Affinage

RRM2

Ribonucleoside-diphosphate reductase subunit M2 · UniProt P31350

Length
389 aa
Mass
44.9 kDa
Annotated
2026-06-10
100 papers in source corpus 28 papers cited in narrative 28 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2006 Medium

    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

    PMID:17222798

    Open questions at the time
    • does not define how RRM2 activates NF-kB
    • enzymatic versus non-enzymatic contribution not separated
  2. 2009 Medium

    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

    PMID:19250552

    Open questions at the time
    • molecular intermediary between RRM2 and TSP-1/VEGF unresolved
  3. 2013 Medium

    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

    PMID:23335963 PMID:23719266 PMID:24362250

    Open questions at the time
    • direct RRM2-Bcl-2 binding mechanism not biochemically resolved
    • whether AKT regulation is transcriptional or post-translational not fully separated
  4. 2014 Medium

    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

    PMID:24423925

    Open questions at the time
    • does not establish viral replication dependence on RRM2 directly
  5. 2015 High

    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

    PMID:25838540

    Open questions at the time
    • does not address how acute RRM2 modulation behaves in tumors
    • cell-type-specific thresholds of protection unknown
  6. 2016 Medium

    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

    PMID:27764728 PMID:27845331 PMID:34234118

    Open questions at the time
    • relative weighting of these transcriptional inputs across tissues unclear
  7. 2018 Medium

    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

    PMID:30518875

    Open questions at the time
    • degron and ubiquitination site on RRM2 not mapped
  8. 2019 Medium

    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

    PMID:31649026

    Open questions at the time
    • direct CDK2 phosphosite on RRM2 driving degradation not identified here
  9. 2020 Medium

    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

    PMID:32587247 PMID:33191406 PMID:33372599

    Open questions at the time
    • structural basis of RRM2-GSS interaction unresolved
    • kinase setting RRM2 T33 phosphorylation not identified
  10. 2021 Medium

    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

    PMID:33858512 PMID:34319001 PMID:37863324

    Open questions at the time
    • how a reductase subunit stabilizes ANXA1 mechanistically unclear
    • whether cGAS/STING activation is solely a consequence of dNTP depletion not resolved
  11. 2022 Medium

    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

    PMID:35857500 PMID:36130505

    Open questions at the time
    • direct USP7-RRM2 deubiquitination assay not described
    • RRM2 ubiquitin acceptor sites unmapped
  12. 2023 Medium

    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

    PMID:36597126 PMID:37341611

    Open questions at the time
    • redundancy/specificity between USP7 and USP12 toward RRM2 not addressed
  13. 2024 Medium

    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

    PMID:38894712 PMID:39343925 PMID:39398252 PMID:39630361

    Open questions at the time
    • how crotonylation at K283 alters RRM2 enzymatic versus non-enzymatic activity unclear
    • RRM2-YBX1 direct binding (#21) not biochemically detailed

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140313 molecular sequestering activity 4 GO:0016491 oxidoreductase activity 2
Localization
GO:0005829 cytosol 2
Pathway
R-HSA-1640170 Cell Cycle 3 R-HSA-69306 DNA Replication 2 R-HSA-8953897 Cellular responses to stimuli 2
Partners
ANXA1BCL-2CDK1GSSIGF2BP3USP12USP7YBX1
Complex memberships
ribonucleotide reductase

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 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. RRM2 overexpression, RNAi knockdown, NF-κB transcriptional activity assay, invasion assay Biochemical and biophysical research communications Medium 17222798
2009 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. RRM2 overexpression in KB cells, siRNA knockdown, ELISA/Western blot for TSP-1/VEGF, in vivo xenograft angiogenesis assay, endothelial chemotaxis assay Molecular cancer Medium 19250552
2013 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. siRNA knockdown, immunoblotting, confocal microscopy, tissue fractionation, gene overexpression/knockdown, immunohistochemistry, quantum dot immunofluorescence Clinical cancer research Medium 23719266
2013 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. 3′ UTR luciferase reporter assay, shRNA library screening, miRNA overexpression, qRT-PCR, patient-derived PDAC tissue analysis PloS one Medium 23335963
2013 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. Gene expression profiling, RNAi, RRM2 inhibitor (didox), in vitro and in vivo growth assays, DNA damage markers Molecular cancer research Medium 24362250
2014 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. Luciferase reporter assay (RRM2 promoter), Western blot, ELISA, ROS measurement by flow cytometry, HUVEC tube formation assay, xenograft model British journal of cancer Medium 24423925
2015 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. Rrm2 transgenic mouse model (Rrm2TG), RNR enzymatic activity assay, chromosomal fragile site breakage analysis, survival curve analysis of ATR-mutant mice Genes & development High 25838540
2016 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. BRCA1 knockdown, RRM2 expression analysis, replication stress assays, DNA damage markers, tumor growth assays, triapine (RRM2 inhibitor) treatment Nature communications Medium 27845331
2016 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. RRM2 depletion (shRNA), dNTP pool measurement, productive replication assay, ATR/Chk1/E2F1 inhibition experiments Virology Medium 27764728
2016 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. ChIP, promoter reporter assay, MYBL2 overexpression/knockdown, co-immunoprecipitation identifying TAF15/MuvB complex members, DNA synthesis assay Cell death & disease Medium 34234118
2019 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. ATR/CHK1/WEE1 inhibitors, CDK2 activation assays, proteasome inhibition rescue, Western blot for RRM2 protein levels, DNA damage markers, apoptosis assays Molecular cancer research Medium 31649026
2018 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. Molecular docking, Western blot for RRM2 protein, dNTP pool measurement, cell cycle analysis, RNR activity assay, cyclin F knockdown rescue Oncogene Medium 30518875
2020 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. Co-immunoprecipitation, proximity ligation assay (PLA), immunofluorescence, cell viability assay, metabolite measurement, Western blot, ELISA Cancer cell international Medium 33372599
2020 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. mTORC1/2 inhibitors, CRISPR/Cas9 4E-BP1 knockout, inducible mutant 4E-BP1 expression, Western blot, xenograft growth assay Oncogene Medium 33191406
2020 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. RAP-MS (in vivo RNA antisense purification + mass spectrometry), SILAC proteomics, ChIP (YBX1 binding to RRM2 promoter), dNTP pool measurement, rescue with exogenous dNTPs Nature communications Medium 32587247
2021 RRM2 stabilizes ANXA1 protein and activates the AKT pathway independent of its ribonucleotide reductase enzymatic activity, promoting sunitinib resistance in renal cell carcinoma. Co-immunoprecipitation, Western blot, RRM2 knockdown/overexpression, AKT pathway inhibitors, sunitinib resistance assay Advanced science Medium 34319001
2021 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. ChIP-qPCR, DNA pulldown-Western blot, luciferase reporter assay, E2F8 knockdown/overexpression, cell cycle and DNA synthesis assays Biochemical pharmacology Medium 37863324
2021 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. RRM2 shRNA knockdown, immunofluorescence, immunoblotting, flow cytometric analysis of CD8+ T cells, xenograft and syngeneic mouse models, comet assay Cell & bioscience Medium 33858512
2022 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. Global transcriptomic and proteomic analysis, USP7 knockdown (shRNA), RRM2 ectopic expression rescue, in vivo PDX dropout screens, pharmacological USP7 inhibition (P5091) Cell reports Medium 36130505
2022 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. Zebrafish neuroblastoma model (RRM2 + MYCN co-overexpression), in vitro knockdown, CHK1 inhibitor + RRM2 overexpression/inhibition, patient-derived xenograft models Science advances Medium 35857500
2023 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. Co-immunoprecipitation (USP12-RRM2 interaction), deubiquitination assay, USP12 knockdown, DNA replication stress assays, in vivo tumor growth assay Molecular carcinogenesis Medium 37341611
2024 RRM2 stabilizes YBX1 protein and upregulates TGFBR1 expression, activating the TGF-beta signaling pathway to promote pancreatic cancer progression and liver metastasis. RRM2 knockdown/overexpression, Western blot for YBX1/TGFBR1, TGF-beta pathway readouts, in vivo liver metastasis model iScience Low 39398252
2024 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). SILAC-based quantitative crotonylome, p53 knockout, SIRT7 knockdown/overexpression, Western blot for crotonylation, apoptosis markers Frontiers in molecular biosciences Medium 38894712
2024 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. 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 Molecular and cellular biochemistry Medium 39630361
2023 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. 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 Molecular cancer Medium 36597126
2024 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. RNA pull-down, silver staining, mass spectrometry, RIP assay, Western blot for ubiquitination, invasion/migration assays, in vivo tumor model Journal of experimental & clinical cancer research Medium 39343925
2022 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. 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 Experimental and therapeutic medicine Low 36160885
2023 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. 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 Poultry science Low 38198913

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2021 RRM2 Regulates Sensitivity to Sunitinib and PD-1 Blockade in Renal Cancer by Stabilizing ANXA1 and Activating the AKT Pathway. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 139 34319001
2020 RRM2 protects against ferroptosis and is a tumor biomarker for liver cancer. Cancer cell international 125 33372599
2007 Potent siRNA inhibitors of ribonucleotide reductase subunit RRM2 reduce cell proliferation in vitro and in vivo. Clinical cancer research : an official journal of the American Association for Cancer Research 124 17404105
2016 BRCA1-regulated RRM2 expression protects glioblastoma cells from endogenous replication stress and promotes tumorigenicity. Nature communications 105 27845331
2020 Inhibiting RRM2 to enhance the anticancer activity of chemotherapy. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 103 33227712
2013 RRM2 regulates Bcl-2 in head and neck and lung cancers: a potential target for cancer therapy. Clinical cancer research : an official journal of the American Association for Cancer Research 101 23719266
2020 The lncRNA lincNMR regulates nucleotide metabolism via a YBX1 - RRM2 axis in cancer. Nature communications 100 32587247
2022 Ribonucleotide reductase M2 (RRM2): Regulation, function and targeting strategy in human cancer. Genes & diseases 98 37588202
2009 Overexpression of RRM2 decreases thrombspondin-1 and increases VEGF production in human cancer cells in vitro and in vivo: implication of RRM2 in angiogenesis. Molecular cancer 93 19250552
2006 RRM2 induces NF-kappaB-dependent MMP-9 activation and enhances cellular invasiveness. Biochemical and biophysical research communications 88 17222798
2014 Increased expression of RRM2 by human papillomavirus E7 oncoprotein promotes angiogenesis in cervical cancer. British journal of cancer 86 24423925
2023 MicroRNA-1 attenuates the growth and metastasis of small cell lung cancer through CXCR4/FOXM1/RRM2 axis. Molecular cancer 80 36597126
2019 LncRNA AFAP1-AS1 Supresses miR-139-5p and Promotes Cell Proliferation and Chemotherapy Resistance of Non-small Cell Lung Cancer by Competitively Upregulating RRM2. Frontiers in oncology 74 31696057
2012 Systemic delivery of siRNA nanoparticles targeting RRM2 suppresses head and neck tumor growth. Journal of controlled release : official journal of the Controlled Release Society 71 22342644
2010 Expression of ribonucleotide reductase M2 subunit in gastric cancer and effects of RRM2 inhibition in vitro. Human pathology 71 20825972
2013 Differential processing of let-7a precursors influences RRM2 expression and chemosensitivity in pancreatic cancer: role of LIN-28 and SET oncoprotein. PloS one 68 23335963
2018 DSCAM-AS1 promotes tumor growth of breast cancer by reducing miR-204-5p and up-regulating RRM2. Molecular carcinogenesis 67 30457164
2019 Inhibition of the ATR-CHK1 Pathway in Ewing Sarcoma Cells Causes DNA Damage and Apoptosis via the CDK2-Mediated Degradation of RRM2. Molecular cancer research : MCR 60 31649026
2015 Increased Rrm2 gene dosage reduces fragile site breakage and prolongs survival of ATR mutant mice. Genes & development 56 25838540
2020 Sorafenib Inhibits Ribonucleotide Reductase Regulatory Subunit M2 (RRM2) in Hepatocellular Carcinoma Cells. Biomolecules 55 31936661
2016 Cell cycle dependent RRM2 may serve as proliferation marker and pharmaceutical target in adrenocortical cancer. American journal of cancer research 55 27725909
2018 siRNA Knockdown of RRM2 Effectively Suppressed Pancreatic Tumor Growth Alone or Synergistically with Doxorubicin. Molecular therapy. Nucleic acids 54 30153565
2018 DHS (trans-4,4'-dihydroxystilbene) suppresses DNA replication and tumor growth by inhibiting RRM2 (ribonucleotide reductase regulatory subunit M2). Oncogene 52 30518875
2021 RRM2 silencing suppresses malignant phenotype and enhances radiosensitivity via activating cGAS/STING signaling pathway in lung adenocarcinoma. Cell & bioscience 51 33858512
2019 Long noncoding RNA LINC00958 regulates cell sensitivity to radiotherapy through RRM2 by binding to microRNA-5095 in cervical cancer. Journal of cellular physiology 50 31169309
2018 RRM2 promotes the progression of human glioblastoma. Journal of cellular physiology 50 29667764
2016 HPV31 utilizes the ATR-Chk1 pathway to maintain elevated RRM2 levels and a replication-competent environment in differentiating Keratinocytes. Virology 48 27764728
2018 Suppression of RRM2 inhibits cell proliferation, causes cell cycle arrest and promotes the apoptosis of human neuroblastoma cells and in human neuroblastoma RRM2 is suppressed following chemotherapy. Oncology reports 45 29749541
2018 Tumor suppressive activity of PIWI-interacting RNA in human fibrosarcoma mediated through repression of RRM2. Molecular carcinogenesis 45 30362638
2021 Celastrol Modulates Multiple Signaling Pathways to Inhibit Proliferation of Pancreatic Cancer via DDIT3 and ATF3 Up-Regulation and RRM2 and MCM4 Down-Regulation. OncoTargets and therapy 44 34194230
2013 AKT-induced tamoxifen resistance is overturned by RRM2 inhibition. Molecular cancer research : MCR 44 24362250
2017 Onset of disorder and protein aggregation due to oxidation-induced intermolecular disulfide bonds: case study of RRM2 domain from TDP-43. Scientific reports 43 28894122
2019 RRM2 Regulated By LINC00667/miR-143-3p Signal Is Responsible For Non-Small Cell Lung Cancer Cell Progression. OncoTargets and therapy 42 31819489
2016 Overexpression of RRM2 in gastric cancer cell promotes their invasiveness via AKT/NF-κB signaling pathway. Die Pharmazie 40 27348973
2016 Suppression of c-Myc and RRM2 expression in pancreatic cancer cells by the sphingosine kinase-2 inhibitor ABC294640. Oncotarget 40 27517489
2019 miR-140-3p impedes the proliferation of human cervical cancer cells by targeting RRM2 to induce cell-cycle arrest and early apoptosis. Bioorganic & medicinal chemistry 38 31902649
2020 MicroRNA-4500 Inhibits Migration, Invasion, and Angiogenesis of Breast Cancer Cells via RRM2-Dependent MAPK Signaling Pathway. Molecular therapy. Nucleic acids 37 32615527
2020 MicroRNA-20a-5p suppresses tumor angiogenesis of non-small cell lung cancer through RRM2-mediated PI3K/Akt signaling pathway. Molecular and cellular biochemistry 37 33125611
2019 Identification of lncRNA NEAT1/miR-21/RRM2 axis as a novel biomarker in breast cancer. Journal of cellular physiology 37 31621912
2021 A MYBL2 complex for RRM2 transactivation and the synthetic effect of MYBL2 knockdown with WEE1 inhibition against colorectal cancer. Cell death & disease 36 34234118
2011 KRAS-mediated up-regulation of RRM2 expression is essential for the proliferation of colorectal cancer cell lines. Anticancer research 35 21873171
2022 RRM2 enhances MYCN-driven neuroblastoma formation and acts as a synergistic target with CHK1 inhibition. Science advances 32 35857500
2022 Targeting the USP7/RRM2 axis drives senescence and sensitizes melanoma cells to HDAC/LSD1 inhibitors. Cell reports 32 36130505
2020 RRM2 elicits the metastatic potential of breast cancer cells by regulating cell invasion, migration and VEGF expression via the PI3K/AKT signaling. Oncology letters 32 32256828
2013 RRM1 and RRM2 pharmacogenetics: association with phenotypes in HapMap cell lines and acute myeloid leukemia patients. Pharmacogenomics 31 24024897
2020 Structural heterogeneity in RNA recognition motif 2 (RRM2) of TAR DNA-binding protein 43 (TDP-43): clue to amyotrophic lateral sclerosis. Journal of biomolecular structure & dynamics 30 31914861
2022 RRM2 Alleviates Doxorubicin-Induced Cardiotoxicity through the AKT/mTOR Signaling Pathway. Biomolecules 29 35204799
2010 RRM2 computational phosphoprotein network construction and analysis between no-tumor hepatitis/cirrhotic liver tissues and human hepatocellular carcinoma (HCC). Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 29 20798514
2019 Silencing RRM2 inhibits multiple myeloma by targeting the Wnt/β‑catenin signaling pathway. Molecular medicine reports 28 31322175
2020 Osalmid, a Novel Identified RRM2 Inhibitor, Enhances Radiosensitivity of Esophageal Cancer. International journal of radiation oncology, biology, physics 27 32763454
2001 Amplification of Mycn, Ddx1, Rrm2, and Odc1 in rat uterine endometrial carcinomas. Genes, chromosomes & cancer 26 11433525
2023 The key cellular senescence related molecule RRM2 regulates prostate cancer progression and resistance to docetaxel treatment. Cell & bioscience 24 37968699
2018 Characterization of TDP-43 RRM2 Partially Folded States and Their Significance to ALS Pathogenesis. Biophysical journal 24 30309612
2017 Novel chimeric transcript RRM2-c2orf48 promotes metastasis in nasopharyngeal carcinoma. Cell death & disease 24 28906488
2016 Targeting RRM2 and Mutant BRAF Is a Novel Combinatorial Strategy for Melanoma. Molecular cancer research : MCR 24 27297629
2022 LncRNA HOTAIR facilitates proliferation and represses apoptosis of retinoblastoma cells through the miR-20b-5p/RRM2/PI3K/AKT axis. Orphanet journal of rare diseases 23 35248107
2024 LncOCMRL1 promotes oral squamous cell carcinoma growth and metastasis via the RRM2/EMT pathway. Journal of experimental & clinical cancer research : CR 22 39343925
2018 miR-211 regulates the expression of RRM2 in tumoral metastasis and recurrence in colorectal cancer patients with a k-ras gene mutation. Oncology letters 22 29731918
2018 Nano-Diamino-Tetrac (NDAT) Enhances Resveratrol-Induced Antiproliferation by Action on the RRM2 Pathway in Colorectal Cancers. Hormones & cancer 22 30027502
2018 An enhanced RRM2 siRNA delivery to rheumatoid arthritis fibroblast-like synoviocytes through a liposome‑protamine-DNA-siRNA complex with cell permeable peptides. International journal of molecular medicine 22 30106091
2022 E2F2 enhances the chemoresistance of pancreatic cancer to gemcitabine by regulating the cell cycle and upregulating the expression of RRM2. Medical oncology (Northwood, London, England) 21 35716217
2020 The SNHG16/miR-30a axis promotes breast cancer cell proliferation and invasion by regulating RRM2. Neoplasma 21 32122142
2023 Targeting of RRM2 suppresses DNA damage response and activates apoptosis in atypical teratoid rhabdoid tumor. Journal of experimental & clinical cancer research : CR 20 38124207
2022 Yap is essential for uterine decidualization through Rrm2/GSH/ROS pathway in response to Bmp2. International journal of biological sciences 19 35414789
2020 LncRNA TTN-AS1 Regulates miR-524-5p and RRM2 to Promote Breast Cancer Progression. OncoTargets and therapy 19 32547107
2020 The translational repressor 4E-BP1 regulates RRM2 levels and functions as a tumor suppressor in Ewing sarcoma tumors. Oncogene 19 33191406
2023 MiR-17- 5p/RRM2 regulated gemcitabine resistance in lung cancer A549 cells. Cell cycle (Georgetown, Tex.) 17 37115505
2022 RRM2 Mediates the Anti-Tumor Effect of the Natural Product Pectolinarigenin on Glioblastoma Through Promoting CDK1 Protein Degradation by Increasing Autophagic Flux. Frontiers in oncology 17 35651787
2018 The promoted delivery of RRM2 siRNA to vascular smooth muscle cells through liposome-polycation-DNA complex conjugated with cell penetrating peptides. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 17 29710515
2022 MiR-200c-3p and miR-485-5p overexpression elevates cisplatin sensitivity and suppresses the malignant phenotypes of non-small cell lung cancer cells through targeting RRM2. Thoracic cancer 16 35599447
2021 MicroRNA-520a Suppresses Pathogenesis and Progression of Non-Small-Cell Lung Cancer through Targeting the RRM2/Wnt Axis. Analytical cellular pathology (Amsterdam) 16 33859925
2021 Identification of CDKL3 as a critical regulator in development of glioma through regulating RRM2 and the JNK signaling pathway. Cancer science 15 34097336
2021 The High Expression of RRM2 Can Predict the Malignant Transformation of Endometriosis. Advances in therapy 15 34424503
2021 RRM2 Improves Cardiomyocyte Proliferation after Myocardial Ischemia Reperfusion Injury through the Hippo-YAP Pathway. Disease markers 15 34868394
2024 FOXM1-activated IGF2BP3 promotes cell malignant phenotypes and M2 macrophage polarization in hepatocellular carcinoma by inhibiting ferroptosis via stabilizing RRM2 mRNA in an m6A-dependent manner. Molecular and cellular biochemistry 14 39630361
2024 Resveratrol promotes mitophagy via the MALAT1/miR-143-3p/RRM2 axis and suppresses cancer progression in hepatocellular carcinoma. Journal of integrative medicine 14 39675939
2022 The Core-Targeted RRM2 Gene of Berberine Hydrochloride Promotes Breast Cancer Cell Migration and Invasion via the Epithelial-Mesenchymal Transition. Pharmaceuticals (Basel, Switzerland) 14 36678539
2024 Celastrol induces ferroptosis by suppressing RRM2 in hepatocellular carcinoma. Heliyon 13 39071636
2021 Molecular Targeting of RRM2, NF-κB, and Mutant TP53 for the Treatment of Triple-Negative Breast Cancer. Molecular cancer therapeutics 13 33536192
2023 E2F8 exerts cancer-promoting effects by transcriptionally activating RRM2 and E2F8 knockdown synergizes with WEE1 inhibition in suppressing lung adenocarcinoma. Biochemical pharmacology 12 37863324
2019 SiRNA-Mediated RRM2 Gene Silencing Combined with Cisplatin in the Treatment of Epithelial Ovarian Cancer In Vivo: An Experimental Study of Nude Mice. International journal of medical sciences 12 31673243
2024 IGF2BP3 regulates the expression of RRM2 and promotes the progression of rheumatoid arthritis via RRM2/Akt/MMP-9 pathway. PloS one 11 38820515
2023 USP12 promotes nonsmall cell lung cancer progression through deubiquitinating and stabilizing RRM2. Molecular carcinogenesis 11 37341611
2023 Diosmetin suppresses the progression of ESCC by CDK2/Rb/E2F2/RRM2 pathway and synergies with cisplatin. Oncogene 11 37349644
2022 MiR-202-3p inhibits the proliferation and metastasis of lung adenocarcinoma cells by targeting RRM2. Annals of translational medicine 11 36660663
2017 ALS-causing cleavages of TDP-43 abolish its RRM2 structure and unlock CTD for enhanced aggregation and toxicity. Biochemical and biophysical research communications 11 28257838
2022 Identification of RRM2 in peripheral blood mononuclear cells as a novel biomarker for the diagnosis of rheumatoid arthritis. Clinical and experimental rheumatology 10 35200126
2022 Circ_0008285 knockdown represses tumor development by miR-384/RRM2 axis in hepatocellular carcinoma. Annals of hepatology 10 35964907
2022 RRM2 regulates osteogenesis of mouse embryo fibroblasts via the Wnt/β‑catenin signaling pathway. Experimental and therapeutic medicine 10 36160885
2020 Downregulation of RRM2 Attenuates Retroperitoneal Liposarcoma Progression via the Akt/mTOR/4EBP1 Pathway: Clinical, Biological, and Therapeutic Significance. OncoTargets and therapy 10 32753891
2024 lncRNA CYTOR promotes lung adenocarcinoma gemcitabine resistance and epithelial-mesenchymal transition by sponging miR-125a-5p and upregulating ANLN and RRM2. Acta biochimica et biophysica Sinica 9 38273783
2024 Circular RNA RRM2 alleviates metabolic dysfunction-associated steatotic liver disease by targeting miR-142-5p to increase NRG1 expression. American journal of physiology. Gastrointestinal and liver physiology 9 39259911
2022 Novel human-derived EML4-ALK fusion cell lines identify ribonucleotide reductase RRM2 as a target of activated ALK in NSCLC. Lung cancer (Amsterdam, Netherlands) 9 35933914
2020 Cancer Fighting SiRNA-RRM2 Loaded Nanorobots. Pharmaceutical nanotechnology 9 32003677
2020 Zinc Binds to RRM2 Peptide of TDP-43. International journal of molecular sciences 9 33260324
2025 Targeting HCG18 counteracts ferroptosis resistance via blocking the miR-30a-5p/RRM2/GSS pathway in hepatocellular carcinoma. International journal of biological sciences 8 40303288
2024 p53 deficiency mediates cisplatin resistance by upregulating RRM2 and crotonylation of RRM2K283 through the downregulation of SIRT7. Frontiers in molecular biosciences 8 38894712
2024 RRM2 promotes liver metastasis of pancreatic cancer by stabilizing YBX1 and activating the TGF-beta pathway. iScience 8 39398252
2024 RRM2 Is a Putative Biomarker and Promotes Bladder Cancer Progression via PI3K/AKT/mTOR Pathway. Journal of cellular physiology 8 39676643
2023 RRM2 promotes the proliferation of chicken myoblasts, inhibits their differentiation and muscle regeneration. Poultry science 8 38198913

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