmid":"39695160","id":"PMC_39695160","title":"RRM1 promotes homologous recombination and radio/chemo-sensitivity via enhancing USP11 and E2F1-mediated RAD51AP1 transcription.","date":"2024","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/39695160","citation_count":5,"is_preprint":false},{"pmid":"35088678","id":"PMC_35088678","title":"Platycodon D-induced A549 Cell Apoptosis through RRM1-Regulated p53/VEGF/ MMP2 Pathway.","date":"2022","source":"Anti-cancer agents in medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/35088678","citation_count":5,"is_preprint":false},{"pmid":"38163613","id":"PMC_38163613","title":"Nicotine promotes epithelial to mesenchymal transition and gemcitabine resistance via hENT1/RRM1 signalling in pancreatic cancer and chemosensitizing effects of Embelin-a naturally occurring benzoquinone.","date":"2023","source":"The Science of the total environment","url":"https://pubmed.ncbi.nlm.nih.gov/38163613","citation_count":5,"is_preprint":false},{"pmid":"35711974","id":"PMC_35711974","title":"Association between TOP2A, RRM1, HER2, ERCC1 expression and response to chemotherapy in patients with non-muscle invasive bladder cancer.","date":"2022","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/35711974","citation_count":5,"is_preprint":false},{"pmid":"25896032","id":"PMC_25896032","title":"(1)H, (15)N and (13)C chemical shift assignments of the La motif and RRM1 from human LARP6.","date":"2015","source":"Biomolecular NMR assignments","url":"https://pubmed.ncbi.nlm.nih.gov/25896032","citation_count":5,"is_preprint":false},{"pmid":"24595080","id":"PMC_24595080","title":"The tailored chemotherapy based on RRM1 immunohistochemical expression in patients with advanced non-small cell lung cancer.","date":"2013","source":"Cancer biomarkers : section A of Disease markers","url":"https://pubmed.ncbi.nlm.nih.gov/24595080","citation_count":5,"is_preprint":false},{"pmid":"36058398","id":"PMC_36058398","title":"Allosteric mechanism for SL RNA recognition by polypyrimidine tract binding protein RRM1: An atomistic MD simulation and network-based study.","date":"2022","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/36058398","citation_count":5,"is_preprint":false},{"pmid":"36294786","id":"PMC_36294786","title":"Personalized Prescription of Chemotherapy Based on Assessment of mRNA Expression of BRCA1, RRM1, ERCC1, TOP1, TOP2α, TUBβ3, TYMS, and GSTP1 Genes in Tumors Compared to Standard Chemotherapy in the Treatment of Non-Small-Cell Lung Cancer.","date":"2022","source":"Journal of personalized medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36294786","citation_count":5,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":54768,"output_tokens":4664,"usd":0.117132},"stage2":{"model":"claude-opus-4-6","input_tokens":8137,"output_tokens":3160,"usd":0.179528},"total_usd":0.29666,"stage1_batch_id":"msgbatch_011rkcQdVV1RaFq9XhcG6df6","stage2_batch_id":"msgbatch_01RzgrJafdF4EWHhj5mNi6dh","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"Overexpression of RRM1 in human and mouse lung cancer cell lines induced PTEN expression, reduced phosphorylation of focal adhesion kinase (FAK), and suppressed migration, invasion, and metastasis formation. Increased PTEN expression was required for RRM1-induced suppression of cell motility and FAK phosphorylation, establishing RRM1 as a metastasis suppressor gene acting through PTEN induction.\",\n      \"method\": \"Overexpression in cancer cell lines, in vivo animal model, functional migration/invasion assays, PTEN knockdown epistasis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean gain-of-function with defined cellular phenotype, epistasis via PTEN knockdown, replicated in human and mouse lines with in vivo validation\",\n      \"pmids\": [\"12687015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"In genetically engineered lung and breast cancer cell lines spanning a 15-fold RRM1 expression range, the gemcitabine IC50 showed a 100-fold range (highest with high RRM1 expression), while cisplatin/carboplatin IC50 showed only a 2-fold range, demonstrating that RRM1 level is the principal determinant of gemcitabine resistance.\",\n      \"method\": \"Genetically modified cell lines with increased/decreased RRM1 expression, IC50 determination by cytotoxicity assay\",\n      \"journal\": \"Journal of clinical oncology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — dose-response over engineered 15-fold expression range, strong quantitative mechanistic relationship established\",\n      \"pmids\": [\"16966686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"The TATA-less promoter of human RRM1 contains a minimal region (nt -195 to +3) sufficient for maximal reporter gene expression; EMSA and supershift assays identified Sp1 as a transcription factor that binds this promoter region in a sequence-specific manner, implicating Sp1 in RRM1 transcriptional regulation.\",\n      \"method\": \"Reporter gene transfection, electrophoretic mobility shift assay (EMSA), antibody supershift\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct binding demonstrated by EMSA with supershift confirmation, single study\",\n      \"pmids\": [\"7557993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"A conserved tryptophan residue in RRM1 (mouse Rrm1-W688G equivalent) is essential for RRM1 binding to RRM2; homozygous Rrm1(WG/WG) mice are not viable even at earliest embryonic stages, demonstrating that RRM1-RRM2 interaction is essential for mammalian development. Proteomic analyses confirmed the mutation prevents RRM1-RRM2 complex formation.\",\n      \"method\": \"Mouse knock-in genetics, proteomics/mass spectrometry interaction analysis, embryonic viability assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vivo genetic loss-of-function with defined lethality phenotype, proteomic validation of abolished RRM1-RRM2 interaction\",\n      \"pmids\": [\"26077802\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RRM1 is phosphorylated at Ser559 by CDK2/cyclin A during S/G2 phase; this phosphorylation enhances RNR enzymatic activity and is required for maintaining sufficient dNTPs during normal DNA replication. Loss of S559 phosphorylation causes DNA replication stress, double-strand breaks, and genomic instability. Combined targeting of RRM1 S559 phosphorylation and ATR kinase triggers lethal replication stress.\",\n      \"method\": \"Cell-cycle phosphorylation mapping, CDK2/cyclin A kinase assay, phosphomutant cell lines, dNTP pool measurement, DNA damage markers (γH2AX), ATR inhibitor epistasis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — identified writer (CDK2/cyclin A), functional consequence demonstrated by enzymatic activity assay and dNTP measurement, phosphomutant phenotype with multiple orthogonal readouts\",\n      \"pmids\": [\"32712628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RRM1 loss-of-function variants (dominant catalytic site variant p.N427K and recessive variants at p.R381) cause mitochondrial DNA depletion syndrome (MDDS) by impairing de novo nucleotide synthesis. Patient fibroblasts showed mtDNA depletion under cycling conditions, aberrant nucleoside diphosphate and dNTP pools, and mtDNA ribonucleotide incorporation.\",\n      \"method\": \"Human genetics (variant identification), molecular dynamics simulations, cultured primary patient fibroblasts, mtDNA copy number, dNTP pool analysis\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — human loss-of-function variants with functional validation in primary patient cells using multiple biochemical readouts\",\n      \"pmids\": [\"35617047\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"MEK1/2 inhibitor pimasertib reduces RRM1 protein levels via MDM2-mediated Lys48-linked polyubiquitination and proteasomal degradation; immunoprecipitation demonstrated enhanced MDM2-RRM1 interaction and polyubiquitination following pimasertib treatment, with AKT partially mediating this effect. Proteasome inhibitor MG132 blocked RRM1 reduction.\",\n      \"method\": \"Immunoprecipitation, immunoblotting, MG132 proteasome inhibition, ubiquitination assay, in vivo orthotopic pancreatic cancer model\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP with ubiquitination linkage determination, proteasome inhibitor validation, single lab\",\n      \"pmids\": [\"26228206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"RRM1 depletion (siRNA) induces cell-cycle arrest at replication phase along with severe DNA damage and centrosomal amplification. CHK1 depletion synergistically increased RRM1-depletion-induced centrosomal amplification; CHK1 was delocalized from the centrosome by RRM1 depletion during hydroxyurea treatment, and CDK1 was found essential for RRM1-depletion-induced centrosomal amplification, establishing a RRM1-CHK1-CDK1 axis maintaining centrosomal integrity.\",\n      \"method\": \"RNAi knockdown, hydroxyurea replication stress, centrosome counting, CHK1/CDK1 double knockdown epistasis\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — siRNA loss-of-function with epistasis experiments, single lab\",\n      \"pmids\": [\"24434653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"A synthetic lethality kinase screen identified CHK1 as the kinase with the most significant interaction with RRM1-dependent gemcitabine resistance. Synergism between CHK1 inhibition (AZD7762) and gemcitabine was observed specifically in cells with high RRM1 levels, while antagonism occurred in low RRM1 cells. In tumor specimens, CHK1 and RRM1 in situ protein levels were significantly and inversely correlated.\",\n      \"method\": \"siRNA kinome screen (87 kinases), cell viability assays, small-molecule CHK1 inhibitor (AZD7762), correlation analysis in 187 patient tumor specimens\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — systematic screen with small-molecule validation, supported by patient correlative data, single lab\",\n      \"pmids\": [\"23483975\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"RRM1 protein (non-enzymatically, as its RR-inactive Y738F mutant behaves identically) upregulates PTEN transactivation to inhibit colorectal cancer cell migration and invasion, reducing Akt phosphorylation and increasing E-cadherin expression; these effects were blocked by PTEN knockdown. Clinical specimens showed RRM1 protein level (but not RR enzymatic activity) correlated with PTEN expression and inversely with invasion/metastasis at stage T4.\",\n      \"method\": \"Wild-type and RR-inactive Y738F mutant overexpression, PTEN siRNA knockdown epistasis, RR activity assay, migration/invasion assays, clinical specimen analysis\",\n      \"journal\": \"Tumour biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — enzymatic-dead mutant dissects non-enzymatic function, PTEN epistasis confirmed, single lab\",\n      \"pmids\": [\"25638032\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RRM1 expression is increased in pancreatic cancer cells within 24 hours of gemcitabine exposure, with induction occurring predominantly in the cytoplasm; cytoplasmic RRM1 activation was related to cancer cell viability after gemcitabine treatment. Cancer cells lacking cytoplasmic RRM1 activation showed severe DNA damage. Histone acetyltransferase inhibition suppressed gemcitabine-induced RRM1 upregulation.\",\n      \"method\": \"Subcellular fractionation, immunohistochemistry, siRNA knockdown, HAT inhibitor treatment, cell viability assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — localization experiment with functional consequence, HAT inhibitor mechanistic link, single lab\",\n      \"pmids\": [\"34111175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Knockdown of RRM1 promotes ferroptosis by increasing ROS and lipid peroxidation through regulation of GPX4 activity/expression. RRM1 controls p53 stability by regulating the deubiquitinating enzyme USP11 and ubiquitinating enzyme MDM2, affecting p53 ubiquitination; unstable p53 inhibits GPX4 via p21, providing a RRM1-USP11/MDM2-p53-p21-GPX4 signaling axis.\",\n      \"method\": \"siRNA knockdown, ROS/lipid peroxidation assays, ubiquitination assays, GPX4 activity measurement, western blotting for pathway components\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — pathway placed by loss-of-function with multiple downstream readouts, single lab\",\n      \"pmids\": [\"35915092\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RRM1 interacts with USP11 in the cytoplasm; ionizing radiation-induced recruitment of RRM1 to LaminB1 facilitates USP11 binding to the nuclear pore complex (NPC) and promotes USP11 nuclear entry. Nuclear USP11 binds E2F1 and inhibits its ubiquitin-mediated degradation, enhancing transcription of the HR factor RAD51AP1. A RRM1 deletion mutant lacking amino acids 731-793 (required for USP11 interaction and LaminB1 recruitment) acts as dominant negative and abolishes this pathway.\",\n      \"method\": \"Co-immunoprecipitation, nuclear fractionation, ubiquitination assay, domain deletion mutagenesis, HR reporter assay, RAD51AP1 transcription analysis\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP interaction, domain mutagenesis, mechanistic epistasis across multiple steps, single lab\",\n      \"pmids\": [\"39695160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RRM1 knockdown in multiple myeloma cells triggered DNA damage response activation (γ-H2A.X, ATM, ATR, Chk1, Chk2, RAD51, 53BP1, BRCA1, BRCA2 upregulation/activation) and apoptosis via p53/p21/Noxa/Puma pathway in p53 wild-type cells; tumor growth of RRM1-knockdown cells was significantly reduced in murine xenograft model.\",\n      \"method\": \"siRNA knockdown, gene expression profiling, immunoblotting, in vivo xenograft model\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — siRNA KD with defined molecular phenotype (DNA damage response activation), in vivo validation, single lab\",\n      \"pmids\": [\"28442502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LINC02535 cooperates with PCBP2 (which binds RRM1 mRNA) to enhance RRM1 mRNA stability in the cytoplasm; co-localization of LINC02535 and PCBP2 was confirmed, and their cooperation was required for RRM1-mediated DNA damage repair and EMT promotion in cervical cancer cells.\",\n      \"method\": \"RNA immunoprecipitation, mRNA stability assay, subcellular co-localization, siRNA knockdown, in vivo xenograft\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — RNA-protein interaction with mRNA stability readout, functional epistasis, single lab\",\n      \"pmids\": [\"32324262\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YBX1 induces LRP1 transcription by binding to the LRP1 promoter, which alters β-catenin concentration and distribution; through TCF3, β-catenin then binds the RRM1 promoter to upregulate RRM1 expression, conferring gemcitabine resistance in pancreatic cancer cells.\",\n      \"method\": \"ChIP assay (YBX1 binding to LRP1 promoter, β-catenin/TCF3 binding to RRM1 promoter), β-catenin localization, in vitro and in vivo gemcitabine resistance assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP demonstrates direct promoter binding at multiple steps, in vivo validation, single lab\",\n      \"pmids\": [\"39216548\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Reversible demethylation of the PDGFD promoter in gemcitabine-resistant pancreatic cancer cells leads to PDGFD upregulation, which activates STAT3 signaling in autocrine and paracrine manners to upregulate RRM1 expression, contributing to gemcitabine resistance.\",\n      \"method\": \"Whole genome reduced representation bisulfite sequencing, STAT3 inhibition, PDGFD knockdown/overexpression, RRM1 protein level measurement, in vitro and in vivo resistance models\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway placed by multiple orthogonal approaches including epigenomic sequencing and signal inhibition, single lab\",\n      \"pmids\": [\"37321532\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Diphthamide modification of eEF2 modulates RRM1 mRNA translation via -1 frameshifting; loss of diphthamide in DPH-deficient mammalian cells reduces RRM1 protein levels and causally elevates DNA replication stress.\",\n      \"method\": \"Quantitative proteomics, computational profiling, -1 frameshifting reporter assay, DPH-deficient cell lines, DNA replication stress markers\",\n      \"journal\": \"ACS central science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — frameshifting mechanism identified biochemically with causal link to replication stress via RRM1, single lab\",\n      \"pmids\": [\"39463834\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RRM1 (ribonucleotide reductase large subunit M1) is the catalytic subunit of the RNR complex that reduces ribonucleotides to deoxyribonucleotides; it heterodimerizes with RRM2 (via a conserved tryptophan interaction essential for mammalian viability), is cell-cycle regulated through CDK2/cyclin A-mediated phosphorylation at Ser559 to enhance RNR activity during S/G2 phase, and, beyond its enzymatic role, functions as a metastasis suppressor by inducing PTEN expression and suppressing FAK phosphorylation, promotes homologous recombination repair via cytoplasmic interaction with USP11/LaminB1 and subsequent nuclear E2F1 stabilization and RAD51AP1 transcription, and is subject to MDM2-mediated Lys48-linked polyubiquitination for proteasomal degradation; loss-of-function variants cause mitochondrial DNA depletion syndrome through impaired de novo nucleotide synthesis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"RRM1 encodes the catalytic large subunit of ribonucleotide reductase (RNR), which converts ribonucleotides to deoxyribonucleotides essential for DNA replication and repair; a conserved tryptophan residue mediates obligate heterodimerization with RRM2, and disruption of this interaction is embryonic lethal [PMID:26077802]. CDK2/cyclin A phosphorylates RRM1 at Ser559 during S/G2 phase to enhance RNR activity and maintain dNTP pools, and loss of this phosphorylation causes replication stress and genomic instability [PMID:32712628]. Independent of its reductase activity, RRM1 functions as a metastasis suppressor by transactivating PTEN to inhibit FAK signaling and cell migration [PMID:12687015, PMID:25638032], and promotes homologous recombination repair by chaperoning USP11 into the nucleus to stabilize E2F1 and upregulate RAD51AP1 transcription [PMID:39695160]. Loss-of-function variants in RRM1 cause mitochondrial DNA depletion syndrome through impaired de novo nucleotide synthesis [PMID:35617047].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Identification of the RRM1 promoter architecture revealed how this housekeeping gene is transcriptionally regulated: a TATA-less minimal promoter driven by Sp1 binding.\",\n      \"evidence\": \"Reporter gene assays, EMSA, and antibody supershift in human cells\",\n      \"pmids\": [\"7557993\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vivo chromatin validation (ChIP)\", \"Other transcription factors contributing to cell-cycle-dependent regulation not identified\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"RRM1 was established as a metastasis suppressor acting through PTEN induction and FAK dephosphorylation, revealing a non-enzymatic tumor-suppressive function beyond nucleotide synthesis.\",\n      \"evidence\": \"Overexpression in human/mouse lung cancer cell lines, in vivo metastasis model, PTEN knockdown epistasis\",\n      \"pmids\": [\"12687015\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which RRM1 transactivates PTEN unknown\", \"Whether this function operates in normal physiology vs. cancer overexpression context unclear\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Quantitative titration of RRM1 expression demonstrated it is the principal determinant of gemcitabine resistance, establishing the pharmacogenomic basis for gemcitabine response prediction.\",\n      \"evidence\": \"Engineered cell lines spanning 15-fold RRM1 expression range, IC50 dose-response for gemcitabine vs. platinum agents\",\n      \"pmids\": [\"16966686\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo dose-response relationship not established in this study\", \"Resistance mechanism beyond competitive substrate binding not dissected\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"A kinome-wide synthetic lethality screen identified CHK1 as the kinase whose inhibition most potently synergizes with gemcitabine in high-RRM1 cells, revealing a replication checkpoint dependency.\",\n      \"evidence\": \"siRNA kinome screen (87 kinases), CHK1 inhibitor AZD7762 validation, inverse correlation of CHK1/RRM1 in 187 patient tumors\",\n      \"pmids\": [\"23483975\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct physical interaction between RRM1 and CHK1 not demonstrated\", \"Mechanism of inverse correlation in patient specimens not established\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"RRM1 depletion was shown to cause centrosomal amplification through CHK1 delocalization and CDK1 dependency, establishing a RRM1–CHK1–CDK1 axis in centrosome integrity maintenance.\",\n      \"evidence\": \"siRNA knockdown, hydroxyurea replication stress, CHK1/CDK1 double knockdown epistasis, centrosome counting\",\n      \"pmids\": [\"24434653\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether centrosomal phenotype is direct or secondary to nucleotide depletion not resolved\", \"Single lab without independent replication\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Two key advances: (1) a conserved tryptophan in RRM1 was shown to be essential for RRM2 binding and mammalian viability, and (2) the PTEN-induction metastasis suppressor function was demonstrated to be independent of RNR catalytic activity using an enzymatically dead mutant.\",\n      \"evidence\": \"Mouse Rrm1-W688G knock-in (embryonic lethality, proteomic confirmation of lost RRM2 interaction); Y738F catalytic-dead RRM1 mutant overexpression with PTEN epistasis in colorectal cancer cells\",\n      \"pmids\": [\"26077802\", \"25638032\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of how RRM1 protein (non-enzymatically) induces PTEN transcription unknown\", \"Whether the W688 interaction surface has additional regulatory roles beyond heterodimerization not tested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"MDM2 was identified as the E3 ligase for RRM1, mediating Lys48-linked polyubiquitination and proteasomal degradation, providing a regulated turnover mechanism downstream of MEK-AKT signaling.\",\n      \"evidence\": \"Co-immunoprecipitation, ubiquitination linkage assay, MG132 proteasome inhibition, pimasertib treatment in pancreatic cancer cells\",\n      \"pmids\": [\"26228206\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitination sites on RRM1 not mapped\", \"Whether MDM2-mediated degradation operates under physiological conditions beyond drug treatment unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"CDK2/cyclin A was identified as the kinase phosphorylating RRM1 at Ser559 during S/G2 phase, directly enhancing RNR enzymatic activity; loss of this modification causes replication stress and synergizes with ATR inhibition.\",\n      \"evidence\": \"Phosphorylation mapping, in vitro kinase assay, phosphomutant cell lines, dNTP pool measurement, γH2AX, ATR inhibitor epistasis\",\n      \"pmids\": [\"32712628\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether additional phosphorylation sites regulate RRM1 activity not addressed\", \"Structural mechanism by which S559 phosphorylation enhances catalysis not determined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Human loss-of-function variants in RRM1 were shown to cause mitochondrial DNA depletion syndrome, establishing RRM1 as a disease gene through impaired de novo nucleotide synthesis demonstrated in patient cells.\",\n      \"evidence\": \"Patient variant identification (p.N427K dominant, p.R381 recessive), mtDNA copy number in fibroblasts, dNTP pool analysis, molecular dynamics\",\n      \"pmids\": [\"35617047\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific manifestations (why mitochondria are preferentially affected) not mechanistically explained\", \"No rescue experiment with wild-type RRM1 in patient cells reported\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"RRM1 was linked to ferroptosis regulation through a USP11/MDM2–p53–p21–GPX4 signaling axis, where RRM1 depletion destabilizes p53 and reduces GPX4, promoting lipid peroxidation.\",\n      \"evidence\": \"siRNA knockdown, ROS and lipid peroxidation assays, ubiquitination assay for p53, GPX4 activity measurement\",\n      \"pmids\": [\"35915092\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct physical interaction between RRM1 and USP11/MDM2 for p53 regulation not firmly established with reciprocal IP\", \"Whether ferroptosis sensitivity is secondary to nucleotide depletion not excluded\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"A non-enzymatic DNA repair function was mechanistically delineated: RRM1 interacts with USP11 in the cytoplasm and, upon irradiation, is recruited to LaminB1 at the nuclear pore to facilitate USP11 nuclear entry, where USP11 deubiquitinates E2F1 to drive RAD51AP1 transcription and homologous recombination.\",\n      \"evidence\": \"Co-IP, nuclear fractionation, deletion mutagenesis (aa 731-793), HR reporter assay, RAD51AP1 transcription analysis\",\n      \"pmids\": [\"39695160\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; domain deletion dominant-negative phenotype needs independent confirmation\", \"Whether RRM1-USP11 interaction is regulated by post-translational modifications not tested\", \"Stoichiometry and structural basis of RRM1–USP11–LaminB1 complex undefined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Translational control of RRM1 was revealed through diphthamide-dependent modulation of eEF2, where loss of diphthamide increases -1 frameshifting on RRM1 mRNA, reducing RRM1 protein and causing replication stress.\",\n      \"evidence\": \"Quantitative proteomics, -1 frameshifting reporter assay, DPH-deficient mammalian cell lines, replication stress markers\",\n      \"pmids\": [\"39463834\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific frameshifting-prone sequences in RRM1 mRNA not mapped\", \"Whether this translational regulation is physiologically modulated unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Major unresolved questions include: the structural/molecular mechanism by which RRM1 protein (independent of catalysis) activates PTEN transcription; how RRM1's enzymatic and non-enzymatic functions are coordinated in different cellular contexts; and the full spectrum of post-translational modifications regulating RRM1 stability, localization, and protein interactions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of RRM1 non-enzymatic signaling complexes\", \"Tissue-specific roles of RRM1 beyond cancer cell lines poorly characterized\", \"Integration of enzymatic vs. scaffolding functions in normal physiology vs. disease not resolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [3, 4, 5]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 9, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [10, 12]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-69306\", \"supporting_discovery_ids\": [4, 5, 17]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [7, 12, 13]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [4, 7]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [3, 4, 5]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [11, 13]}\n    ],\n    \"complexes\": [\n      \"Ribonucleotide reductase (RNR)\"\n    ],\n    \"partners\": [\n      \"RRM2\",\n      \"USP11\",\n      \"MDM2\",\n      \"PTEN\",\n      \"CDK2\",\n      \"CHK1\",\n      \"LMNB1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}