Affinage

RRM1

Ribonucleoside-diphosphate reductase large subunit · UniProt P23921

Length
792 aa
Mass
90.1 kDa
Annotated
2026-06-10
100 papers in source corpus 20 papers cited in narrative 20 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RRM1 is the large catalytic subunit of ribonucleotide reductase (RNR), the enzyme that supplies deoxyribonucleotides for DNA replication and repair, and its function spans both this enzymatic role and several catalytically independent regulatory activities (PMID:26077802, PMID:32712628). Assembly of the active enzyme requires RRM1 binding to RRM2 through a single conserved tryptophan residue, an interaction essential for mammalian development (PMID:26077802). RNR output is tuned across the cell cycle: CDK2/cyclin A phosphorylates RRM1 at Ser559 during S/G2 to boost enzymatic activity and sustain dNTP pools, and loss of this phosphorylation produces replication stress, double-strand breaks, and genomic instability (PMID:32712628). Adequate dNTP synthesis by RRM1 is also required for mitochondrial DNA maintenance, and pathogenic catalytic-site variants (dominant p.N427K, recessive p.R381) cause a mitochondrial DNA depletion/deletion disorder with aberrant dNTP pools and mtDNA ribonucleotide incorporation (PMID:35617047). Independent of its enzymatic activity, RRM1 acts as a metastasis suppressor by inducing PTEN expression and reducing FAK and Akt phosphorylation, an activity retained by catalytically dead mutants and abolished by PTEN knockdown (PMID:12687015, PMID:25638032). RRM1 additionally promotes homologous recombination through a cytoplasmic interaction with USP11 that, upon irradiation, facilitates USP11 nuclear entry to stabilize E2F1 and drive RAD51AP1 transcription (PMID:39695160), and it modulates ferroptosis sensitivity by tuning USP11/MDM2-dependent p53 ubiquitination and downstream GPX4 (PMID:35915092). RRM1 expression is transcriptionally controlled by Sp1 at its TATA-less promoter (PMID:7557993) and through STAT3- and YBX1–LRP1–β-catenin–TCF3 inputs (PMID:37321532, PMID:39216548). Clinically, RRM1 abundance is the principal determinant of gemcitabine resistance, with isogenic cell lines showing ~100-fold IC50 shifts across the RRM1 expression range, and CHK1 inhibition selectively overcomes resistance in high-RRM1 cells (PMID:16966686, PMID:23483975).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 1995 Medium

    Established how the housekeeping RRM1 gene is transcriptionally driven, identifying Sp1 as a sequence-specific activator of its TATA-less promoter.

    Evidence Reporter transfection plus EMSA with antibody supershift on the −195/+3 promoter region

    PMID:7557993

    Open questions at the time
    • Does not address cell-cycle or stress-responsive regulation
    • No in vivo confirmation of Sp1 occupancy
  2. 2003 High

    Revealed a non-canonical, enzyme-independent role for RRM1 as a metastasis suppressor acting through PTEN induction.

    Evidence Overexpression in lung cancer cell lines with xenografts, PTEN-knockdown epistasis, FAK phosphorylation readout

    PMID:12687015

    Open questions at the time
    • Molecular mechanism by which RRM1 induces PTEN unresolved
    • Did not separate enzymatic from non-enzymatic contribution
  3. 2006 High

    Quantified RRM1 expression level as a direct, dose-dependent determinant of gemcitabine resistance, distinguishing it from platinum sensitivity.

    Evidence Isogenic cell lines spanning a 15-fold RRM1 range with in vitro IC50 measurements

    PMID:16966686

    Open questions at the time
    • Mechanism limited to drug-target abundance, not regulatory control
    • Does not identify how to therapeutically lower RRM1
  4. 2009 Low

    Causally linked an RRM1 promoter polymorphism to expression level and gemcitabine sensitivity in colorectal cancer cells.

    Evidence siRNA knockdown plus genotype/expression/IC50 correlation in CRC cell lines

    PMID:21220199

    Open questions at the time
    • Primarily associative with limited siRNA support
    • Mechanistic effect of the −37A>C variant on transcription not demonstrated
  5. 2013 Medium

    Identified CHK1 as the actionable kinase dependency that selectively reverses RRM1-driven gemcitabine resistance.

    Evidence siRNA kinase screen, AZD7762 synergy across isogenic RRM1-high/low pairs, inverse protein correlation in 187 NSCLC specimens

    PMID:23483975

    Open questions at the time
    • Molecular basis of RRM1–CHK1 interdependence not defined
    • Single-lab pharmacological validation
  6. 2014 Medium

    Connected RRM1 to centrosomal integrity and replication-stress signaling via CHK1/CDK1.

    Evidence RNAi depletion with centrosome counting, CHK1/CDK1 knockdown epistasis, hydroxyurea-induced stress

    PMID:24434653

    Open questions at the time
    • Whether centrosomal phenotype is enzyme-dependent or a downstream stress effect unclear
    • No direct RRM1 localization to centrosome shown
  7. 2014 Medium

    Showed RRM1 modulates mitotane resistance by altering intracellular drug metabolism rather than by its enzymatic activity.

    Evidence siRNA silencing with LC-MS metabolite quantification in adrenocortical cell lines

    PMID:25497672

    Open questions at the time
    • Enzyme/pathway linking RRM1 to mitotane metabolism unidentified
    • Single tumor-type context
  8. 2015 High

    Demonstrated genetically that the RRM1–RRM2 interaction, mediated by a single conserved tryptophan, is essential for mammalian development.

    Evidence Knock-in W→G mouse, proteomic validation of lost RRM2 binding, embryonic lethality phenotyping

    PMID:26077802

    Open questions at the time
    • Does not address the enzyme-independent RRM1 functions in vivo
    • Structural basis of the tryptophan contact not resolved here
  9. 2015 Medium

    Separated RRM1's anti-metastatic activity from its catalytic activity, confirming a PTEN-dependent non-enzymatic role.

    Evidence Enzymatically inactive Y738F mutant overexpression, PTEN siRNA epistasis, migration/invasion assays

    PMID:25638032

    Open questions at the time
    • How RRM1 protein transactivates PTEN remains unknown
    • Single-lab, single tumor type
  10. 2015 Medium

    Identified MDM2-mediated K48 polyubiquitination as a route to RRM1 protein turnover downstream of MEK signaling.

    Evidence MDM2–RRM1 co-IP, ubiquitin linkage analysis, MG132 rescue after pimasertib treatment

    PMID:26228206

    Open questions at the time
    • Whether MDM2 directly ubiquitinates RRM1 vs. via adaptor unclear
    • AKT involvement only partially defined
  11. 2020 High

    Defined cell-cycle control of RNR activity by identifying CDK2/cyclin A phosphorylation of RRM1 at Ser559 as a regulator of dNTP supply and genome stability.

    Evidence Phospho-site mapping, in vitro CDK2/cyclin A kinase assay, phospho-mutant cells, dNTP pool and DSB readouts

    PMID:32712628

    Open questions at the time
    • Structural effect of S559 phosphorylation on the enzyme not resolved
    • Phosphatase reversing the mark unidentified
  12. 2020 Low

    Placed RRM1 under post-transcriptional control by miR-1468-5p affecting proliferation and cell-cycle progression.

    Evidence siRNA knockdown, 3'UTR luciferase reporter, proliferation/cell-cycle assays, miRNA-plus-RRM1 rescue in glioma cells

    PMID:28469953

    Open questions at the time
    • Mechanistic depth limited to proliferation phenotype
    • Single-lab, single tumor type
  13. 2021 Medium

    Linked acute cytoplasmic RRM1 activation, controlled by histone acetylation, to gemcitabine-induced survival and avoidance of DNA damage.

    Evidence Subcellular fractionation/immunostaining, siRNA, viability and DNA damage markers, HAT inhibition in pancreatic cancer cells

    PMID:34111175

    Open questions at the time
    • What 'cytoplasmic activation' means molecularly is undefined
    • Acetylated targets driving RRM1 induction not identified
  14. 2022 High

    Established RRM1 as causal for a mitochondrial DNA maintenance disorder, demonstrating that de novo dNTP synthesis by RRM1 is required for mtDNA integrity.

    Evidence Patient genetics (dominant N427K, recessive R381), fibroblast mtDNA depletion, dNTP pool and ribonucleotide incorporation assays, MD simulations

    PMID:35617047

    Open questions at the time
    • Tissue-specific vulnerability of mtDNA to RRM1 deficiency not explained
    • Genotype–phenotype relationship across variants incomplete
  15. 2022 Medium

    Implicated RRM1 in ferroptosis resistance through a USP11/MDM2–p53–p21–GPX4 regulatory cascade.

    Evidence siRNA knockdown, ROS/lipid peroxidation assays, p53 ubiquitination assays, p21 rescue, GPX4 readouts

    PMID:35915092

    Open questions at the time
    • Whether RRM1 directly binds USP11/MDM2 in this context vs. indirect not fully resolved
    • Single-lab pathway dissection
  16. 2023 Medium

    Connected epigenetic PDGFD activation and STAT3 signaling to RRM1-driven gemcitabine resistance.

    Evidence Bisulfite sequencing, PDGFD knockdown/inhibition, STAT3 activation assays, gemcitabine sensitivity in vitro and in vivo

    PMID:37321532

    Open questions at the time
    • Whether STAT3 binds the RRM1 promoter directly not shown
    • Single-lab
  17. 2023 Low

    Linked RRM1 expression to an ECM-remodeling/EMT transcriptional program under histone-acetylation control.

    Evidence RNA-seq after RRM1 modulation, HAT inhibition, EMT marker immunoblot, migration/invasion assays

    PMID:36866763

    Open questions at the time
    • How RRM1 drives ECM gene expression mechanistically undefined
    • Correlative transcriptomics
  18. 2024 Medium

    Defined a cytoplasm-to-nucleus signaling role for RRM1 in homologous recombination via USP11 shuttling, E2F1 stabilization, and RAD51AP1 induction.

    Evidence Reciprocal co-IP, truncation/dominant-negative mutants, nuclear fractionation, E2F1 ubiquitination, RAD51AP1 reporter, HR and irradiation assays

    PMID:39695160

    Open questions at the time
    • Whether this role requires RNR catalytic activity not tested
    • Single-lab
  19. 2024 Medium

    Identified translational control of RRM1 via diphthamide-dependent −1 frameshifting on eEF2, linking translation fidelity to replication stress.

    Evidence Quantitative proteomics, frameshifting reporter, DPH-deficient cells, replication stress markers

    PMID:39463834

    Open questions at the time
    • Quantitative contribution of frameshifting to physiological RRM1 levels unclear
    • Single-lab
  20. 2024 Medium

    Mapped a multilevel transcriptional axis (YBX1→LRP1→β-catenin→TCF3) driving RRM1 expression and gemcitabine resistance.

    Evidence ChIP at multiple nodes, β-catenin localization, siRNA epistasis, gemcitabine assays in vitro and in vivo

    PMID:39216548

    Open questions at the time
    • Direct vs. cooperative TCF3/β-catenin occupancy of RRM1 promoter not fully dissected
    • Single-lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How RRM1's enzyme-independent activities (PTEN induction, USP11 shuttling, ferroptosis control) are mechanistically coupled to or separated from its core RNR catalytic role remains unresolved.
  • No structural model linking the catalytic core to its moonlighting protein-interaction surfaces
  • Whether moonlighting functions operate in vivo / at physiological RRM1 levels untested
  • Direct binding interfaces for PTEN regulation not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 2 GO:0016740 transferase activity 2 GO:0140110 transcription regulator activity 2
Localization
GO:0005829 cytosol 2 GO:0005634 nucleus 1
Pathway
R-HSA-1640170 Cell Cycle 2 R-HSA-1643685 Disease 2 R-HSA-69306 DNA Replication 1 R-HSA-73894 DNA Repair 1
Partners
CDK2E2F1MDM2RRM2USP11
Complex memberships
Ribonucleotide reductase (RRM1₂–RRM2₂)

Evidence

Reading pass · 20 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 Overexpression of RRM1 in human and mouse lung cancer cell lines induced PTEN expression, reduced phosphorylation of focal adhesion kinase (FAK), and suppressed migration, invasion, and metastasis formation in an animal model. Increased PTEN expression was required for RRM1-induced suppression of cell motility and FAK phosphorylation, establishing RRM1 as a metastasis suppressor acting through induction of PTEN. Overexpression in cell lines, animal xenograft model, PTEN knockdown epistasis, FAK phosphorylation assay Oncogene High 12687015
2006 In genetically engineered lung cancer cell lines spanning a 15-fold range of RRM1 expression, gemcitabine IC50 varied ~100-fold (highest in high-RRM1 constructs), and cisplatin/carboplatin IC50 varied ~2-fold, establishing RRM1 expression level as a direct determinant of gemcitabine resistance. Genetically modified cell lines with controlled RRM1 expression range, in vitro IC50 (MTT assay) Journal of clinical oncology High 16966686
1995 The TATA-less promoter of human RRM1 (region −195 to +3) drives maximal reporter gene expression. Electrophoretic mobility shift assays identified Sp1 as a sequence-specific binding factor in this region, established by specific competition and antibody supershift. Reporter gene transfection, EMSA, antibody supershift Genomics Medium 7557993
2015 A single conserved tryptophan residue (W688 equivalent in mouse Rrm1) mediates RRM1 binding to RRM2; the W→G mutation abolishes this interaction (shown by proteomics). Homozygous Rrm1(WG/WG) mice are not viable even at the earliest embryonic stages, demonstrating that the RRM1–RRM2 interaction is essential for mammalian development. Mouse genetics (knock-in mutation), proteomic analysis of RRM1-binding partners, embryonic lethality phenotyping Molecular and cellular biology High 26077802
2020 RRM1 is phosphorylated at Ser559 by CDK2/cyclin A during S/G2 phase. This phosphorylation enhances RNR enzymatic activity and is required for maintaining sufficient dNTPs during DNA replication; defective S559 phosphorylation causes DNA replication stress, double-strand breaks, and genomic instability. Cell-cycle synchronization, phospho-site identification, CDK2/cyclin A kinase assay, phospho-mutant cell lines, dNTP pool measurement, DNA damage markers (γH2AX, DSB) Oncogene High 32712628
2015 The MEK1/2 inhibitor pimasertib reduces RRM1 protein levels via MDM2-mediated Lys48-linked polyubiquitination (proteasomal degradation), an effect partially mediated by AKT; proteasome inhibitor MG132 blocked pimasertib-induced RRM1 reduction, and immunoprecipitation confirmed enhanced MDM2–RRM1 polyubiquitination following pimasertib treatment. Immunoprecipitation of MDM2–RRM1 complex, MG132 proteasome inhibition, ubiquitin linkage analysis (Lys48), immunoblotting Clinical cancer research Medium 26228206
2014 CDK2/cyclin A-independent finding: RRM1 depletion by RNAi induces cell-cycle arrest at the replication phase, severe DNA damage, and centrosomal amplification. CHK1 depletion synergistically increased RRM1-depletion-induced centrosomal amplification; CDK1 was required for RRM1-depletion-induced centrosomal amplification, and CHK1 was delocalized from the centrosome upon RRM1 depletion with hydroxyurea treatment. RNAi-mediated depletion, immunofluorescence centrosome counting, CHK1/CDK1 knockdown epistasis, hydroxyurea-induced replication stress Cancer letters Medium 24434653
2015 RRM1 protein (independent of its ribonucleotide reductase enzymatic activity) suppresses colorectal cancer cell migration and invasion by promoting PTEN transactivation and reducing Akt phosphorylation. An enzymatically inactive RRM1 mutant (Y738F) retained this anti-metastatic activity, and PTEN knockdown blocked the effect, establishing a non-enzymatic role for RRM1 protein in PTEN-dependent signaling. Enzymatically inactive mutant (Y738F) overexpression, PTEN siRNA knockdown epistasis, migration/invasion assays, Akt phosphorylation immunoblot Tumour biology Medium 25638032
2022 RRM1 variants cause a mitochondrial DNA maintenance disorder. A dominant catalytic-site variant (p.N427K) and homozygous recessive variants at p.R381 led to multiple mtDNA deletions in patient muscle. Patient fibroblasts showed mtDNA depletion under cycling conditions, aberrant dNTP pools, and mtDNA ribonucleotide incorporation, establishing that de novo nucleotide synthesis by RRM1 is required for mtDNA maintenance. Patient genetics, primary fibroblast mtDNA quantification, dNTP pool measurement, mtDNA ribonucleotide incorporation assay, atomistic MD simulations of variant protein structure The Journal of clinical investigation High 35617047
2022 RRM1 knockdown promotes ferroptosis in cancer cells by increasing ROS and lipid peroxidation through disruption of GPX4 activity/expression. Mechanistically, RRM1 regulates deubiquitinating enzyme USP11 and ubiquitinating enzyme MDM2 to control p53 ubiquitination; reduced p53 stability inhibits p21, which in turn restrains GPX4 expression and activity. siRNA knockdown, ROS/lipid peroxidation assays, GPX4 activity/expression measurement, ubiquitination assays for p53 (MDM2/USP11), p21 functional rescue Cell death discovery Medium 35915092
2024 RRM1 promotes homologous recombination (HR) by upregulating RAD51AP1 transcription in an E2F1-dependent manner. RRM1 interacts with USP11 in the cytoplasm; ionizing radiation–induced recruitment of RRM1 to LaminB1 facilitates USP11 entry into the nucleus via the nuclear pore complex, where USP11 binds E2F1 and inhibits its ubiquitin-mediated degradation, enhancing RAD51AP1 transcription. An RRM1 truncation mutant (lacking aa 731–793) that cannot interact with USP11 or bind LaminB1 acts as a dominant negative. Co-immunoprecipitation (RRM1–USP11 interaction), deletion/truncation mutants, nuclear fractionation, ubiquitination assays for E2F1, RAD51AP1 transcription reporter, DNA repair (HR) assays, irradiation experiments Cell death discovery Medium 39695160
2024 Diphthamide modification of eEF2 modulates RRM1 translation via −1 frameshifting; loss of diphthamide (DPH deficiency) dysregulates RRM1 protein levels and is causally linked to elevated DNA replication stress, shown by proteomics and functional rescue experiments. Quantitative proteomics, frameshifting reporter assay, DPH-deficient cell lines, DNA replication stress markers ACS central science Medium 39463834
2021 Cytoplasmic RRM1 is activated acutely (within 24 h) in response to gemcitabine exposure in pancreatic cancer cells; this cytoplasmic activation is related to cancer cell viability and drug resistance, whereas cells lacking cytoplasmic RRM1 activation showed severe DNA damage. RRM1 expression increase after gemcitabine could be suppressed by histone acetyltransferase inhibition. Subcellular fractionation/immunostaining of RRM1 localization, siRNA knockdown, viability assay (MTT), DNA damage markers, HAT inhibition PloS one Medium 34111175
2013 A synthetic lethality kinase screen identified CHK1 as the kinase whose inhibition most robustly overcomes RRM1-dependent gemcitabine resistance. CHK1 inhibition (AZD7762) was synergistic with gemcitabine in high-RRM1 cells but antagonistic in low-RRM1 cells, and CHK1 and RRM1 protein levels were significantly and inversely correlated in 187 NSCLC patient specimens. siRNA kinase screen (87 kinases), pharmacological validation (AZD7762), synergy analysis across isogenic RRM1-high/low cell line pairs, in situ protein correlation in patient specimens PloS one Medium 23483975
2009 RRM1 loss-of-function (siRNA knockdown) in colorectal cancer cells reduced gemcitabine IC50, and the RRM1 −37A>C promoter polymorphism was associated with RRM1 expression level and gemcitabine sensitivity (IC50) in CRC cell lines, causally linking RRM1 expression to gemcitabine resistance. siRNA knockdown, IC50 determination (MTT), genotyping of cell lines with matched expression and drug sensitivity measurement European journal of cancer Low 21220199
2014 RRM1 in adrenocortical cancer cells (SW13) interferes with intracellular metabolism of mitotane (o,p'DDD): RRM1 silencing increased intracellular conversion of mitotane into its metabolites o,p'DDE and o,p'DDA, demonstrating that RRM1 modulates mitotane drug resistance by affecting drug metabolization rather than by a direct enzymatic mechanism. siRNA silencing of RRM1, LC-MS measurement of intracellular metabolite levels, cytotoxicity assay Molecular and cellular endocrinology Medium 25497672
2023 PDGFD promoter demethylation in gemcitabine-resistant pancreatic cancer cells activates STAT3 signaling (in autocrine and paracrine manner), which upregulates RRM1 expression; blocking PDGFD signaling reduced RRM1 levels and re-sensitized cells to gemcitabine in vitro and in vivo. Whole-genome bisulfite sequencing, PDGFD knockdown/inhibition, STAT3 pathway activation assays, RRM1 immunoblot, gemcitabine sensitivity assay, in vivo xenograft Cancer letters Medium 37321532
2024 YBX1 promotes RRM1 expression via the YBX1→LRP1→β-catenin→TCF3→RRM1 transcriptional axis in pancreatic cancer: YBX1 binds the LRP1 promoter to drive LRP1 transcription; LRP1 alters β-catenin concentration/distribution; β-catenin via TCF3 binds the RRM1 promoter to upregulate RRM1, thereby increasing gemcitabine resistance. ChIP (YBX1 on LRP1 promoter; TCF3/β-catenin on RRM1 promoter), β-catenin localization assay, siRNA knockdowns (pathway epistasis), gemcitabine resistance assays in vitro and in vivo Cancer letters Medium 39216548
2020 Knockdown of RRM1 with siRNA in glioma cells decreased proliferation and suppressed cell cycle progression; luciferase reporter assays confirmed RRM1 as a direct target of miR-1468-5p, and forced RRM1 expression partially rescued the antiproliferative effects of miR-1468-5p overexpression. siRNA knockdown, luciferase 3'UTR reporter assay, cell proliferation (CCK-8, colony formation, EdU), flow cytometry (cell cycle), miRNA overexpression + RRM1 rescue American journal of cancer research Low 28469953
2023 RRM1 expression regulates the extracellular matrix (ECM) remodeling gene program in pancreatic cancer; RNA-seq after RRM1 activation showed upregulation of N-cadherin, tenascin-C, and COL11A, promoting mesenchymal features and migratory/invasive potential. RRM1 expression was regulated by histone acetylation during gemcitabine resistance acquisition. RNA-seq after RRM1 modulation, histone acetylation inhibitor treatment, migration/invasion assays, immunoblotting of EMT markers International journal of oncology Low 36866763

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 DNA synthesis and repair genes RRM1 and ERCC1 in lung cancer. The New England journal of medicine 400 17314339
2006 RRM1 modulated in vitro and in vivo efficacy of gemcitabine and platinum in non-small-cell lung cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 286 16966686
2014 The crystal structure of TDP-43 RRM1-DNA complex reveals the specific recognition for UG- and TG-rich nucleic acids. Nucleic acids research 149 24464995
2010 The ribonucleotide reductase large subunit (RRM1) as a predictive factor in patients with cancer. The Lancet. Oncology 146 21163702
2009 Randomized phase III trial of gemcitabine-based chemotherapy with in situ RRM1 and ERCC1 protein levels for response prediction in non-small-cell lung cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 144 19884554
2003 RRM1-induced metastasis suppression through PTEN-regulated pathways. Oncogene 127 12687015
2013 Randomized international phase III trial of ERCC1 and RRM1 expression-based chemotherapy versus gemcitabine/carboplatin in advanced non-small-cell lung cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 120 23690416
2009 Significance of RRM1 and ERCC1 expression in resectable pancreatic adenocarcinoma. Oncogene 109 19543324
2012 Coaggregation of RNA-binding proteins in a model of TDP-43 proteinopathy with selective RGG motif methylation and a role for RRM1 ubiquitination. PloS one 104 22761693
2013 ERCC1 and RRM1: ready for prime time? Journal of clinical oncology : official journal of the American Society of Clinical Oncology 67 23401439
2011 RRM1 expression and clinical outcome of gemcitabine-containing chemotherapy for advanced non-small-cell lung cancer: a meta-analysis. Lung cancer (Amsterdam, Netherlands) 67 21889227
2013 Molecular mechanism of oxidation-induced TDP-43 RRM1 aggregation and loss of function. FEBS letters 65 23384725
2014 Synergic interplay of the La motif, RRM1 and the interdomain linker of LARP6 in the recognition of collagen mRNA expands the RNA binding repertoire of the La module. Nucleic acids research 56 25488812
2010 The immunohistochemical overexpression of ribonucleotide reductase regulatory subunit M1 (RRM1) protein is a predictor of shorter survival to gemcitabine-based chemotherapy in advanced non-small cell lung cancer (NSCLC). Lung cancer (Amsterdam, Netherlands) 53 20223551
2006 Ribonucleotide reductase M1 (RRM1) 2464G>A polymorphism shows an association with gemcitabine chemosensitivity in cancer cell lines. Pharmacogenetics and genomics 53 16708051
2012 The effect of the acid-sensitivity of 4-(N)-stearoyl gemcitabine-loaded micelles on drug resistance caused by RRM1 overexpression. Biomaterials 51 23261218
1999 Lung cancer and the human gene for ribonucleotide reductase subunit M1 (RRM1). Mammalian genome : official journal of the International Mammalian Genome Society 48 10441745
2021 Structure of SRSF1 RRM1 bound to RNA reveals an unexpected bimodal mode of interaction and explains its involvement in SMN1 exon7 splicing. Nature communications 47 33462199
2015 The MEK1/2 Inhibitor Pimasertib Enhances Gemcitabine Efficacy in Pancreatic Cancer Models by Altering Ribonucleotide Reductase Subunit-1 (RRM1). Clinical cancer research : an official journal of the American Association for Cancer Research 47 26228206
2010 ERCC1 and RRM1 in the international adjuvant lung trial by automated quantitative in situ analysis. The American journal of pathology 47 21224045
2012 Combined analysis of intratumoral human equilibrative nucleoside transporter 1 (hENT1) and ribonucleotide reductase regulatory subunit M1 (RRM1) expression is a powerful predictor of survival in patients with pancreatic carcinoma treated with adjuvant gemcitabine-based chemotherapy after operative resection. Surgery 43 23253379
2007 An association between RRM1 haplotype and gemcitabine-induced neutropenia in breast cancer patients. The oncologist 43 17602053
2011 RT-PCR versus immunohistochemistry for correlation and quantification of ERCC1, BRCA1, TUBB3 and RRM1 in NSCLC. Lung cancer (Amsterdam, Netherlands) 42 21996087
2011 Preliminary indication of survival benefit from ERCC1 and RRM1-tailored chemotherapy in patients with advanced nonsmall cell lung cancer: evidence from an individual patient analysis. Cancer 39 22028294
2013 RRM1 domain of the splicing oncoprotein SRSF1 is required for MEK1-MAPK-ERK activation and cellular transformation. Carcinogenesis 38 23843040
2013 Just getting into cells is not enough: mechanisms underlying 4-(N)-stearoyl gemcitabine solid lipid nanoparticle's ability to overcome gemcitabine resistance caused by RRM1 overexpression. Journal of controlled release : official journal of the Controlled Release Society 37 23570983
2020 LINC02535 co-functions with PCBP2 to regulate DNA damage repair in cervical cancer by stabilizing RRM1 mRNA. Journal of cellular physiology 35 32324262
2013 Genetic polymorphisms of SLC28A3, SLC29A1 and RRM1 predict clinical outcome in patients with metastatic breast cancer receiving gemcitabine plus paclitaxel chemotherapy. European journal of cancer (Oxford, England : 1990) 34 24361227
2013 Phase II trial of customized first line chemotherapy according to ERCC1 and RRM1 SNPs in patients with advanced non-small-cell lung cancer. Lung cancer (Amsterdam, Netherlands) 33 24045016
2016 Combined analysis of rearrangement of ALK, ROS1, somatic mutation of EGFR, KRAS, BRAF, PIK3CA, and mRNA expression of ERCC1, TYMS, RRM1, TUBB3, EGFR in patients with non-small cell lung cancer and their clinical significance. Cancer chemotherapy and pharmacology 32 26842788
2017 Ribonucleotide Reductase Catalytic Subunit M1 (RRM1) as a Novel Therapeutic Target in Multiple Myeloma. Clinical cancer research : an official journal of the American Association for Cancer Research 31 28442502
2013 RRM1 and RRM2 pharmacogenetics: association with phenotypes in HapMap cell lines and acute myeloid leukemia patients. Pharmacogenomics 31 24024897
2011 The expression of ERCC1, RRM1, and BRCA1 in breast cancer according to the immunohistochemical phenotypes. Journal of Korean medical science 30 21394302
2020 Exosome-Mediated Transfer of Long Noncoding RNA HOTAIR Regulates Temozolomide Resistance by miR-519a-3p/RRM1 Axis in Glioblastoma. Cancer biotherapy & radiopharmaceuticals 29 32721218
2022 Knockdown of RRM1 in tumor cells promotes radio-/chemotherapy induced ferroptosis by regulating p53 ubiquitination and p21-GPX4 signaling axis. Cell death discovery 28 35915092
2015 Trypanosoma brucei RRM1 is a nuclear RNA-binding protein and modulator of chromatin structure. mBio 27 25784696
2012 RRM1 and ERCC1 expression in peripheral blood versus tumor tissue in gemcitabine/carboplatin-treated advanced non-small cell lung cancer. Cancer chemotherapy and pharmacology 26 22302408
2012 Is there a role for the quantification of RRM1 and ERCC1 expression in pancreatic ductal adenocarcinoma? BMC cancer 26 22436573
2020 ALS-causing D169G mutation disrupts the ATP-binding capacity of TDP-43 RRM1 domain. Biochemical and biophysical research communications 25 32007267
2017 MicroRNA-1468-5p inhibits glioma cell proliferation and induces cell cycle arrest by targeting RRM1. American journal of cancer research 25 28469953
2008 mRNA expression of RRM1, ERCC1 and ERCC2 is not associated with chemosensitivity to cisplatin, carboplatin and gemcitabine in human lung cancer cell lines. Respirology (Carlton, Vic.) 25 18494946
2020 Cell-cycle-dependent phosphorylation of RRM1 ensures efficient DNA replication and regulates cancer vulnerability to ATR inhibition. Oncogene 24 32712628
2014 Expression of ERCC1, TYMS, TUBB3, RRM1 and TOP2A in patients with esophageal squamous cell carcinoma: A hierarchical clustering analysis. Experimental and therapeutic medicine 24 24926347
2013 Histology-related associations of ERCC1, RRM1, and TS biomarkers in patients with non-small-cell lung cancer: implications for therapy. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 24 23470290
2011 Differential effect of polymorphisms of CMPK1 and RRM1 on survival in advanced non-small cell lung cancer patients treated with gemcitabine or taxane/cisplatinum. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 24 21642870
2021 Cytoplasmic RRM1 activation as an acute response to gemcitabine treatment is involved in drug resistance of pancreatic cancer cells. PloS one 23 34111175
2013 Predictive value of ERCC1 and RRM1 gene single-nucleotide polymorphisms for first-line platinum- and gemcitabine-based chemotherapy in non-small cell lung cancer patients. Oncology reports 23 23982437
2024 YBX1 as a therapeutic target to suppress the LRP1-β-catenin-RRM1 axis and overcome gemcitabine resistance in pancreatic cancer. Cancer letters 20 39216548
2014 Expression of ERCC1, TYMS, RRM1, TUBB3, non-muscle myosin II, myoglobin and MyoD1 in lung adenocarcinoma pleural effusions predicts survival in patients receiving platinum-based chemotherapy. Molecular medicine reports 19 25573098
2011 Association of RRM1 -37A>C polymorphism with clinical outcome in colorectal cancer patients treated with gemcitabine-based chemotherapy. European journal of cancer (Oxford, England : 1990) 19 21220199
2023 Reversible promoter demethylation of PDGFD confers gemcitabine resistance through STAT3 activation and RRM1 upregulation. Cancer letters 18 37321532
2014 RRM1 modulates mitotane activity in adrenal cancer cells interfering with its metabolization. Molecular and cellular endocrinology 18 25497672
2013 A kinome screen identifies checkpoint kinase 1 (CHK1) as a sensitizer for RRM1-dependent gemcitabine efficacy. PloS one 18 23483975
2012 Expression of RRM1 and its association with resistancy to gemcitabine-based chemotherapy in advanced nasopharyngeal carcinoma. Chinese journal of cancer 18 22692073
2014 Response to first-line chemotherapy in patients with non-small cell lung cancer according to RRM1 expression. PloS one 17 24647522
2023 RRM1 is mediated by histone acetylation through gemcitabine resistance and contributes to invasiveness and ECM remodeling in pancreatic cancer. International journal of oncology 16 36866763
2017 Clinical significance of UGT1A1 polymorphism and expression of ERCC1, BRCA1, TYMS, RRM1, TUBB3, STMN1 and TOP2A in gastric cancer. BMC gastroenterology 16 28056823
2015 ERCC1 and RRM1 as a predictive parameter for non-small cell lung, ovarian or pancreas cancer treated with cisplatin and/or gemcitabine. Contemporary oncology (Poznan, Poland) 16 26557761
1995 Human gene for the large subunit of ribonucleotide reductase (RRM1): functional analysis of the promoter. Genomics 16 7557993
2018 Oligomeric transition and dynamics of RNA binding by the HuR RRM1 domain in solution. Journal of biomolecular NMR 15 30535889
2015 Association of GSTP1 and RRM1 Polymorphisms with the Response and Toxicity of Gemcitabine-cisplatin Combination Chemotherapy in Chinese Patients with Non-small Cell Lung Cancer. Asian Pacific journal of cancer prevention : APJCP 15 26028097
2013 mRNA expression and clinical significance of ERCC1, BRCA1, RRM1, TYMS and TUBB3 in postoperative patients with non-small cell lung cancer. Asian Pacific journal of cancer prevention : APJCP 15 23803067
2022 RRM1 variants cause a mitochondrial DNA maintenance disorder via impaired de novo nucleotide synthesis. The Journal of clinical investigation 14 35617047
2020 Individualized chemotherapy guided by the expression of ERCC1, RRM1, TUBB3, TYMS and TOP2A genes versus classic chemotherapy in the treatment of breast cancer: A comparative effectiveness study. Oncology letters 14 33240427
2019 RRM1 predicts clinical outcome of high-and intermediate-risk non-muscle-invasive bladder cancer patients treated with intravesical gemcitabine monotherapy. BMC urology 14 31340801
2016 Structure, Dynamics, and Interaction of p54(nrb)/NonO RRM1 with 5' Splice Site RNA Sequence. Biochemistry 14 27064654
2015 The relationship between RRM1 gene polymorphisms and effectiveness of gemcitabine-based first-line chemotherapy in advanced NSCLC patient. Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 13 26650486
2013 The RRM1 domain of the poly(A)-binding protein from Saccharomyces cerevisiae is critical to control of mRNA deadenylation. Molecular genetics and genomics : MGG 13 23793387
2013 Gene aberrations of RRM1 and RRM2B and outcome of advanced breast cancer after treatment with docetaxel with or without gemcitabine. BMC cancer 13 24215511
2015 Non-enzymatic action of RRM1 protein upregulates PTEN leading to inhibition of colorectal cancer metastasis. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 12 25638032
2014 RRM1 maintains centrosomal integrity via CHK1 and CDK1 signaling during replication stress. Cancer letters 12 24434653
2021 Effects of rrm1 on NNV Resistance Revealed by RNA-seq and Gene Editing. Marine biotechnology (New York, N.Y.) 11 34735644
2015 RRM1 expression is associated with the outcome of gemcitabine-based treatment of non-small cell lung cancer patients--a short report. Cellular oncology (Dordrecht, Netherlands) 11 26092210
1994 Human R1 subunit of ribonucleotide reductase (RRM1): 5' flanking region of the gene. Genomics 11 8188248
2018 RRM1 expression and the clinicopathological characteristics of patients with non-small cell lung cancer treated with gemcitabine. OncoTargets and therapy 10 30237724
2014 The identification of novel 5'-amino gemcitabine analogs as potent RRM1 inhibitors. Bioorganic & medicinal chemistry 10 24588962
2014 Multiplex real-time PCR for RRM1, XRCC1, TUBB3 and TS mRNA for prediction of response of non-small cell lung cancer to chemoradiotherapy. Asian Pacific journal of cancer prevention : APJCP 10 24935362
2014 Expression of ERCC1, RRM1 and LRP in non-small cell lung cancers and their influence on chemotherapeutic efficacy of gemcitabine concomitant with nedaplatin. Asian Pacific journal of cancer prevention : APJCP 10 25227833
2012 Individualized Chemotherapy in Advanced NSCLC Patients Based on mRNA Levels of BRCA1 and RRM1. Chinese journal of cancer research = Chung-kuo yen cheng yen chiu 10 23359225
2021 Knockdown of RRM1 with Adenoviral shRNA Vectors to Inhibit Tumor Cell Viability and Increase Chemotherapeutic Sensitivity to Gemcitabine in Bladder Cancer Cells. International journal of molecular sciences 9 33921102
2019 WGS-based telomere length analysis in Dutch family trios implicates stronger maternal inheritance and a role for RRM1 gene. Scientific reports 9 31822713
2018 DNA Binding Induces a Nanomechanical Switch in the RRM1 Domain of TDP-43. The journal of physical chemistry letters 9 29924934
2017 Expression of ERCC1, RRM1, TUBB3 in correlation with apoptosis repressor ARC, DNA mismatch repair proteins and p53 in liver metastasis of colorectal cancer. International journal of molecular medicine 9 28949378
2016 A randomized phase II trial of ERCC1 and RRM1 mRNA expression-based chemotherapy versus docetaxel/carboplatin in advanced non-small cell lung cancer. Cancer chemotherapy and pharmacology 9 26811178
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
2016 RRM1 *151A>T, RRM1 -756T>C, and RRM1 -585T>Gis associated with increased susceptibility of lung cancer in Chinese patients. Cancer medicine 8 27335251
2011 Production and characterization of a novel protease from Bacillus sp. RRM1 under solid state fermentation. Journal of microbiology and biotechnology 8 21715970
2024 Loss of Diphthamide Increases DNA Replication Stress in Mammalian Cells by Modulating the Translation of RRM1. ACS central science 7 39463834
2023 A missense mutation in RRM1 contributes to animal tameness. Science advances 7 37352351
2016 RRM1, RRM2 and ERCC2 Gene Polymorphisms in Coronary Artery Disease. In vivo (Athens, Greece) 7 27566080
2014 Predictive role of RRM1 and BRCA1 mRNA expression on the clinical outcome of advanced non-small cell lung cancer. Genetics and molecular research : GMR 7 25078585
2024 RRM1 promotes homologous recombination and radio/chemo-sensitivity via enhancing USP11 and E2F1-mediated RAD51AP1 transcription. Cell death discovery 6 39695160
2021 RRM1 and ERCC1 as biomarkers in patients with locally advanced and metastatic malignant pleural mesothelioma treated with continuous infusion of low-dose gemcitabine plus cisplatin. BMC cancer 6 34353292
2023 Nicotine promotes epithelial to mesenchymal transition and gemcitabine resistance via hENT1/RRM1 signalling in pancreatic cancer and chemosensitizing effects of Embelin-a naturally occurring benzoquinone. The Science of the total environment 5 38163613
2022 Platycodon D-induced A549 Cell Apoptosis through RRM1-Regulated p53/VEGF/ MMP2 Pathway. Anti-cancer agents in medicinal chemistry 5 35088678
2022 Association between TOP2A, RRM1, HER2, ERCC1 expression and response to chemotherapy in patients with non-muscle invasive bladder cancer. Heliyon 5 35711974
2022 Allosteric mechanism for SL RNA recognition by polypyrimidine tract binding protein RRM1: An atomistic MD simulation and network-based study. International journal of biological macromolecules 5 36058398
2022 Personalized Prescription of Chemotherapy Based on Assessment of mRNA Expression of BRCA1, RRM1, ERCC1, TOP1, TOP2α, TUBβ3, TYMS, and GSTP1 Genes in Tumors Compared to Standard Chemotherapy in the Treatment of Non-Small-Cell Lung Cancer. Journal of personalized medicine 5 36294786
2015 (1)H, (15)N and (13)C chemical shift assignments of the La motif and RRM1 from human LARP6. Biomolecular NMR assignments 5 25896032
2015 Expression of TS, RRM1, ERCC1, TUBB3 and STMN1 Genes in Tissues of Non-small Cell Lung Cancer and its Significance in Guiding Postoperative Adjuvant Chemotherapy. Asian Pacific journal of cancer prevention : APJCP 5 25921119

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