Affinage

RRM2

Ribonucleoside-diphosphate reductase subunit M2 · UniProt P31350

Length
389 aa
Mass
44.9 kDa
Annotated
2026-04-28
100 papers in source corpus 27 papers cited in narrative 28 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RRM2 encodes the regulatory subunit of ribonucleotide reductase (RNR), whose physical association with the catalytic subunit RRM1 via a conserved tryptophan residue is essential for holoenzyme activity, dNTP synthesis, and mammalian viability (PMID:26077802). As the rate-limiting component of RNR, RRM2-driven dNTP supply protects against replication stress–induced genomic instability at common fragile sites and is transcriptionally activated by E2F1/E2F8, MYBL2, FOXM1, and BRCA1, while its protein turnover is governed by cyclin F– and WEE1-dependent ubiquitination countered by USP7 and USP12 deubiquitination and by SIRT7-mediated decrotonylation at K283 (PMID:25838540, PMID:36130505, PMID:37341611, PMID:34234118, PMID:36597126, PMID:38894712). Beyond its enzymatic role in nucleotide metabolism, RRM2 exerts catalytic-activity-independent functions including stabilization of ANXA1 to activate AKT signaling, regulation of Bcl-2 protein stability to suppress apoptosis, and interaction with glutathione synthetase (GSS) to sustain glutathione synthesis and inhibit ferroptosis (PMID:34319001, PMID:23719266, PMID:33372599). RRM2 silencing activates cGAS/STING innate immune signaling and increases tumor CD8+ T cell infiltration, linking its depletion to anti-tumor immunity (PMID:33858512).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 2006 Medium

    Whether RRM2 influences cellular phenotypes beyond dNTP supply was unknown; overexpression in pancreatic cancer cells activated NF-κB and upregulated MMP-9, establishing a non-canonical role for RRM2 in promoting invasion.

    Evidence RRM2 overexpression and RNAi in pancreatic cancer cells with NF-κB reporter and invasion assays

    PMID:17222798

    Open questions at the time
    • No direct physical interaction between RRM2 and NF-κB pathway components demonstrated
    • Enzymatic-activity independence not tested
  2. 2009 Medium

    The relationship between RRM2 and tumor angiogenesis was undefined; gain- and loss-of-function experiments showed RRM2 suppresses TSP-1 and induces VEGF, promoting angiogenesis in vivo.

    Evidence RRM2 overexpression/siRNA, ELISA, endothelial chemotaxis, xenograft vascularization

    PMID:19250552

    Open questions at the time
    • Mechanism linking RRM2 to TSP-1 repression not identified
    • Whether this requires RNR catalytic activity is unknown
  3. 2013 Medium

    Whether RRM2 directly regulates apoptotic machinery was unknown; RRM2 depletion destabilized Bcl-2 protein and triggered intrinsic apoptosis, and the two proteins co-localize, linking RRM2 to anti-apoptotic signaling beyond dNTP supply.

    Evidence siRNA knockdown, confocal co-localization, tissue immunohistochemistry in head/neck and lung cancer

    PMID:23719266

    Open questions at the time
    • Direct binding between RRM2 and Bcl-2 not shown by co-IP or structural methods
    • Whether stabilization requires RRM2 enzymatic activity untested
  4. 2015 High

    The structural basis for RRM1–RRM2 holoenzyme assembly was unresolved; identification of a single conserved tryptophan mediating the interaction, with lethality upon its mutation in mice, established this contact as essential for RNR function and development.

    Evidence Rrm1-WG/WG knock-in mice, proteomic interaction analysis, genetic epistasis

    PMID:26077802

    Open questions at the time
    • Full atomic-resolution structure of the mammalian RRM1–RRM2 interface not reported
    • Whether compensatory interactions exist in specific tissues unknown
  5. 2015 High

    Whether increasing RRM2/dNTP levels could rescue replication stress in vivo was untested; Rrm2 transgenic mice showed reduced fragile-site breakage and extended lifespan of ATR-mutant animals, proving RRM2-driven dNTP supply is a conserved genome-protection mechanism.

    Evidence Transgenic Rrm2-overexpressing mice, RNR activity assay, fragile-site cytogenetics, ATR-mutant survival analysis

    PMID:25838540

    Open questions at the time
    • Tissue-specific thresholds of dNTP sufficiency not defined
    • Whether dNTP-independent functions of RRM2 also contribute to rescue unclear
  6. 2016 High

    Upstream transcriptional regulators of RRM2 in replication-stress contexts were incompletely mapped; BRCA1 was shown to co-activate RRM2 transcription, with BRCA1 loss reducing RRM2 and increasing replication stress in glioblastoma.

    Evidence BRCA1 knockdown, DNA fiber assay, γH2AX staining, xenograft models

    PMID:27845331

    Open questions at the time
    • Whether BRCA1 binds the RRM2 promoter directly or acts through intermediates not fully resolved
    • Generalizability beyond glioblastoma untested
  7. 2016 Medium

    How viruses co-opt host dNTP synthesis in differentiated cells was unclear; HPV31 E7 was shown to maintain RRM2 via ATR-Chk1-E2F1, and RRM2 depletion abolished productive viral replication, establishing RRM2 as essential for viral DNA synthesis.

    Evidence RRM2 siRNA in differentiating keratinocytes, dNTP measurement, viral DNA replication assay

    PMID:27764728

    Open questions at the time
    • Whether other HPV types use the same mechanism untested
    • Direct E2F1 binding to RRM2 promoter not shown in this study
  8. 2018 Medium

    The E3 ligase pathway controlling RRM2 turnover was not fully defined; cyclin F was identified as mediating proteasomal degradation of RRM2 upon drug treatment, linking cell-cycle-dependent ubiquitination to RNR activity control.

    Evidence Molecular docking, RNR activity assay, dNTP quantification, cyclin F epistasis, xenograft

    PMID:30518875

    Open questions at the time
    • Direct cyclin F–RRM2 binding site not mapped
    • Whether cyclin F targets RRM2 constitutively or only under drug stress unclear
  9. 2020 Medium

    Post-transcriptional control of RRM2 protein was incompletely understood; 4E-BP1 was shown to selectively repress RRM2 cap-dependent translation downstream of mTORC1/2 signaling, adding a translational layer to RRM2 regulation.

    Evidence CRISPR/Cas9 4E-BP1 knockout, mTOR inhibitor treatment, inducible 4E-BP1 expression, xenograft

    PMID:33191406

    Open questions at the time
    • Specific 5'UTR features of RRM2 mRNA conferring 4E-BP1 sensitivity not identified
    • Whether this mechanism operates in non-cancer cells untested
  10. 2020 High

    Whether RRM2 regulates ferroptosis was unknown; RRM2 was found to interact with GSS in a phosphorylation-dependent manner (T33), sustaining GSH synthesis and suppressing ferroptosis; dephosphorylation promotes co-degradation of both proteins.

    Evidence Co-IP, proximity ligation assay, T33 phospho-mutagenesis, proteasome inhibition, ferroptosis assays in liver cancer cells

    PMID:33372599

    Open questions at the time
    • Kinase responsible for T33 phosphorylation not identified
    • Whether this mechanism is independent of RNR catalytic activity not tested
  11. 2020 High

    How lncRNAs regulate nucleotide metabolism was unclear; lincNMR was shown to bind YBX1, which controls RRM2 expression; lincNMR depletion reduced dNTP pools rescuable by exogenous dNTPs, placing a lncRNA–RBP axis upstream of RRM2.

    Evidence RAP-MS, triple-label SILAC, siRNA, dNTP rescue across multiple cancer cell lines

    PMID:32587247

    Open questions at the time
    • Whether YBX1 acts transcriptionally or post-transcriptionally on RRM2 mRNA not fully resolved
    • Stoichiometry of lincNMR–YBX1 complex unknown
  12. 2021 Medium

    Whether RRM2 has functions independent of its RNR enzymatic activity was formally untested; RRM2 was shown to stabilize ANXA1 and activate AKT signaling to drive sunitinib resistance in renal cell carcinoma, independently of catalytic activity.

    Evidence Co-IP, enzymatic-activity-independent mutant, xenograft, patient tissue analysis

    PMID:34319001

    Open questions at the time
    • Structural basis of the RRM2–ANXA1 interaction unknown
    • Whether enzymatic-independent functions extend to other cancer types untested
  13. 2021 Medium

    How RRM2 loss affects anti-tumor immunity was unknown; RRM2 silencing activated the cGAS/STING pathway in a STING-dependent manner, increased CD8+ T cell infiltration, and synergized with radiation.

    Evidence shRNA knockdown, flow cytometry, IHC, xenograft with irradiation in lung adenocarcinoma

    PMID:33858512

    Open questions at the time
    • Whether cytosolic DNA from replication stress or another signal triggers cGAS not resolved
    • Immunocompetent syngeneic model not used
  14. 2021 Medium

    Direct transcriptional activators of RRM2 during S phase were incompletely catalogued; MYBL2 was shown to directly bind the RRM2 promoter in complex with TAF15 and MuvB, activating transcription essential for DNA synthesis.

    Evidence ChIP, promoter reporter, knockdown/overexpression rescue, xenograft in colorectal cancer cells

    PMID:34234118

    Open questions at the time
    • Whether MYBL2–MuvB complex is the dominant S-phase driver versus E2F factors is unclear
    • Interplay among multiple transcription factors at the RRM2 promoter not mapped simultaneously
  15. 2022 High

    How RRM2 protein is stabilized during S phase was undefined; USP7 was identified as a deubiquitinase that directly binds and deubiquitinates RRM2 in S phase, with USP7 loss causing replication stress and senescence rescued by ectopic RRM2.

    Evidence Co-IP, proteomics, shRNA, ectopic RRM2 rescue, PDX dropout screen in melanoma

    PMID:36130505

    Open questions at the time
    • Whether USP7 and USP12 act redundantly or in distinct contexts unknown
    • Ubiquitin chain type specificity not determined
  16. 2022 Medium

    WEE1 kinase was implicated in RRM2 protein turnover; WEE1 inhibition reduced RRM2 protein and synergized with MYBL2 knockdown, defining convergent transcriptional and post-translational control axes.

    Evidence WEE1 inhibitor MK-1775, combination with MYBL2 knockdown, xenograft

    PMID:34234118

    Open questions at the time
    • Whether WEE1 acts directly on RRM2 or via CDK-mediated phosphorylation-dependent ubiquitination unresolved
    • Direct WEE1–RRM2 interaction not demonstrated
  17. 2023 Medium

    Whether additional deubiquitinases regulate RRM2 was unknown; USP12 was identified as a second DUB that directly deubiquitinates RRM2, with USP12 loss reducing RRM2 and causing replication stress in NSCLC.

    Evidence Co-IP, ubiquitination assay, USP12 knockdown, xenograft

    PMID:37341611

    Open questions at the time
    • Relationship and potential redundancy between USP7 and USP12 on RRM2 not tested
    • Whether USP12 regulation is cell-cycle-phase specific unknown
  18. 2023 Medium

    E2F8 was identified as a direct transcriptional activator of RRM2 in lung adenocarcinoma; combined E2F8 knockdown with WEE1 inhibition synergistically depleted RRM2, showing convergent therapeutic vulnerability.

    Evidence ChIP-qPCR, DNA pulldown, luciferase reporter, knockdown/overexpression, xenograft

    PMID:37863324

    Open questions at the time
    • Relative contributions of E2F1, E2F8, and MYBL2 to RRM2 transcription across tissues not compared
    • Whether E2F8 cooperates with or competes with E2F1 at the RRM2 promoter unknown
  19. 2023 Medium

    FOXM1 was shown to directly bind the RRM2 promoter in SCLC, adding another transcription factor to the regulatory network; miR-1/CXCR4 axis suppresses FOXM1–RRM2 signaling and metastasis.

    Evidence ChIP, dual-luciferase, miR-1 gain/loss of function, intracardiac metastasis model

    PMID:36597126

    Open questions at the time
    • How CXCR4 signaling enables FOXM1 promoter binding mechanistically is unclear
    • Whether FOXM1 and MYBL2 bind the same or distinct RRM2 promoter regions unknown
  20. 2024 Medium

    A novel post-translational modification — lysine crotonylation at K283 — was identified on RRM2; SIRT7 decrotonylates this site, and p53 loss reduces SIRT7, leading to RRM2 hyper-crotonylation and cisplatin resistance.

    Evidence SILAC crotonylome, p53 KO cells, SIRT7 knockdown/overexpression, K283 mutagenesis, apoptosis assays in colon cancer

    PMID:38894712

    Open questions at the time
    • Writer enzyme (crotonyltransferase) for K283 not identified
    • How crotonylation stabilizes RRM2 protein mechanistically is unresolved
  21. 2024 Medium

    Post-transcriptional stabilization of RRM2 mRNA by m6A was established; IGF2BP3 reads m6A marks on RRM2 mRNA to sustain its expression, linking epitranscriptomic regulation to GSH synthesis and ferroptosis suppression.

    Evidence MeRIP, RIP, ChIP, dual-luciferase, rescue experiments, xenograft in hepatocellular carcinoma

    PMID:39630361

    Open questions at the time
    • Specific m6A sites on RRM2 mRNA not mapped at single-nucleotide resolution
    • Whether m6A regulation of RRM2 operates in normal tissue homeostasis unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • A unified quantitative model integrating the multiple transcriptional (E2F1, E2F8, MYBL2, FOXM1, BRCA1), translational (4E-BP1), and post-translational (USP7, USP12, cyclin F, WEE1, SIRT7/K283Cr) regulatory inputs that converge on RRM2 protein levels across cell cycle phases and stress conditions has not been constructed.
  • No integrated systems-level model of RRM2 regulation across cell cycle and stress contexts
  • Structural basis of RRM2 enzymatic-activity-independent protein–protein interactions (ANXA1, GSS, Bcl-2) unresolved
  • T33 kinase identity and upstream signaling controlling RRM2–GSS interaction unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005829 cytosol 2
Pathway
R-HSA-1430728 Metabolism 4 R-HSA-162582 Signal Transduction 4 R-HSA-1640170 Cell Cycle 4 R-HSA-69306 DNA Replication 4 R-HSA-5357801 Programmed Cell Death 3 R-HSA-73894 DNA Repair 2 R-HSA-168256 Immune System 1
Partners
ANXA1CDK1GSSRRM1SIRT7USP12USP7YBX1
Complex memberships
Ribonucleotide reductase (RNR) holoenzyme (RRM1–RRM2)

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 A single conserved tryptophan residue (W688 equivalent in mammalian RRM1) mediates the physical interaction between the catalytic subunit RRM1 and the regulatory subunit RRM2; mutation of this residue abolishes RRM1–RRM2 binding and is lethal in homozygous mice, establishing that RRM1–RRM2 complex formation is essential for mammalian ribonucleotide reductase (RNR) activity and development. Mutagenesis in mouse model (knock-in Rrm1-WG/WG), proteomic/interaction analysis, genetic epistasis in mice Molecular and cellular biology High 26077802
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 that RRM2-driven dNTP supply is a conserved mammalian mechanism that protects against replication stress-induced genomic instability. Transgenic mouse genetics (Rrm2 overexpression), RNR activity assay, cytogenetic fragile-site analysis, survival analysis of ATR-mutant mice Genes & development High 25838540
2016 BRCA1 acts as a transcriptional co-activator of RRM2 in glioblastoma; BRCA1 depletion reduces RRM2 expression, increases replication stress and DNA damage, and impairs tumor growth, placing RRM2 downstream of BRCA1 in a protective replication-stress response pathway. siRNA/shRNA knockdown of BRCA1, Western blot, DNA fiber assay, γH2AX immunofluorescence, xenograft tumor models Nature communications High 27845331
2006 RRM2 overexpression in pancreatic adenocarcinoma cells activates NF-κB transcription factor activity and upregulates MMP-9 expression in an NF-κB-dependent manner, thereby enhancing cellular invasiveness; RNAi-mediated silencing of RRM2 reverses these effects. RRM2 overexpression and RNAi knockdown, NF-κB reporter assay, invasion assay, MMP-9 Western blot Biochemical and biophysical research communications Medium 17222798
2009 RRM2 overexpression in human cancer cells decreases thrombospondin-1 (TSP-1) expression and increases VEGF production at the mRNA and protein level, promoting tumor angiogenesis; siRNA-mediated RRM2 knockdown reverses both effects and reduces endothelial chemotaxis and vascularization in xenografts. RRM2 overexpression and siRNA knockdown, RT-PCR, ELISA, endothelial chemotaxis assay, in vivo xenograft vascularization Molecular cancer Medium 19250552
2013 RRM2 depletion in head and neck and lung cancer cells induces apoptosis through the intrinsic (mitochondrial) pathway by reducing Bcl-2 protein stability; RRM2 and Bcl-2 co-localize intracellularly and show significant co-expression in patient tissues, indicating RRM2 directly regulates Bcl-2 protein degradation. siRNA knockdown, Western blot, confocal microscopy, tissue fractionation, gene overexpression/knockdown, immunohistochemistry, quantum dot immunofluorescence in patient specimens Clinical cancer research Medium 23719266
2020 RRM2 inhibits ferroptosis in liver cancer cells by sustaining glutathione (GSH) synthesis via interaction with glutathione synthetase (GSS); phosphorylation of RRM2 at Threonine 33 (T33) normally blocks the RRM2–GSS interaction, preventing their co-degradation by the proteasome; under ferroptotic stress, dephosphorylation of T33 promotes RRM2–GSS binding, leading to simultaneous proteasomal degradation of both proteins. Co-immunoprecipitation, proximity ligation assay (PLA), immunofluorescence, phosphorylation mutagenesis, proteasome inhibition, cell viability and ferroptosis assays Cancer cell international High 33372599
2021 RRM2 stabilizes ANXA1 protein and activates the AKT signaling pathway in renal cell carcinoma cells, promoting sunitinib resistance; this function is independent of RRM2's ribonucleotide reductase enzymatic activity. RRM2 knockdown/overexpression, co-IP, Western blot, cell viability assays, xenograft mouse model, patient tissue analysis Advanced science Medium 34319001
2022 USP7 deubiquitinase directly interacts with and deubiquitinates RRM2 during S phase of the cell cycle, stabilizing RRM2 protein; USP7 knockdown reduces RRM2 levels, causes DNA replication stress, and induces cellular senescence in melanoma cells; ectopic RRM2 expression rescues the senescent phenotype caused by USP7 depletion. shRNA knockdown, co-IP, proteomics/transcriptomics, ectopic RRM2 expression rescue, in vivo PDX drop-out screens Cell reports High 36130505
2023 USP12 deubiquitinase directly interacts with and deubiquitinates RRM2, stabilizing its protein level in non-small cell lung cancer cells; USP12 knockdown reduces RRM2 protein, induces DNA replication stress, and retards tumor growth in vivo. Co-IP, Western blot, ubiquitination assay, USP12 knockdown, xenograft tumor model Molecular carcinogenesis Medium 37341611
2021 MYBL2 transcription factor directly binds the RRM2 gene promoter and activates its transcription during S phase in colorectal cancer cells, forming a complex with TAF15 and MuvB components; this transcriptional activation is essential for RRM2-dependent DNA synthesis and cell cycle progression. Chromatin immunoprecipitation (ChIP), promoter reporter assay, MYBL2 knockdown/overexpression, rescue experiments, xenograft model Cell death & disease Medium 34234118
2023 E2F8 transcription factor directly binds the RRM2 promoter and activates its transcription in lung adenocarcinoma, driving RRM2-dependent DNA synthesis and cell cycle progression; combined E2F8 knockdown with WEE1 inhibitor MK-1775 synergistically suppresses RRM2 levels and tumor growth. Luciferase reporter assay, ChIP-qPCR, DNA pulldown-Western blot, overexpression/knockdown experiments, xenograft model Biochemical pharmacology Medium 37863324
2016 HPV31 maintains elevated RRM2 levels in differentiating keratinocytes through viral E7 expression and activation of the ATR-Chk1-E2F1 signaling axis; RRM2 depletion blocks productive HPV31 replication, demonstrating that RRM2 provides dNTPs essential for viral DNA synthesis in differentiating cells. RRM2 siRNA knockdown, dNTP pool measurement, Western blot, quantitative viral DNA replication assay Virology Medium 27764728
2018 The synthetic compound DHS (trans-4,4'-dihydroxystilbene) targets RRM2 and induces cyclin F-mediated proteasomal degradation of RRM2, reducing RNR activity and dNTP synthesis, thereby inhibiting DNA replication, causing S-phase arrest and apoptosis in cancer cells. Molecular docking, Western blot, RNR activity assay, dNTP quantification, cell cycle flow cytometry, xenograft models Oncogene Medium 30518875
2020 The translational repressor 4E-BP1 specifically regulates RRM2 protein levels in a cap-dependent translation-dependent manner; mTORC1/2 inhibition (but not mTORC1 alone) activates 4E-BP1, inhibits protein synthesis, and selectively reduces RRM2 protein; CRISPR/Cas9 knockout of 4E-BP1 rescues RRM2 levels under mTORC1/2 inhibition. CRISPR/Cas9 4E-BP1 knockout, mTOR inhibitor treatment, mutant 4E-BP1 inducible expression, Western blot, xenograft model Oncogene Medium 33191406
2022 RRM2 expression is regulated at the protein level by the ubiquitin-proteasome system during the cell cycle; WEE1 kinase is involved in a degradation pathway of RRM2, and inhibition of WEE1 (by MK-1775) reduces RRM2 protein, with this effect synergizing with transcriptional suppression of RRM2 by MYBL2 knockdown. WEE1 inhibitor treatment, Western blot, combination knockdown experiments, xenograft model Cell death & disease Medium 34234118
2024 IGF2BP3 stabilizes RRM2 mRNA in an m6A-dependent manner (reading m6A modifications on RRM2 mRNA) in hepatocellular carcinoma, sustaining RRM2 protein expression and GSH synthesis to suppress ferroptosis; ChIP and dual-luciferase assays confirmed FOXM1 transcriptionally activates IGF2BP3; overexpression of RRM2 rescues ferroptosis and malignant phenotypes induced by IGF2BP3 knockdown. m6A RNA immunoprecipitation (MeRIP), RNA immunoprecipitation (RIP), ChIP assay, dual-luciferase reporter, co-IP, ferroptosis assays, rescue experiments, xenograft model Molecular and cellular biochemistry Medium 39630361
2023 FOXM1 transcription factor directly binds to the RRM2 promoter and regulates its transcriptional activity in small cell lung cancer; miR-1 targets CXCR4, which prevents FOXM1 from binding the RRM2 promoter, thus downregulating RRM2 and suppressing SCLC growth and metastasis. Chromatin immunoprecipitation (ChIP), dual-luciferase assay, miR-1 gain/loss of function, intracardiac mouse metastasis model, transcriptomic analysis Molecular cancer Medium 36597126
2011 Oncogenic KRAS signaling upregulates RRM2 expression in colorectal cancer cells; re-expression of KRAS in KRAS-disrupted HKe3 cells restores RRM2 protein; RRM2 knockdown impairs KRAS-driven cell proliferation under serum-starved conditions and anchorage-independent growth. KRAS re-expression in isogenic cell lines, lentiviral shRNA knockdown of RRM2, Western blot, cell proliferation and colony formation assays Anticancer research Medium 21873171
2013 Elevated AKT signaling in breast cancer cells transcriptionally upregulates RRM2 expression, and RRM2 mediates AKT-induced tamoxifen resistance by increasing DNA repair capacity and protecting from tamoxifen-induced apoptosis; RNAi knockdown of RRM2 reverses tamoxifen-resistant growth and activates proapoptotic pathways. Gene expression profiling, RNAi knockdown, small-molecule RRM2 inhibitor (didox), cell proliferation and apoptosis assays, in vivo xenograft model Molecular cancer research Medium 24362250
2021 RRM2 silencing in lung adenocarcinoma cells induces cGAS/STING pathway activation and its downstream targets in a STING-dependent manner, increases CD8+ T cell infiltration in tumors, and synergizes with radiation to further activate cGAS/STING signaling and promote apoptosis. shRNA RRM2 knockdown, Western blot, flow cytometry (CD8+ T cells), immunohistochemistry, xenograft mouse model, combination with irradiation Cell & bioscience Medium 33858512
2022 RRM2 interacts with CDK1 in chicken myoblasts (ortholog study); forced RRM2 induction alleviates excessive replicative stress induced by CHK1 inhibition in neuroblastoma, and RRM2 co-overexpression with MYCN accelerates tumor formation and activates ATR-CHK1 signaling in a zebrafish model; combined RRM2-CHK1 inhibition is synergistic in high-risk neuroblastoma. Co-immunoprecipitation, zebrafish tumor model (MYCN + RRM2 co-overexpression), CHK1 inhibitor treatment, patient-derived xenograft experiments Science advances Medium 35857500
2024 p53 deficiency leads to downregulation of SIRT7, which is the decrotonylase for RRM2; loss of SIRT7 results in increased lysine crotonylation of RRM2 at K283 (RRM2-K283Cr), which upregulates RRM2 protein and promotes cisplatin resistance by inhibiting apoptosis in colon cancer cells. SILAC-based quantitative crotonylome, p53 knockout cells, SIRT7 knockdown/overexpression, site-specific mutagenesis (K283), apoptosis assays Frontiers in molecular biosciences Medium 38894712
2016 In gastric cancer cells, RRM2 activates AKT, IKBα, and NF-κB signaling in a time-dependent manner; AKT and NF-κB inhibitors (GSK690693 and BAY117082) block RRM2-induced increases in MMP-2 and MMP-9 expression and cellular invasion, demonstrating that RRM2 promotes invasiveness via an AKT/NF-κB axis. RRM2 stimulation, pharmacological AKT and NF-κB inhibitors, Western blot, invasion and migration assays Die Pharmazie Low 27348973
2019 RRM2 silencing in multiple myeloma cells inhibits RNR enzymatic activity, induces apoptosis through increased Bax and cleaved caspase-3/PARP, and activates the DNA-damage response (γH2AX); RRM2 knockdown inhibits the Wnt/β-catenin pathway by increasing GSK-3β phosphorylation. siRNA knockdown, RNR activity assay, Western blot, Annexin V apoptosis assay, flow cytometry Molecular medicine reports Low 31322175
2024 lncOCMRL1 suppresses RRM2 ubiquitination in oral squamous cell carcinoma cells, stabilizing RRM2 protein and thereby inducing epithelial-mesenchymal transition (EMT) to promote proliferation, invasion, and migration. RNA pull-down, RIP, mass spectrometry, Western blot, ubiquitination assay, invasion/migration assays, in vivo xenograft model Journal of experimental & clinical cancer research Medium 39343925
2020 The lncRNA lincNMR binds to YBX1 (identified by in vivo RNA Antisense Purification mass spectrometry) and regulates RRM2, TYMS, and TK1 expression; lincNMR depletion reduces dNTP pools and causes proliferation defects rescued by exogenous dNTPs, placing lincNMR upstream of YBX1 which then controls RRM2 expression and nucleotide metabolism. Triple-label SILAC proteomics, in vivo RNA Antisense Purification mass spectrometry (RAP-MS), siRNA knockdown, dNTP quantification, dNTP rescue experiments, ChIP (YBX1 promoter binding) Nature communications High 32587247
2022 RRM2 promotes osteogenic differentiation of mouse embryo fibroblasts via the canonical Wnt/β-catenin signaling pathway; RRM2 overexpression increases β-catenin protein, p-GSK-3β/GSK-3β ratio, and downstream Wnt target gene expression, while RRM2 knockdown has opposite effects. Adenoviral RRM2 overexpression, siRNA knockdown, Western blot, RT-qPCR, ALP activity assay, Alizarin Red S staining Experimental and therapeutic medicine Low 36160885

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) 132 34319001
2020 RRM2 protects against ferroptosis and is a tumor biomarker for liver cancer. Cancer cell international 124 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 104 27845331
2020 Inhibiting RRM2 to enhance the anticancer activity of chemotherapy. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 102 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 99 32587247
2018 Atomic-level evidence for packing and positional amyloid polymorphism by segment from TDP-43 RRM2. Nature structural & molecular biology 94 29531287
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
2022 Ribonucleotide reductase M2 (RRM2): Regulation, function and targeting strategy in human cancer. Genes & diseases 92 37588202
2006 RRM2 induces NF-kappaB-dependent MMP-9 activation and enhances cellular invasiveness. Biochemical and biophysical research communications 87 17222798
2014 Increased expression of RRM2 by human papillomavirus E7 oncoprotein promotes angiogenesis in cervical cancer. British journal of cancer 85 24423925
2006 A peptide motif in Raver1 mediates splicing repression by interaction with the PTB RRM2 domain. Nature structural & molecular biology 84 16936729
2017 Gambogic acid sensitizes gemcitabine efficacy in pancreatic cancer by reducing the expression of ribonucleotide reductase subunit-M2 (RRM2). Journal of experimental & clinical cancer research : CR 76 28797284
2023 MicroRNA-1 attenuates the growth and metastasis of small cell lung cancer through CXCR4/FOXM1/RRM2 axis. Molecular cancer 75 36597126
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 70 20825972
2018 DSCAM-AS1 promotes tumor growth of breast cancer by reducing miR-204-5p and up-regulating RRM2. Molecular carcinogenesis 67 30457164
2015 Increased Rrm2 gene dosage reduces fragile site breakage and prolongs survival of ATR mutant mice. Genes & development 56 25838540
2016 Cell cycle dependent RRM2 may serve as proliferation marker and pharmaceutical target in adrenocortical cancer. American journal of cancer research 55 27725909
2020 Sorafenib Inhibits Ribonucleotide Reductase Regulatory Subunit M2 (RRM2) in Hepatocellular Carcinoma Cells. Biomolecules 53 31936661
2018 siRNA Knockdown of RRM2 Effectively Suppressed Pancreatic Tumor Growth Alone or Synergistically with Doxorubicin. Molecular therapy. Nucleic acids 53 30153565
2021 RRM2 silencing suppresses malignant phenotype and enhances radiosensitivity via activating cGAS/STING signaling pathway in lung adenocarcinoma. Cell & bioscience 51 33858512
2018 DHS (trans-4,4'-dihydroxystilbene) suppresses DNA replication and tumor growth by inhibiting RRM2 (ribonucleotide reductase regulatory subunit M2). Oncogene 51 30518875
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 47 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
2013 AKT-induced tamoxifen resistance is overturned by RRM2 inhibition. Molecular cancer research : MCR 44 24362250
2019 RRM2 Regulated By LINC00667/miR-143-3p Signal Is Responsible For Non-Small Cell Lung Cancer Cell Progression. OncoTargets and therapy 42 31819489
2017 Onset of disorder and protein aggregation due to oxidation-induced intermolecular disulfide bonds: case study of RRM2 domain from TDP-43. Scientific reports 41 28894122
2016 Overexpression of RRM2 in gastric cancer cell promotes their invasiveness via AKT/NF-κB signaling pathway. Die Pharmazie 40 27348973
2019 Potential tumor‑suppressive role of microRNA‑99a‑3p in sunitinib‑resistant renal cell carcinoma cells through the regulation of RRM2. International journal of oncology 38 30816432
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 36 33125611
2019 Identification of lncRNA NEAT1/miR-21/RRM2 axis as a novel biomarker in breast cancer. Journal of cellular physiology 36 31621912
2021 A MYBL2 complex for RRM2 transactivation and the synthetic effect of MYBL2 knockdown with WEE1 inhibition against colorectal cancer. Cell death & disease 35 34234118
2019 MiR-20a-5p regulates gemcitabine chemosensitivity by targeting RRM2 in pancreatic cancer cells and serves as a predictor for gemcitabine-based chemotherapy. Bioscience reports 35 30777929
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 31 35857500
2022 Targeting the USP7/RRM2 axis drives senescence and sensitizes melanoma cells to HDAC/LSD1 inhibitors. Cell reports 30 36130505
2011 Purification and characterization of a protease produced by Bacillus megaterium RRM2: application in detergent and dehairing industries. Journal of basic microbiology 30 21780140
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
2022 RRM2 Alleviates Doxorubicin-Induced Cardiotoxicity through the AKT/mTOR Signaling Pathway. Biomolecules 28 35204799
2020 Osalmid, a Novel Identified RRM2 Inhibitor, Enhances Radiosensitivity of Esophageal Cancer. International journal of radiation oncology, biology, physics 27 32763454
2019 Silencing RRM2 inhibits multiple myeloma by targeting the Wnt/β‑catenin signaling pathway. Molecular medicine reports 26 31322175
2001 Amplification of Mycn, Ddx1, Rrm2, and Odc1 in rat uterine endometrial carcinomas. Genes, chromosomes & cancer 26 11433525
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 22 35248107
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
2024 LncOCMRL1 promotes oral squamous cell carcinoma growth and metastasis via the RRM2/EMT pathway. Journal of experimental & clinical cancer research : CR 21 39343925
2020 The SNHG16/miR-30a axis promotes breast cancer cell proliferation and invasion by regulating RRM2. Neoplasma 21 32122142
2023 The key cellular senescence related molecule RRM2 regulates prostate cancer progression and resistance to docetaxel treatment. Cell & bioscience 20 37968699
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) 19 35716217
2020 The translational repressor 4E-BP1 regulates RRM2 levels and functions as a tumor suppressor in Ewing sarcoma tumors. Oncogene 19 33191406
2022 Yap is essential for uterine decidualization through Rrm2/GSH/ROS pathway in response to Bmp2. International journal of biological sciences 18 35414789
2020 LncRNA TTN-AS1 Regulates miR-524-5p and RRM2 to Promote Breast Cancer Progression. OncoTargets and therapy 18 32547107
2023 Targeting of RRM2 suppresses DNA damage response and activates apoptosis in atypical teratoid rhabdoid tumor. Journal of experimental & clinical cancer research : CR 17 38124207
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
2023 MiR-17- 5p/RRM2 regulated gemcitabine resistance in lung cancer A549 cells. Cell cycle (Georgetown, Tex.) 16 37115505
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 PLEK2, RRM2, GCSH: A Novel WWOX-Dependent Biomarker Triad of Glioblastoma at the Crossroads of Cytoskeleton Reorganization and Metabolism Alterations. Cancers 16 34204789
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 16 29710515
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
2017 Knockdown of TBRG4 affects tumorigenesis in human H1299 lung cancer cells by regulating DDIT3, CAV1 and RRM2. Oncology letters 15 29387213
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 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 12 39630361
2024 Resveratrol promotes mitophagy via the MALAT1/miR-143-3p/RRM2 axis and suppresses cancer progression in hepatocellular carcinoma. Journal of integrative medicine 12 39675939
2021 Molecular Targeting of RRM2, NF-κB, and Mutant TP53 for the Treatment of Triple-Negative Breast Cancer. Molecular cancer therapeutics 12 33536192
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 Celastrol induces ferroptosis by suppressing RRM2 in hepatocellular carcinoma. Heliyon 11 39071636
2023 E2F8 exerts cancer-promoting effects by transcriptionally activating RRM2 and E2F8 knockdown synergizes with WEE1 inhibition in suppressing lung adenocarcinoma. Biochemical pharmacology 11 37863324
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
2017 Mutation in the RRM2 domain of TDP-43 in Amyotrophic Lateral Sclerosis with rapid progression associated with ubiquitin positive aggregates in cultured motor neurons. Amyotrophic lateral sclerosis & frontotemporal degeneration 11 28705014
2023 USP12 promotes nonsmall cell lung cancer progression through deubiquitinating and stabilizing RRM2. Molecular carcinogenesis 10 37341611
2023 Diosmetin suppresses the progression of ESCC by CDK2/Rb/E2F2/RRM2 pathway and synergies with cisplatin. Oncogene 10 37349644
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 IGF2BP3 regulates the expression of RRM2 and promotes the progression of rheumatoid arthritis via RRM2/Akt/MMP-9 pathway. PloS one 9 38820515
2022 Identification of RRM2 in peripheral blood mononuclear cells as a novel biomarker for the diagnosis of rheumatoid arthritis. Clinical and experimental rheumatology 9 35200126
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
2015 A Single Conserved Residue Mediates Binding of the Ribonucleotide Reductase Catalytic Subunit RRM1 to RRM2 and Is Essential for Mouse Development. Molecular and cellular biology 9 26077802
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 8 38273783
2024 p53 deficiency mediates cisplatin resistance by upregulating RRM2 and crotonylation of RRM2K283 through the downregulation of SIRT7. Frontiers in molecular biosciences 8 38894712
2023 RRM2 promotes the proliferation of chicken myoblasts, inhibits their differentiation and muscle regeneration. Poultry science 8 38198913
2022 LncRNA PART1 Stimulates the Development of Ovarian Cancer by Up-regulating RACGAP1 and RRM2. Reproductive sciences (Thousand Oaks, Calif.) 8 35553409
2016 APLP2, RRM2, and PRC1: New Putative Markers for the Differential Diagnosis of Thyroid Follicular Lesions. Thyroid : official journal of the American Thyroid Association 8 27796194
2024 RRM2 Is a Putative Biomarker and Promotes Bladder Cancer Progression via PI3K/AKT/mTOR Pathway. Journal of cellular physiology 7 39676643
2016 RRM1, RRM2 and ERCC2 Gene Polymorphisms in Coronary Artery Disease. In vivo (Athens, Greece) 7 27566080