{"gene":"RRM2","run_date":"2026-06-10T07:46:28","timeline":{"discoveries":[{"year":2006,"finding":"RRM2 overexpression increases pancreatic adenocarcinoma cellular invasiveness and MMP-9 expression in a NF-κB-dependent manner; RNAi-mediated silencing of RRM2 attenuates cellular invasiveness and NF-κB activity, establishing NF-κB as a key mediator of RRM2-driven invasion.","method":"RRM2 overexpression, RNAi knockdown, NF-κB transcriptional activity assay, invasion assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal gain- and loss-of-function with defined molecular pathway readout, single lab","pmids":["17222798"],"is_preprint":false},{"year":2009,"finding":"RRM2 overexpression decreases thrombospondin-1 (TSP-1) and increases VEGF production, promoting tumor angiogenesis; siRNA-mediated RRM2 attenuation reverses these effects in vitro and in vivo.","method":"RRM2 overexpression in KB cells, siRNA knockdown, ELISA/Western blot for TSP-1/VEGF, in vivo xenograft angiogenesis assay, endothelial chemotaxis assay","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal gain/loss-of-function with orthogonal in vitro and in vivo readouts, single lab","pmids":["19250552"],"is_preprint":false},{"year":2013,"finding":"RRM2 knockdown leads to apoptosis via the intrinsic pathway in HNSCC and NSCLC cells; RRM2 regulates Bcl-2 protein stability such that RRM2 depletion increases Bcl-2 degradation; RRM2 and Bcl-2 colocalize in cancer cells.","method":"siRNA knockdown, immunoblotting, confocal microscopy, tissue fractionation, gene overexpression/knockdown, immunohistochemistry, quantum dot immunofluorescence","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (subcellular fractionation, confocal co-localization, rescue experiments), single lab","pmids":["23719266"],"is_preprint":false},{"year":2013,"finding":"let-7 miRNAs directly bind the 3′ UTR of RRM2 transcripts to post-transcriptionally regulate RRM2 expression; reduced mature let-7a (due to defective processing regulated by LIN-28 and SET oncoprotein) correlates with RRM2 overexpression and gemcitabine resistance in pancreatic cancer.","method":"3′ UTR luciferase reporter assay, shRNA library screening, miRNA overexpression, qRT-PCR, patient-derived PDAC tissue analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct 3′ UTR binding validated by luciferase assay plus patient tissue correlation, single lab","pmids":["23335963"],"is_preprint":false},{"year":2013,"finding":"RRM2 is an AKT-regulated gene; cells with elevated AKT upregulate RRM2 expression, leading to increased DNA repair and protection from tamoxifen-induced apoptosis; RNAi-mediated RRM2 inhibition reverses tamoxifen-resistant cell growth and activates DNA damage and proapoptotic pathways.","method":"Gene expression profiling, RNAi, RRM2 inhibitor (didox), in vitro and in vivo growth assays, DNA damage markers","journal":"Molecular cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — expression profiling with functional validation by RNAi and small-molecule inhibitor in vitro and in vivo, single lab","pmids":["24362250"],"is_preprint":false},{"year":2014,"finding":"HPV E7 upregulates RRM2 at the transcriptional level through E7-pRb interaction and E2F binding to the RRM2 promoter; RRM2 overexpression enhances HIF-1α and VEGF expression via ROS-activated ERK1/2 signaling, promoting angiogenesis in cervical cancer.","method":"Luciferase reporter assay (RRM2 promoter), Western blot, ELISA, ROS measurement by flow cytometry, HUVEC tube formation assay, xenograft model","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter luciferase assay plus multiple functional readouts, single lab","pmids":["24423925"],"is_preprint":false},{"year":2015,"finding":"Increased Rrm2 gene dosage in mice produces supraphysiological RNR activity, reduces chromosomal breakage at common fragile sites, and significantly extends the lifespan of ATR-mutant mice, demonstrating genetic conservation of the ATR-RNR axis in mammals.","method":"Rrm2 transgenic mouse model (Rrm2TG), RNR enzymatic activity assay, chromosomal fragile site breakage analysis, survival curve analysis of ATR-mutant mice","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic epistasis with RNR activity measurement and multiple phenotypic readouts; replicated across multiple mouse genotypes in one rigorous study","pmids":["25838540"],"is_preprint":false},{"year":2016,"finding":"BRCA1 acts as a transcriptional co-activator of RRM2; BRCA1-mediated RRM2 expression protects GBM cells from endogenous replication stress, DNA damage accumulation, and apoptosis; BRCA1 depletion phenocopies RRM2 inhibition (with triapine) in reducing tumor growth.","method":"BRCA1 knockdown, RRM2 expression analysis, replication stress assays, DNA damage markers, tumor growth assays, triapine (RRM2 inhibitor) treatment","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic link between BRCA1 and RRM2 transcription with functional rescue, single lab, multiple orthogonal readouts","pmids":["27845331"],"is_preprint":false},{"year":2016,"finding":"HPV31 maintains elevated RRM2 levels in differentiating keratinocytes through expression of E7 and activation of the ATR-Chk1-E2F1 DNA damage response pathway; RRM2 depletion blocks HPV31 productive replication, indicating RRM2 provides dNTPs for viral DNA synthesis.","method":"RRM2 depletion (shRNA), dNTP pool measurement, productive replication assay, ATR/Chk1/E2F1 inhibition experiments","journal":"Virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with specific viral replication phenotype and pathway placement via inhibitor experiments, single lab","pmids":["27764728"],"is_preprint":false},{"year":2016,"finding":"MYBL2 directly binds the RRM2 gene promoter and promotes RRM2 transcription during S-phase together with TAF15 and MuvB components; MYBL2-driven cell proliferation and DNA synthesis in CRC are RRM2-dependent.","method":"ChIP, promoter reporter assay, MYBL2 overexpression/knockdown, co-immunoprecipitation identifying TAF15/MuvB complex members, DNA synthesis assay","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus co-IP identifying the transcriptional complex, with functional rescue, single lab","pmids":["34234118"],"is_preprint":false},{"year":2019,"finding":"Inhibition of the ATR-CHK1 pathway in Ewing sarcoma cells activates CDK2, which targets RRM2 for proteasome-mediated degradation; similarly, WEE1 inhibition activates CDK2 and depletes RRM2, causing DNA damage and apoptosis.","method":"ATR/CHK1/WEE1 inhibitors, CDK2 activation assays, proteasome inhibition rescue, Western blot for RRM2 protein levels, DNA damage markers, apoptosis assays","journal":"Molecular cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway dissected with multiple inhibitors and rescue experiments, single lab","pmids":["31649026"],"is_preprint":false},{"year":2018,"finding":"DHS (trans-4,4'-dihydroxystilbene) induces cyclin F-mediated proteasomal degradation of RRM2; molecular docking identifies RRM2 as a direct DHS target; DHS treatment reduces RNR activity, decreases dNTP synthesis, causes S-phase arrest and DNA damage.","method":"Molecular docking, Western blot for RRM2 protein, dNTP pool measurement, cell cycle analysis, RNR activity assay, cyclin F knockdown rescue","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — docking plus functional validation of cyclin F-dependent degradation with RNR activity readout, single lab","pmids":["30518875"],"is_preprint":false},{"year":2020,"finding":"RRM2 inhibits ferroptosis in liver cancer cells by sustaining glutathione (GSH) synthesis via interaction with glutathione synthetase (GSS); under ferroptotic stress, RRM2 is dephosphorylated at Threonine 33 (T33), promoting RRM2-GSS interaction and translocation of both proteins to the proteasome for simultaneous degradation; T33 phosphorylation normally blocks this interaction.","method":"Co-immunoprecipitation, proximity ligation assay (PLA), immunofluorescence, cell viability assay, metabolite measurement, Western blot, ELISA","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP and PLA with phospho-site functional validation, multiple orthogonal methods, single lab","pmids":["33372599"],"is_preprint":false},{"year":2020,"finding":"The translational repressor 4E-BP1 specifically regulates RRM2 protein levels; inhibition of mTORC1/2 (but not mTORC1 alone) activates 4E-BP1 and reduces RRM2 protein; CRISPR knockout of 4E-BP1 rescues mTORC1/2 inhibitor-induced RRM2 depletion, demonstrating cap-dependent translation as a regulatory mechanism for RRM2.","method":"mTORC1/2 inhibitors, CRISPR/Cas9 4E-BP1 knockout, inducible mutant 4E-BP1 expression, Western blot, xenograft growth assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR rescue experiment with genetic and pharmacological orthogonal approaches, single lab","pmids":["33191406"],"is_preprint":false},{"year":2020,"finding":"YBX1 (identified by in vivo RNA antisense purification/RAP-MS as a direct lincNMR interaction partner) binds to the RRM2 promoter region and regulates RRM2 expression; lincNMR depletion decreases dNTP levels and RRM2/TYMS/TK1 expression, while exogenous dNTPs rescue the proliferation defect.","method":"RAP-MS (in vivo RNA antisense purification + mass spectrometry), SILAC proteomics, ChIP (YBX1 binding to RRM2 promoter), dNTP pool measurement, rescue with exogenous dNTPs","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RAP-MS plus ChIP identifying YBX1-RRM2 promoter axis, with functional dNTP rescue, single lab","pmids":["32587247"],"is_preprint":false},{"year":2021,"finding":"RRM2 stabilizes ANXA1 protein and activates the AKT pathway independent of its ribonucleotide reductase enzymatic activity, promoting sunitinib resistance in renal cell carcinoma.","method":"Co-immunoprecipitation, Western blot, RRM2 knockdown/overexpression, AKT pathway inhibitors, sunitinib resistance assay","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP showing RRM2-ANXA1 interaction plus pathway inhibitor validation, with non-enzymatic activity claim supported by reductase-dead mutant context, single lab","pmids":["34319001"],"is_preprint":false},{"year":2021,"finding":"MYBL2 constitutes a dynamic S-phase transcription complex (with TAF15 and MuvB) that directly binds the RRM2 promoter to activate its transcription; E2F8 also directly binds the RRM2 promoter and transactivates RRM2, demonstrating multiple E2F/MYBL2 family members converge on RRM2 transcription.","method":"ChIP-qPCR, DNA pulldown-Western blot, luciferase reporter assay, E2F8 knockdown/overexpression, cell cycle and DNA synthesis assays","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-qPCR and DNA pulldown confirm direct E2F8-RRM2 promoter binding with functional validation, single lab","pmids":["37863324"],"is_preprint":false},{"year":2021,"finding":"RRM2 silencing activates the cGAS/STING signaling pathway in lung adenocarcinoma cells, increases CD8+ T cell infiltration in tumors, and synergizes with radiation to promote apoptosis and enhance cGAS/STING pathway activation.","method":"RRM2 shRNA knockdown, immunofluorescence, immunoblotting, flow cytometric analysis of CD8+ T cells, xenograft and syngeneic mouse models, comet assay","journal":"Cell & bioscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with STING pathway readout and in vivo immune cell infiltration, single lab","pmids":["33858512"],"is_preprint":false},{"year":2022,"finding":"USP7 deubiquitinates RRM2 during S phase of the cell cycle; USP7 downregulation reduces RRM2 protein levels and induces cellular senescence in melanoma; ectopic RRM2 expression in USP7-depleted cells rescues the senescent phenotype.","method":"Global transcriptomic and proteomic analysis, USP7 knockdown (shRNA), RRM2 ectopic expression rescue, in vivo PDX dropout screens, pharmacological USP7 inhibition (P5091)","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo dropout screen plus RRM2 rescue of senescence phenotype, multiple methods, single lab; deubiquitination mechanism inferred but direct biochemical deubiquitination assay not explicitly described in abstract","pmids":["36130505"],"is_preprint":false},{"year":2022,"finding":"RRM2 forced induction alleviates excessive replicative stress induced by CHK1 inhibition in neuroblastoma; high RRM2 expression correlates with high CHK1 activity; RRM2 inhibition enhances intrinsic replication stress checkpoint addiction; combinatorial RRM2-CHK1 inhibition acts synergistically in high-risk neuroblastoma models.","method":"Zebrafish neuroblastoma model (RRM2 + MYCN co-overexpression), in vitro knockdown, CHK1 inhibitor + RRM2 overexpression/inhibition, patient-derived xenograft models","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo zebrafish model plus PDX with genetic epistasis between RRM2 and CHK1, multiple orthogonal methods, single lab","pmids":["35857500"],"is_preprint":false},{"year":2023,"finding":"USP12 directly interacts with and deubiquitinates RRM2 in NSCLC cells, stabilizing RRM2 protein; USP12 knockdown reduces RRM2 levels, causes DNA replication stress, and retards tumor growth in vivo.","method":"Co-immunoprecipitation (USP12-RRM2 interaction), deubiquitination assay, USP12 knockdown, DNA replication stress assays, in vivo tumor growth assay","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus deubiquitination assay with in vivo functional validation, single lab","pmids":["37341611"],"is_preprint":false},{"year":2024,"finding":"RRM2 stabilizes YBX1 protein and upregulates TGFBR1 expression, activating the TGF-beta signaling pathway to promote pancreatic cancer progression and liver metastasis.","method":"RRM2 knockdown/overexpression, Western blot for YBX1/TGFBR1, TGF-beta pathway readouts, in vivo liver metastasis model","journal":"iScience","confidence":"Low","confidence_rationale":"Tier 3 / Weak — protein stabilization and pathway activation described but direct binding/interaction experiment details not specified in abstract; single lab, single-method descriptions","pmids":["39398252"],"is_preprint":false},{"year":2024,"finding":"p53 deficiency increases RRM2 protein expression and crotonylation of RRM2 at K283 (RRM2K283Cr) by downregulating SIRT7, the decrotonylase of RRM2; elevated RRM2K283Cr promotes cisplatin resistance by inhibiting apoptosis (reduced cleaved-PARP1 and cleaved-caspase3).","method":"SILAC-based quantitative crotonylome, p53 knockout, SIRT7 knockdown/overexpression, Western blot for crotonylation, apoptosis markers","journal":"Frontiers in molecular biosciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative proteomics identifying specific K283 crotonylation site plus genetic validation of SIRT7 as decrotonylase, single lab","pmids":["38894712"],"is_preprint":false},{"year":2024,"finding":"IGF2BP3 enhances RRM2 mRNA stability and protein expression by reading m6A modification on RRM2 mRNA; IGF2BP3 disruption reduces RRM2 levels, promotes ferroptosis, and inhibits HCC cell malignant phenotypes; FOXM1 transcriptionally activates IGF2BP3, placing FOXM1 upstream of IGF2BP3/RRM2 axis.","method":"MeRIP-qRT-PCR (m6A modification of RRM2 mRNA), RIP assay (IGF2BP3-RRM2 interaction), ChIP and dual-luciferase reporter (FOXM1-IGF2BP3), ferroptosis markers (MDA/GSH/ROS), in vivo xenograft","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP and RIP assays directly demonstrate m6A-dependent IGF2BP3-RRM2 mRNA interaction, plus ChIP for upstream FOXM1, multiple orthogonal methods, single lab","pmids":["39630361"],"is_preprint":false},{"year":2023,"finding":"FOXM1 directly binds to the RRM2 promoter and regulates its transcriptional activity in SCLC; miR-1 targets CXCR4, which prevents FOXM1 from binding the RRM2 promoter, establishing a CXCR4/FOXM1/RRM2 regulatory axis.","method":"Chromatin immunoprecipitation (FOXM1 binding RRM2 promoter), dual-luciferase assay (miR-1 targeting CXCR4), transcriptomic analysis, in vitro and in vivo loss/gain-of-function models","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirming direct FOXM1-RRM2 promoter binding plus luciferase validation of upstream miR-1/CXCR4, single lab","pmids":["36597126"],"is_preprint":false},{"year":2024,"finding":"lncOCMRL1 suppresses RRM2 ubiquitination (identified by RNA pull-down, silver staining, mass spectrometry, and RIP), thereby stabilizing RRM2 protein and promoting EMT-driven invasion and migration of oral squamous cell carcinoma cells.","method":"RNA pull-down, silver staining, mass spectrometry, RIP assay, Western blot for ubiquitination, invasion/migration assays, in vivo tumor model","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA pull-down/MS identifying lncRNA-RRM2 protein interaction with ubiquitination functional readout, single lab","pmids":["39343925"],"is_preprint":false},{"year":2022,"finding":"RRM2 overexpression enhances osteogenic differentiation of mouse embryo fibroblasts by activating the Wnt/β-catenin signaling pathway, increasing β-catenin protein levels, p-GSK-3β/GSK-3β ratio, and downstream target gene expression; RRM2 knockdown reduces osteogenesis.","method":"RRM2 overexpression (adenovirus) and siRNA knockdown, Western blot for β-catenin and p-GSK-3β, RT-qPCR for Wnt target genes, ALP staining, Alizarin Red S staining","journal":"Experimental and therapeutic medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — gain/loss-of-function with pathway readouts but no direct mechanistic link between RRM2 and Wnt components established; single lab, single method type","pmids":["36160885"],"is_preprint":false},{"year":2023,"finding":"RRM2 directly interacts with CDK1 (identified by co-immunoprecipitation and mass spectrometry) in chicken myoblasts; SP1 transcription factor binds the core RRM2 promoter and regulates its transcription; RRM2 promotes myoblast proliferation and inhibits differentiation.","method":"Co-immunoprecipitation and mass spectrometry (RRM2-CDK1), dual luciferase reporter assay (SP1-RRM2 promoter), qRT-PCR, CCK-8 assay, EdU incorporation, flow cytometry, in vivo muscle regeneration assay","journal":"Poultry science","confidence":"Low","confidence_rationale":"Tier 3 / Weak — co-IP/MS identifies CDK1 interaction and SP1 promoter binding validated in chicken (avian model, not mammalian), single lab","pmids":["38198913"],"is_preprint":false}],"current_model":"RRM2, the small catalytic subunit of ribonucleotide reductase (RNR), catalyzes the rate-limiting conversion of ribonucleoside diphosphates to deoxyribonucleoside diphosphates to supply dNTPs for DNA replication and repair; its expression is transcriptionally driven by E2F family members (E2F1, E2F2, E2F8) and MYBL2 (in complex with TAF15/MuvB) at the RRM2 promoter, and post-translationally controlled through CDK2-mediated proteasomal degradation (activated by ATR-CHK1 or WEE1 pathway inhibition), deubiquitination by USP7 and USP12, cyclin F-mediated degradation, m6A-dependent mRNA stabilization by IGF2BP3, and crotonylation at K283 regulated by the decrotonylase SIRT7; beyond its canonical enzymatic role, RRM2 also engages non-enzymatic functions including stabilization of ANXA1 to activate AKT signaling, interaction with Bcl-2 to regulate its stability, binding to GSS to modulate glutathione synthesis and ferroptosis resistance, and stabilization of YBX1 to activate TGF-beta signaling; genetically, increased RRM2/RNR activity suppresses replication stress at fragile sites and rescues ATR-mutant lethality in mice, placing RRM2 in a conserved ATR-RNR axis that buffers replicative stress."},"narrative":{"mechanistic_narrative":"RRM2 is the regulatory small subunit of ribonucleotide reductase whose supply of dNTPs places it at the center of an ATR-RNR axis that buffers replicative stress: supraphysiological Rrm2 gene dosage in mice raises RNR activity, reduces chromosomal breakage at common fragile sites, and rescues the lethality of ATR-mutant animals [PMID:25838540], and forced RRM2 induction similarly alleviates the replication stress imposed by CHK1 inhibition in neuroblastoma [PMID:35857500]. Because RRM2 is the rate-limiting, S-phase-restricted subunit, its abundance is controlled at multiple levels. Transcriptionally, an S-phase MYBL2-TAF15-MuvB complex and E2F8 directly occupy the RRM2 promoter [PMID:34234118, PMID:37863324], with additional promoter input from BRCA1 acting as a co-activator [PMID:27845331] and FOXM1 [PMID:36597126]; viral oncoprotein HPV E7 drives RRM2 through pRb-E2F and the ATR-Chk1-E2F1 pathway to provision dNTPs for viral DNA synthesis [PMID:24423925, PMID:27764728]. Post-transcriptionally RRM2 is repressed by let-7 miRNAs targeting its 3' UTR [PMID:23335963] and stabilized by m6A reading via IGF2BP3 [PMID:39630361] and by cap-dependent translation controlled by 4E-BP1 [PMID:33191406]. RRM2 protein stability is set by a balance of CDK2-triggered, proteasomal degradation activated upon ATR-CHK1 or WEE1 inhibition [PMID:31649026] and cyclin F-mediated turnover [PMID:30518875] against deubiquitination by USP7 and USP12 [PMID:36130505, PMID:37341611]. Beyond catalysis, RRM2 carries out enzyme-independent functions: it stabilizes ANXA1 to activate AKT signaling [PMID:34319001], regulates Bcl-2 stability to set the apoptotic threshold [PMID:23719266], sustains glutathione synthesis through interaction with GSS to resist ferroptosis [PMID:33372599], and stabilizes YBX1 to engage TGF-beta signaling [PMID:39398252]. Through these activities RRM2 promotes tumor invasion, angiogenesis, and therapy resistance across cancers [PMID:17222798, PMID:19250552, PMID:24362250], and its loss activates cGAS/STING immune signaling [PMID:33858512].","teleology":[{"year":2006,"claim":"Established that RRM2 has activities beyond dNTP supply, driving tumor cell invasion through an NF-kB-dependent program.","evidence":"reciprocal RRM2 overexpression/RNAi with NF-kB activity and invasion assays in pancreatic adenocarcinoma cells","pmids":["17222798"],"confidence":"Medium","gaps":["does not define how RRM2 activates NF-kB","enzymatic versus non-enzymatic contribution not separated"]},{"year":2009,"claim":"Linked RRM2 levels to the tumor angiogenic switch by showing it shifts the TSP-1/VEGF balance.","evidence":"RRM2 overexpression/siRNA with ELISA, xenograft angiogenesis and endothelial chemotaxis readouts","pmids":["19250552"],"confidence":"Medium","gaps":["molecular intermediary between RRM2 and TSP-1/VEGF unresolved"]},{"year":2013,"claim":"Defined post-transcriptional and signaling control of RRM2 and connected it to apoptotic and DNA-repair outcomes underlying therapy resistance.","evidence":"let-7 3' UTR luciferase reporters, AKT expression profiling with RNAi/didox, and Bcl-2 stability/colocalization studies across HNSCC, NSCLC, breast and pancreatic models","pmids":["23335963","24362250","23719266"],"confidence":"Medium","gaps":["direct RRM2-Bcl-2 binding mechanism not biochemically resolved","whether AKT regulation is transcriptional or post-translational not fully separated"]},{"year":2014,"claim":"Showed viral oncoproteins co-opt RRM2 transcription to provision dNTPs, tying RRM2 to E7-pRb-E2F control and ROS-driven angiogenic signaling.","evidence":"RRM2 promoter luciferase assays, ROS/HIF-1a/VEGF readouts and HUVEC tube formation in HPV-positive cervical cancer","pmids":["24423925"],"confidence":"Medium","gaps":["does not establish viral replication dependence on RRM2 directly"]},{"year":2015,"claim":"Provided in vivo genetic proof that RNR output via RRM2 buffers replication stress, defining a conserved mammalian ATR-RNR axis.","evidence":"Rrm2 transgenic mice with RNR activity assays, fragile-site breakage analysis, and survival rescue of ATR-mutant mice","pmids":["25838540"],"confidence":"High","gaps":["does not address how acute RRM2 modulation behaves in tumors","cell-type-specific thresholds of protection unknown"]},{"year":2016,"claim":"Mapped transcriptional inputs (MYBL2/MuvB, BRCA1) and demonstrated RRM2 dNTP supply is required for HPV productive replication.","evidence":"ChIP/co-IP of MYBL2-TAF15-MuvB at the RRM2 promoter, BRCA1 knockdown with triapine, and RRM2 depletion with dNTP measurement in differentiating keratinocytes","pmids":["34234118","27845331","27764728"],"confidence":"Medium","gaps":["relative weighting of these transcriptional inputs across tissues unclear"]},{"year":2018,"claim":"Identified cyclin F as a degradation route controlling RRM2 protein and RNR activity, exploitable pharmacologically.","evidence":"molecular docking, cyclin F knockdown rescue, dNTP and RNR activity assays with DHS treatment","pmids":["30518875"],"confidence":"Medium","gaps":["degron and ubiquitination site on RRM2 not mapped"]},{"year":2019,"claim":"Defined the CDK2-dependent degradation mechanism that links replication-checkpoint inhibition to RRM2 loss and cell death.","evidence":"ATR/CHK1/WEE1 inhibitors with CDK2 activation, proteasome-inhibition rescue and RRM2 immunoblotting in Ewing sarcoma","pmids":["31649026"],"confidence":"Medium","gaps":["direct CDK2 phosphosite on RRM2 driving degradation not identified here"]},{"year":2020,"claim":"Expanded RRM2 control to translation and uncovered a non-enzymatic ferroptosis-protective role via GSS, plus a YBX1-promoter regulatory loop.","evidence":"4E-BP1 CRISPR knockout rescue with mTOR inhibitors; RRM2-GSS co-IP/PLA with T33 phospho-site mapping; RAP-MS/ChIP linking YBX1 to the RRM2 promoter with dNTP rescue","pmids":["33191406","33372599","32587247"],"confidence":"Medium","gaps":["structural basis of RRM2-GSS interaction unresolved","kinase setting RRM2 T33 phosphorylation not identified"]},{"year":2021,"claim":"Established enzyme-independent oncogenic functions of RRM2 and its immune-modulatory consequence upon loss.","evidence":"co-IP showing RRM2-ANXA1 stabilization with AKT inhibitors and sunitinib resistance; E2F8 promoter ChIP/luciferase; RRM2 silencing activating cGAS/STING with CD8+ T cell infiltration in vivo","pmids":["34319001","37863324","33858512"],"confidence":"Medium","gaps":["how a reductase subunit stabilizes ANXA1 mechanistically unclear","whether cGAS/STING activation is solely a consequence of dNTP depletion not resolved"]},{"year":2022,"claim":"Defined deubiquitination by USP7 as a stability control whose loss triggers senescence, and showed RRM2 induction relieves CHK1-inhibition replication stress.","evidence":"USP7 knockdown/inhibitor with RRM2 rescue of senescence in melanoma and PDX dropout screens; zebrafish/PDX RRM2-CHK1 epistasis in neuroblastoma","pmids":["36130505","35857500"],"confidence":"Medium","gaps":["direct USP7-RRM2 deubiquitination assay not described","RRM2 ubiquitin acceptor sites unmapped"]},{"year":2023,"claim":"Added USP12 as a second deubiquitinase and FOXM1 as a transcriptional driver within an upstream miR-1/CXCR4 axis.","evidence":"USP12-RRM2 co-IP and deubiquitination assay with in vivo growth; FOXM1 ChIP at the RRM2 promoter with miR-1/CXCR4 luciferase validation","pmids":["37341611","36597126"],"confidence":"Medium","gaps":["redundancy/specificity between USP7 and USP12 toward RRM2 not addressed"]},{"year":2024,"claim":"Identified m6A/IGF2BP3 mRNA stabilization, K283 crotonylation controlled by SIRT7, and lncRNA-mediated ubiquitination control as additional regulatory layers, alongside a YBX1-TGF-beta metastatic function.","evidence":"MeRIP/RIP with FOXM1 ChIP for IGF2BP3 axis; SILAC crotonylome with p53/SIRT7 genetics for K283Cr; lncOCMRL1 RNA pull-down/MS; RRM2-YBX1/TGFBR1 stabilization in metastasis models","pmids":["39630361","38894712","39343925","39398252"],"confidence":"Medium","gaps":["how crotonylation at K283 alters RRM2 enzymatic versus non-enzymatic activity unclear","RRM2-YBX1 direct binding (#21) not biochemically detailed"]},{"year":null,"claim":"It remains unresolved which RRM2 functions in cancer are catalytic dNTP supply versus the several moonlighting protein-stabilization activities, and how the dense web of competing regulators is integrated in a single cell.","evidence":"","pmids":[],"confidence":"Medium","gaps":["no unified quantitative model partitioning enzymatic and non-enzymatic RRM2 outputs","structural basis for RRM2 binding to ANXA1/GSS/YBX1/Bcl-2 unknown","in vivo hierarchy among transcriptional, translational and degradation controls undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[6,11]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[15,12,21,2]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2,12]}],"pathway":[{"term_id":"R-HSA-69306","term_label":"DNA Replication","supporting_discovery_ids":[6,8]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[9,10,16]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[6,19]}],"complexes":["ribonucleotide reductase"],"partners":["ANXA1","GSS","YBX1","BCL-2","CDK1","USP7","USP12","IGF2BP3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P31350","full_name":"Ribonucleoside-diphosphate reductase subunit M2","aliases":["Ribonucleotide reductase small chain","Ribonucleotide reductase small subunit"],"length_aa":389,"mass_kda":44.9,"function":"Provides the precursors necessary for DNA synthesis. Catalyzes the biosynthesis of deoxyribonucleotides from the corresponding ribonucleotides. 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Mice.","date":"2019","source":"International journal of medical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/31673243","citation_count":12,"is_preprint":false},{"pmid":"37341611","id":"PMC_37341611","title":"USP12 promotes nonsmall cell lung cancer progression through deubiquitinating and stabilizing RRM2.","date":"2023","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/37341611","citation_count":11,"is_preprint":false},{"pmid":"38820515","id":"PMC_38820515","title":"IGF2BP3 regulates the expression of RRM2 and promotes the progression of rheumatoid arthritis via RRM2/Akt/MMP-9 pathway.","date":"2024","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/38820515","citation_count":11,"is_preprint":false},{"pmid":"37349644","id":"PMC_37349644","title":"Diosmetin suppresses the progression of ESCC by CDK2/Rb/E2F2/RRM2 pathway and synergies with cisplatin.","date":"2023","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/37349644","citation_count":11,"is_preprint":false},{"pmid":"36660663","id":"PMC_36660663","title":"MiR-202-3p inhibits the proliferation and metastasis of lung adenocarcinoma cells by targeting RRM2.","date":"2022","source":"Annals of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36660663","citation_count":11,"is_preprint":false},{"pmid":"28257838","id":"PMC_28257838","title":"ALS-causing cleavages of TDP-43 abolish its RRM2 structure and unlock CTD for enhanced aggregation and toxicity.","date":"2017","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/28257838","citation_count":11,"is_preprint":false},{"pmid":"36160885","id":"PMC_36160885","title":"RRM2 regulates osteogenesis of mouse embryo fibroblasts via the Wnt/β‑catenin signaling pathway.","date":"2022","source":"Experimental and therapeutic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36160885","citation_count":10,"is_preprint":false},{"pmid":"35964907","id":"PMC_35964907","title":"Circ_0008285 knockdown represses tumor development by miR-384/RRM2 axis in hepatocellular carcinoma.","date":"2022","source":"Annals of hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/35964907","citation_count":10,"is_preprint":false},{"pmid":"35200126","id":"PMC_35200126","title":"Identification of RRM2 in peripheral blood mononuclear cells as a novel biomarker for the diagnosis of rheumatoid arthritis.","date":"2022","source":"Clinical and experimental rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/35200126","citation_count":10,"is_preprint":false},{"pmid":"32753891","id":"PMC_32753891","title":"Downregulation of RRM2 Attenuates Retroperitoneal Liposarcoma Progression via the Akt/mTOR/4EBP1 Pathway: Clinical, Biological, and Therapeutic Significance.","date":"2020","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/32753891","citation_count":10,"is_preprint":false},{"pmid":"32003677","id":"PMC_32003677","title":"Cancer Fighting SiRNA-RRM2 Loaded Nanorobots.","date":"2020","source":"Pharmaceutical nanotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/32003677","citation_count":9,"is_preprint":false},{"pmid":"33260324","id":"PMC_33260324","title":"Zinc Binds to RRM2 Peptide of TDP-43.","date":"2020","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33260324","citation_count":9,"is_preprint":false},{"pmid":"39259911","id":"PMC_39259911","title":"Circular RNA RRM2 alleviates metabolic dysfunction-associated steatotic liver disease by targeting miR-142-5p to increase NRG1 expression.","date":"2024","source":"American journal of physiology. Gastrointestinal and liver physiology","url":"https://pubmed.ncbi.nlm.nih.gov/39259911","citation_count":9,"is_preprint":false},{"pmid":"38273783","id":"PMC_38273783","title":"lncRNA CYTOR promotes lung adenocarcinoma gemcitabine resistance and epithelial-mesenchymal transition by sponging miR-125a-5p and upregulating ANLN and RRM2.","date":"2024","source":"Acta biochimica et biophysica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/38273783","citation_count":9,"is_preprint":false},{"pmid":"35933914","id":"PMC_35933914","title":"Novel human-derived EML4-ALK fusion cell lines identify ribonucleotide reductase RRM2 as a target of activated ALK in NSCLC.","date":"2022","source":"Lung cancer (Amsterdam, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/35933914","citation_count":9,"is_preprint":false},{"pmid":"40303288","id":"PMC_40303288","title":"Targeting HCG18 counteracts ferroptosis resistance via blocking the miR-30a-5p/RRM2/GSS pathway in hepatocellular carcinoma.","date":"2025","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40303288","citation_count":8,"is_preprint":false},{"pmid":"39676643","id":"PMC_39676643","title":"RRM2 Is a Putative Biomarker and Promotes Bladder Cancer Progression via PI3K/AKT/mTOR Pathway.","date":"2024","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/39676643","citation_count":8,"is_preprint":false},{"pmid":"38894712","id":"PMC_38894712","title":"p53 deficiency mediates cisplatin resistance by upregulating RRM2 and crotonylation of RRM2K283 through the downregulation of SIRT7.","date":"2024","source":"Frontiers in molecular biosciences","url":"https://pubmed.ncbi.nlm.nih.gov/38894712","citation_count":8,"is_preprint":false},{"pmid":"38198913","id":"PMC_38198913","title":"RRM2 promotes the proliferation of chicken myoblasts, inhibits their differentiation and muscle regeneration.","date":"2023","source":"Poultry science","url":"https://pubmed.ncbi.nlm.nih.gov/38198913","citation_count":8,"is_preprint":false},{"pmid":"39398252","id":"PMC_39398252","title":"RRM2 promotes liver metastasis of pancreatic cancer by stabilizing YBX1 and activating the TGF-beta pathway.","date":"2024","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/39398252","citation_count":8,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":57117,"output_tokens":7129,"usd":0.139143,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":16285,"output_tokens":4466,"usd":0.096537,"stage2_stop_reason":"end_turn"},"total_usd":0.23568,"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\": 2006,\n      \"finding\": \"RRM2 overexpression increases pancreatic adenocarcinoma cellular invasiveness and MMP-9 expression in a NF-κB-dependent manner; RNAi-mediated silencing of RRM2 attenuates cellular invasiveness and NF-κB activity, establishing NF-κB as a key mediator of RRM2-driven invasion.\",\n      \"method\": \"RRM2 overexpression, RNAi knockdown, NF-κB transcriptional activity assay, invasion assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal gain- and loss-of-function with defined molecular pathway readout, single lab\",\n      \"pmids\": [\"17222798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"RRM2 overexpression decreases thrombospondin-1 (TSP-1) and increases VEGF production, promoting tumor angiogenesis; siRNA-mediated RRM2 attenuation reverses these effects in vitro and in vivo.\",\n      \"method\": \"RRM2 overexpression in KB cells, siRNA knockdown, ELISA/Western blot for TSP-1/VEGF, in vivo xenograft angiogenesis assay, endothelial chemotaxis assay\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal gain/loss-of-function with orthogonal in vitro and in vivo readouts, single lab\",\n      \"pmids\": [\"19250552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RRM2 knockdown leads to apoptosis via the intrinsic pathway in HNSCC and NSCLC cells; RRM2 regulates Bcl-2 protein stability such that RRM2 depletion increases Bcl-2 degradation; RRM2 and Bcl-2 colocalize in cancer cells.\",\n      \"method\": \"siRNA knockdown, immunoblotting, confocal microscopy, tissue fractionation, gene overexpression/knockdown, immunohistochemistry, quantum dot immunofluorescence\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (subcellular fractionation, confocal co-localization, rescue experiments), single lab\",\n      \"pmids\": [\"23719266\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"let-7 miRNAs directly bind the 3′ UTR of RRM2 transcripts to post-transcriptionally regulate RRM2 expression; reduced mature let-7a (due to defective processing regulated by LIN-28 and SET oncoprotein) correlates with RRM2 overexpression and gemcitabine resistance in pancreatic cancer.\",\n      \"method\": \"3′ UTR luciferase reporter assay, shRNA library screening, miRNA overexpression, qRT-PCR, patient-derived PDAC tissue analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct 3′ UTR binding validated by luciferase assay plus patient tissue correlation, single lab\",\n      \"pmids\": [\"23335963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"RRM2 is an AKT-regulated gene; cells with elevated AKT upregulate RRM2 expression, leading to increased DNA repair and protection from tamoxifen-induced apoptosis; RNAi-mediated RRM2 inhibition reverses tamoxifen-resistant cell growth and activates DNA damage and proapoptotic pathways.\",\n      \"method\": \"Gene expression profiling, RNAi, RRM2 inhibitor (didox), in vitro and in vivo growth assays, DNA damage markers\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — expression profiling with functional validation by RNAi and small-molecule inhibitor in vitro and in vivo, single lab\",\n      \"pmids\": [\"24362250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"HPV E7 upregulates RRM2 at the transcriptional level through E7-pRb interaction and E2F binding to the RRM2 promoter; RRM2 overexpression enhances HIF-1α and VEGF expression via ROS-activated ERK1/2 signaling, promoting angiogenesis in cervical cancer.\",\n      \"method\": \"Luciferase reporter assay (RRM2 promoter), Western blot, ELISA, ROS measurement by flow cytometry, HUVEC tube formation assay, xenograft model\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter luciferase assay plus multiple functional readouts, single lab\",\n      \"pmids\": [\"24423925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Increased Rrm2 gene dosage in mice produces supraphysiological RNR activity, reduces chromosomal breakage at common fragile sites, and significantly extends the lifespan of ATR-mutant mice, demonstrating genetic conservation of the ATR-RNR axis in mammals.\",\n      \"method\": \"Rrm2 transgenic mouse model (Rrm2TG), RNR enzymatic activity assay, chromosomal fragile site breakage analysis, survival curve analysis of ATR-mutant mice\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic epistasis with RNR activity measurement and multiple phenotypic readouts; replicated across multiple mouse genotypes in one rigorous study\",\n      \"pmids\": [\"25838540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"BRCA1 acts as a transcriptional co-activator of RRM2; BRCA1-mediated RRM2 expression protects GBM cells from endogenous replication stress, DNA damage accumulation, and apoptosis; BRCA1 depletion phenocopies RRM2 inhibition (with triapine) in reducing tumor growth.\",\n      \"method\": \"BRCA1 knockdown, RRM2 expression analysis, replication stress assays, DNA damage markers, tumor growth assays, triapine (RRM2 inhibitor) treatment\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic link between BRCA1 and RRM2 transcription with functional rescue, single lab, multiple orthogonal readouts\",\n      \"pmids\": [\"27845331\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"HPV31 maintains elevated RRM2 levels in differentiating keratinocytes through expression of E7 and activation of the ATR-Chk1-E2F1 DNA damage response pathway; RRM2 depletion blocks HPV31 productive replication, indicating RRM2 provides dNTPs for viral DNA synthesis.\",\n      \"method\": \"RRM2 depletion (shRNA), dNTP pool measurement, productive replication assay, ATR/Chk1/E2F1 inhibition experiments\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with specific viral replication phenotype and pathway placement via inhibitor experiments, single lab\",\n      \"pmids\": [\"27764728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MYBL2 directly binds the RRM2 gene promoter and promotes RRM2 transcription during S-phase together with TAF15 and MuvB components; MYBL2-driven cell proliferation and DNA synthesis in CRC are RRM2-dependent.\",\n      \"method\": \"ChIP, promoter reporter assay, MYBL2 overexpression/knockdown, co-immunoprecipitation identifying TAF15/MuvB complex members, DNA synthesis assay\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus co-IP identifying the transcriptional complex, with functional rescue, single lab\",\n      \"pmids\": [\"34234118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Inhibition of the ATR-CHK1 pathway in Ewing sarcoma cells activates CDK2, which targets RRM2 for proteasome-mediated degradation; similarly, WEE1 inhibition activates CDK2 and depletes RRM2, causing DNA damage and apoptosis.\",\n      \"method\": \"ATR/CHK1/WEE1 inhibitors, CDK2 activation assays, proteasome inhibition rescue, Western blot for RRM2 protein levels, DNA damage markers, apoptosis assays\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway dissected with multiple inhibitors and rescue experiments, single lab\",\n      \"pmids\": [\"31649026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DHS (trans-4,4'-dihydroxystilbene) induces cyclin F-mediated proteasomal degradation of RRM2; molecular docking identifies RRM2 as a direct DHS target; DHS treatment reduces RNR activity, decreases dNTP synthesis, causes S-phase arrest and DNA damage.\",\n      \"method\": \"Molecular docking, Western blot for RRM2 protein, dNTP pool measurement, cell cycle analysis, RNR activity assay, cyclin F knockdown rescue\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — docking plus functional validation of cyclin F-dependent degradation with RNR activity readout, single lab\",\n      \"pmids\": [\"30518875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RRM2 inhibits ferroptosis in liver cancer cells by sustaining glutathione (GSH) synthesis via interaction with glutathione synthetase (GSS); under ferroptotic stress, RRM2 is dephosphorylated at Threonine 33 (T33), promoting RRM2-GSS interaction and translocation of both proteins to the proteasome for simultaneous degradation; T33 phosphorylation normally blocks this interaction.\",\n      \"method\": \"Co-immunoprecipitation, proximity ligation assay (PLA), immunofluorescence, cell viability assay, metabolite measurement, Western blot, ELISA\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP and PLA with phospho-site functional validation, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"33372599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The translational repressor 4E-BP1 specifically regulates RRM2 protein levels; inhibition of mTORC1/2 (but not mTORC1 alone) activates 4E-BP1 and reduces RRM2 protein; CRISPR knockout of 4E-BP1 rescues mTORC1/2 inhibitor-induced RRM2 depletion, demonstrating cap-dependent translation as a regulatory mechanism for RRM2.\",\n      \"method\": \"mTORC1/2 inhibitors, CRISPR/Cas9 4E-BP1 knockout, inducible mutant 4E-BP1 expression, Western blot, xenograft growth assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR rescue experiment with genetic and pharmacological orthogonal approaches, single lab\",\n      \"pmids\": [\"33191406\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"YBX1 (identified by in vivo RNA antisense purification/RAP-MS as a direct lincNMR interaction partner) binds to the RRM2 promoter region and regulates RRM2 expression; lincNMR depletion decreases dNTP levels and RRM2/TYMS/TK1 expression, while exogenous dNTPs rescue the proliferation defect.\",\n      \"method\": \"RAP-MS (in vivo RNA antisense purification + mass spectrometry), SILAC proteomics, ChIP (YBX1 binding to RRM2 promoter), dNTP pool measurement, rescue with exogenous dNTPs\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RAP-MS plus ChIP identifying YBX1-RRM2 promoter axis, with functional dNTP rescue, single lab\",\n      \"pmids\": [\"32587247\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RRM2 stabilizes ANXA1 protein and activates the AKT pathway independent of its ribonucleotide reductase enzymatic activity, promoting sunitinib resistance in renal cell carcinoma.\",\n      \"method\": \"Co-immunoprecipitation, Western blot, RRM2 knockdown/overexpression, AKT pathway inhibitors, sunitinib resistance assay\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP showing RRM2-ANXA1 interaction plus pathway inhibitor validation, with non-enzymatic activity claim supported by reductase-dead mutant context, single lab\",\n      \"pmids\": [\"34319001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MYBL2 constitutes a dynamic S-phase transcription complex (with TAF15 and MuvB) that directly binds the RRM2 promoter to activate its transcription; E2F8 also directly binds the RRM2 promoter and transactivates RRM2, demonstrating multiple E2F/MYBL2 family members converge on RRM2 transcription.\",\n      \"method\": \"ChIP-qPCR, DNA pulldown-Western blot, luciferase reporter assay, E2F8 knockdown/overexpression, cell cycle and DNA synthesis assays\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-qPCR and DNA pulldown confirm direct E2F8-RRM2 promoter binding with functional validation, single lab\",\n      \"pmids\": [\"37863324\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RRM2 silencing activates the cGAS/STING signaling pathway in lung adenocarcinoma cells, increases CD8+ T cell infiltration in tumors, and synergizes with radiation to promote apoptosis and enhance cGAS/STING pathway activation.\",\n      \"method\": \"RRM2 shRNA knockdown, immunofluorescence, immunoblotting, flow cytometric analysis of CD8+ T cells, xenograft and syngeneic mouse models, comet assay\",\n      \"journal\": \"Cell & bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with STING pathway readout and in vivo immune cell infiltration, single lab\",\n      \"pmids\": [\"33858512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"USP7 deubiquitinates RRM2 during S phase of the cell cycle; USP7 downregulation reduces RRM2 protein levels and induces cellular senescence in melanoma; ectopic RRM2 expression in USP7-depleted cells rescues the senescent phenotype.\",\n      \"method\": \"Global transcriptomic and proteomic analysis, USP7 knockdown (shRNA), RRM2 ectopic expression rescue, in vivo PDX dropout screens, pharmacological USP7 inhibition (P5091)\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo dropout screen plus RRM2 rescue of senescence phenotype, multiple methods, single lab; deubiquitination mechanism inferred but direct biochemical deubiquitination assay not explicitly described in abstract\",\n      \"pmids\": [\"36130505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RRM2 forced induction alleviates excessive replicative stress induced by CHK1 inhibition in neuroblastoma; high RRM2 expression correlates with high CHK1 activity; RRM2 inhibition enhances intrinsic replication stress checkpoint addiction; combinatorial RRM2-CHK1 inhibition acts synergistically in high-risk neuroblastoma models.\",\n      \"method\": \"Zebrafish neuroblastoma model (RRM2 + MYCN co-overexpression), in vitro knockdown, CHK1 inhibitor + RRM2 overexpression/inhibition, patient-derived xenograft models\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo zebrafish model plus PDX with genetic epistasis between RRM2 and CHK1, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"35857500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"USP12 directly interacts with and deubiquitinates RRM2 in NSCLC cells, stabilizing RRM2 protein; USP12 knockdown reduces RRM2 levels, causes DNA replication stress, and retards tumor growth in vivo.\",\n      \"method\": \"Co-immunoprecipitation (USP12-RRM2 interaction), deubiquitination assay, USP12 knockdown, DNA replication stress assays, in vivo tumor growth assay\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus deubiquitination assay with in vivo functional validation, single lab\",\n      \"pmids\": [\"37341611\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RRM2 stabilizes YBX1 protein and upregulates TGFBR1 expression, activating the TGF-beta signaling pathway to promote pancreatic cancer progression and liver metastasis.\",\n      \"method\": \"RRM2 knockdown/overexpression, Western blot for YBX1/TGFBR1, TGF-beta pathway readouts, in vivo liver metastasis model\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — protein stabilization and pathway activation described but direct binding/interaction experiment details not specified in abstract; single lab, single-method descriptions\",\n      \"pmids\": [\"39398252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"p53 deficiency increases RRM2 protein expression and crotonylation of RRM2 at K283 (RRM2K283Cr) by downregulating SIRT7, the decrotonylase of RRM2; elevated RRM2K283Cr promotes cisplatin resistance by inhibiting apoptosis (reduced cleaved-PARP1 and cleaved-caspase3).\",\n      \"method\": \"SILAC-based quantitative crotonylome, p53 knockout, SIRT7 knockdown/overexpression, Western blot for crotonylation, apoptosis markers\",\n      \"journal\": \"Frontiers in molecular biosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative proteomics identifying specific K283 crotonylation site plus genetic validation of SIRT7 as decrotonylase, single lab\",\n      \"pmids\": [\"38894712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IGF2BP3 enhances RRM2 mRNA stability and protein expression by reading m6A modification on RRM2 mRNA; IGF2BP3 disruption reduces RRM2 levels, promotes ferroptosis, and inhibits HCC cell malignant phenotypes; FOXM1 transcriptionally activates IGF2BP3, placing FOXM1 upstream of IGF2BP3/RRM2 axis.\",\n      \"method\": \"MeRIP-qRT-PCR (m6A modification of RRM2 mRNA), RIP assay (IGF2BP3-RRM2 interaction), ChIP and dual-luciferase reporter (FOXM1-IGF2BP3), ferroptosis markers (MDA/GSH/ROS), in vivo xenograft\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP and RIP assays directly demonstrate m6A-dependent IGF2BP3-RRM2 mRNA interaction, plus ChIP for upstream FOXM1, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"39630361\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FOXM1 directly binds to the RRM2 promoter and regulates its transcriptional activity in SCLC; miR-1 targets CXCR4, which prevents FOXM1 from binding the RRM2 promoter, establishing a CXCR4/FOXM1/RRM2 regulatory axis.\",\n      \"method\": \"Chromatin immunoprecipitation (FOXM1 binding RRM2 promoter), dual-luciferase assay (miR-1 targeting CXCR4), transcriptomic analysis, in vitro and in vivo loss/gain-of-function models\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirming direct FOXM1-RRM2 promoter binding plus luciferase validation of upstream miR-1/CXCR4, single lab\",\n      \"pmids\": [\"36597126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"lncOCMRL1 suppresses RRM2 ubiquitination (identified by RNA pull-down, silver staining, mass spectrometry, and RIP), thereby stabilizing RRM2 protein and promoting EMT-driven invasion and migration of oral squamous cell carcinoma cells.\",\n      \"method\": \"RNA pull-down, silver staining, mass spectrometry, RIP assay, Western blot for ubiquitination, invasion/migration assays, in vivo tumor model\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA pull-down/MS identifying lncRNA-RRM2 protein interaction with ubiquitination functional readout, single lab\",\n      \"pmids\": [\"39343925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RRM2 overexpression enhances osteogenic differentiation of mouse embryo fibroblasts by activating the Wnt/β-catenin signaling pathway, increasing β-catenin protein levels, p-GSK-3β/GSK-3β ratio, and downstream target gene expression; RRM2 knockdown reduces osteogenesis.\",\n      \"method\": \"RRM2 overexpression (adenovirus) and siRNA knockdown, Western blot for β-catenin and p-GSK-3β, RT-qPCR for Wnt target genes, ALP staining, Alizarin Red S staining\",\n      \"journal\": \"Experimental and therapeutic medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — gain/loss-of-function with pathway readouts but no direct mechanistic link between RRM2 and Wnt components established; single lab, single method type\",\n      \"pmids\": [\"36160885\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RRM2 directly interacts with CDK1 (identified by co-immunoprecipitation and mass spectrometry) in chicken myoblasts; SP1 transcription factor binds the core RRM2 promoter and regulates its transcription; RRM2 promotes myoblast proliferation and inhibits differentiation.\",\n      \"method\": \"Co-immunoprecipitation and mass spectrometry (RRM2-CDK1), dual luciferase reporter assay (SP1-RRM2 promoter), qRT-PCR, CCK-8 assay, EdU incorporation, flow cytometry, in vivo muscle regeneration assay\",\n      \"journal\": \"Poultry science\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — co-IP/MS identifies CDK1 interaction and SP1 promoter binding validated in chicken (avian model, not mammalian), single lab\",\n      \"pmids\": [\"38198913\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RRM2, the small catalytic subunit of ribonucleotide reductase (RNR), catalyzes the rate-limiting conversion of ribonucleoside diphosphates to deoxyribonucleoside diphosphates to supply dNTPs for DNA replication and repair; its expression is transcriptionally driven by E2F family members (E2F1, E2F2, E2F8) and MYBL2 (in complex with TAF15/MuvB) at the RRM2 promoter, and post-translationally controlled through CDK2-mediated proteasomal degradation (activated by ATR-CHK1 or WEE1 pathway inhibition), deubiquitination by USP7 and USP12, cyclin F-mediated degradation, m6A-dependent mRNA stabilization by IGF2BP3, and crotonylation at K283 regulated by the decrotonylase SIRT7; beyond its canonical enzymatic role, RRM2 also engages non-enzymatic functions including stabilization of ANXA1 to activate AKT signaling, interaction with Bcl-2 to regulate its stability, binding to GSS to modulate glutathione synthesis and ferroptosis resistance, and stabilization of YBX1 to activate TGF-beta signaling; genetically, increased RRM2/RNR activity suppresses replication stress at fragile sites and rescues ATR-mutant lethality in mice, placing RRM2 in a conserved ATR-RNR axis that buffers replicative stress.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RRM2 is the regulatory small subunit of ribonucleotide reductase whose supply of dNTPs places it at the center of an ATR-RNR axis that buffers replicative stress: supraphysiological Rrm2 gene dosage in mice raises RNR activity, reduces chromosomal breakage at common fragile sites, and rescues the lethality of ATR-mutant animals [#6], and forced RRM2 induction similarly alleviates the replication stress imposed by CHK1 inhibition in neuroblastoma [#19]. Because RRM2 is the rate-limiting, S-phase-restricted subunit, its abundance is controlled at multiple levels. Transcriptionally, an S-phase MYBL2-TAF15-MuvB complex and E2F8 directly occupy the RRM2 promoter [#9, #16], with additional promoter input from BRCA1 acting as a co-activator [#7] and FOXM1 [#24]; viral oncoprotein HPV E7 drives RRM2 through pRb-E2F and the ATR-Chk1-E2F1 pathway to provision dNTPs for viral DNA synthesis [#5, #8]. Post-transcriptionally RRM2 is repressed by let-7 miRNAs targeting its 3' UTR [#3] and stabilized by m6A reading via IGF2BP3 [#23] and by cap-dependent translation controlled by 4E-BP1 [#13]. RRM2 protein stability is set by a balance of CDK2-triggered, proteasomal degradation activated upon ATR-CHK1 or WEE1 inhibition [#10] and cyclin F-mediated turnover [#11] against deubiquitination by USP7 and USP12 [#18, #20]. Beyond catalysis, RRM2 carries out enzyme-independent functions: it stabilizes ANXA1 to activate AKT signaling [#15], regulates Bcl-2 stability to set the apoptotic threshold [#2], sustains glutathione synthesis through interaction with GSS to resist ferroptosis [#12], and stabilizes YBX1 to engage TGF-beta signaling [#21]. Through these activities RRM2 promotes tumor invasion, angiogenesis, and therapy resistance across cancers [#0, #1, #4], and its loss activates cGAS/STING immune signaling [#17].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established that RRM2 has activities beyond dNTP supply, driving tumor cell invasion through an NF-kB-dependent program.\",\n      \"evidence\": \"reciprocal RRM2 overexpression/RNAi with NF-kB activity and invasion assays in pancreatic adenocarcinoma cells\",\n      \"pmids\": [\"17222798\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"does not define how RRM2 activates NF-kB\", \"enzymatic versus non-enzymatic contribution not separated\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Linked RRM2 levels to the tumor angiogenic switch by showing it shifts the TSP-1/VEGF balance.\",\n      \"evidence\": \"RRM2 overexpression/siRNA with ELISA, xenograft angiogenesis and endothelial chemotaxis readouts\",\n      \"pmids\": [\"19250552\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"molecular intermediary between RRM2 and TSP-1/VEGF unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined post-transcriptional and signaling control of RRM2 and connected it to apoptotic and DNA-repair outcomes underlying therapy resistance.\",\n      \"evidence\": \"let-7 3' UTR luciferase reporters, AKT expression profiling with RNAi/didox, and Bcl-2 stability/colocalization studies across HNSCC, NSCLC, breast and pancreatic models\",\n      \"pmids\": [\"23335963\", \"24362250\", \"23719266\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"direct RRM2-Bcl-2 binding mechanism not biochemically resolved\", \"whether AKT regulation is transcriptional or post-translational not fully separated\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed viral oncoproteins co-opt RRM2 transcription to provision dNTPs, tying RRM2 to E7-pRb-E2F control and ROS-driven angiogenic signaling.\",\n      \"evidence\": \"RRM2 promoter luciferase assays, ROS/HIF-1a/VEGF readouts and HUVEC tube formation in HPV-positive cervical cancer\",\n      \"pmids\": [\"24423925\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"does not establish viral replication dependence on RRM2 directly\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Provided in vivo genetic proof that RNR output via RRM2 buffers replication stress, defining a conserved mammalian ATR-RNR axis.\",\n      \"evidence\": \"Rrm2 transgenic mice with RNR activity assays, fragile-site breakage analysis, and survival rescue of ATR-mutant mice\",\n      \"pmids\": [\"25838540\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"does not address how acute RRM2 modulation behaves in tumors\", \"cell-type-specific thresholds of protection unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Mapped transcriptional inputs (MYBL2/MuvB, BRCA1) and demonstrated RRM2 dNTP supply is required for HPV productive replication.\",\n      \"evidence\": \"ChIP/co-IP of MYBL2-TAF15-MuvB at the RRM2 promoter, BRCA1 knockdown with triapine, and RRM2 depletion with dNTP measurement in differentiating keratinocytes\",\n      \"pmids\": [\"34234118\", \"27845331\", \"27764728\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"relative weighting of these transcriptional inputs across tissues unclear\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified cyclin F as a degradation route controlling RRM2 protein and RNR activity, exploitable pharmacologically.\",\n      \"evidence\": \"molecular docking, cyclin F knockdown rescue, dNTP and RNR activity assays with DHS treatment\",\n      \"pmids\": [\"30518875\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"degron and ubiquitination site on RRM2 not mapped\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined the CDK2-dependent degradation mechanism that links replication-checkpoint inhibition to RRM2 loss and cell death.\",\n      \"evidence\": \"ATR/CHK1/WEE1 inhibitors with CDK2 activation, proteasome-inhibition rescue and RRM2 immunoblotting in Ewing sarcoma\",\n      \"pmids\": [\"31649026\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"direct CDK2 phosphosite on RRM2 driving degradation not identified here\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Expanded RRM2 control to translation and uncovered a non-enzymatic ferroptosis-protective role via GSS, plus a YBX1-promoter regulatory loop.\",\n      \"evidence\": \"4E-BP1 CRISPR knockout rescue with mTOR inhibitors; RRM2-GSS co-IP/PLA with T33 phospho-site mapping; RAP-MS/ChIP linking YBX1 to the RRM2 promoter with dNTP rescue\",\n      \"pmids\": [\"33191406\", \"33372599\", \"32587247\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"structural basis of RRM2-GSS interaction unresolved\", \"kinase setting RRM2 T33 phosphorylation not identified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established enzyme-independent oncogenic functions of RRM2 and its immune-modulatory consequence upon loss.\",\n      \"evidence\": \"co-IP showing RRM2-ANXA1 stabilization with AKT inhibitors and sunitinib resistance; E2F8 promoter ChIP/luciferase; RRM2 silencing activating cGAS/STING with CD8+ T cell infiltration in vivo\",\n      \"pmids\": [\"34319001\", \"37863324\", \"33858512\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"how a reductase subunit stabilizes ANXA1 mechanistically unclear\", \"whether cGAS/STING activation is solely a consequence of dNTP depletion not resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined deubiquitination by USP7 as a stability control whose loss triggers senescence, and showed RRM2 induction relieves CHK1-inhibition replication stress.\",\n      \"evidence\": \"USP7 knockdown/inhibitor with RRM2 rescue of senescence in melanoma and PDX dropout screens; zebrafish/PDX RRM2-CHK1 epistasis in neuroblastoma\",\n      \"pmids\": [\"36130505\", \"35857500\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"direct USP7-RRM2 deubiquitination assay not described\", \"RRM2 ubiquitin acceptor sites unmapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Added USP12 as a second deubiquitinase and FOXM1 as a transcriptional driver within an upstream miR-1/CXCR4 axis.\",\n      \"evidence\": \"USP12-RRM2 co-IP and deubiquitination assay with in vivo growth; FOXM1 ChIP at the RRM2 promoter with miR-1/CXCR4 luciferase validation\",\n      \"pmids\": [\"37341611\", \"36597126\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"redundancy/specificity between USP7 and USP12 toward RRM2 not addressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified m6A/IGF2BP3 mRNA stabilization, K283 crotonylation controlled by SIRT7, and lncRNA-mediated ubiquitination control as additional regulatory layers, alongside a YBX1-TGF-beta metastatic function.\",\n      \"evidence\": \"MeRIP/RIP with FOXM1 ChIP for IGF2BP3 axis; SILAC crotonylome with p53/SIRT7 genetics for K283Cr; lncOCMRL1 RNA pull-down/MS; RRM2-YBX1/TGFBR1 stabilization in metastasis models\",\n      \"pmids\": [\"39630361\", \"38894712\", \"39343925\", \"39398252\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"how crotonylation at K283 alters RRM2 enzymatic versus non-enzymatic activity unclear\", \"RRM2-YBX1 direct binding (#21) not biochemically detailed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved which RRM2 functions in cancer are catalytic dNTP supply versus the several moonlighting protein-stabilization activities, and how the dense web of competing regulators is integrated in a single cell.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"no unified quantitative model partitioning enzymatic and non-enzymatic RRM2 outputs\", \"structural basis for RRM2 binding to ANXA1/GSS/YBX1/Bcl-2 unknown\", \"in vivo hierarchy among transcriptional, translational and degradation controls undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [6, 11]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [15, 12, 21, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-69306\", \"supporting_discovery_ids\": [6, 8]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [9, 10, 16]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [6, 19]}\n    ],\n    \"complexes\": [\"ribonucleotide reductase\"],\n    \"partners\": [\"ANXA1\", \"GSS\", \"YBX1\", \"Bcl-2\", \"CDK1\", \"USP7\", \"USP12\", \"IGF2BP3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}