Affinage

RRM2B

Ribonucleoside-diphosphate reductase subunit M2 B · UniProt Q7LG56

Length
351 aa
Mass
40.7 kDa
Annotated
2026-06-10
95 papers in source corpus 30 papers cited in narrative 30 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

RRM2B (p53R2) encodes the small subunit of a ribonucleotide reductase (RNR) that supplies deoxyribonucleotides for genome maintenance in resting and non-dividing cells, the function in which it is most critical (PMID:11517226, PMID:12858174, PMID:17416930). It harbors an iron-tyrosyl free radical center and pairs with the catalytic R1 subunit (RRM1) through a C-terminal heptapeptide—the same binding site used by the cycling-cell subunit R2 but with lower R1 affinity—to form an active holoenzyme (PMID:11517226, PMID:14729598, PMID:16376858). Crystallographic and spectroscopic studies define a biferrous active site whose iron assimilation and radical-transfer properties differ from R2, accounting for its distinct kinetic and inhibitor sensitivities (PMID:19728742, PMID:17115699). In quiescent cells the R1–p53R2 complex drives a complete de novo dNTP synthesis pathway dedicated chiefly to mitochondrial DNA replication and DNA repair (PMID:17416930, PMID:22847445); its loss selectively depletes dATP and dGTP, an asymmetry attributable to SAMHD1-mediated degradation and lower RNR output of these nucleotides (PMID:40244665). Expression is induced both by p53 and, independently, by FOXO3 binding the RRM2B promoter (PMID:24947616), while the protein is acutely regulated post-translationally: ATM phosphorylates Ser72 to block MDM2-dependent ubiquitination and stabilize it after genotoxic stress (PMID:19015526), CK2 phosphorylates Ser20 to activate dNTP production supporting CtIP-dependent homologous recombination (PMID:37620447), and caspase-3/8 cleavage at Asp342 removes the R1-binding heptapeptide to inactivate the enzyme during apoptosis (PMID:25878246). Beyond nucleotide supply, p53R2 has intrinsic catalase-like antioxidant activity dependent on specific tyrosines, lowers ROS, and preserves mitochondrial membrane potential and function, acting with PYCR1/PYCR2 and stimulating mitochondrial TrxR2 (PMID:16488986, PMID:21640705, PMID:26733354, PMID:27866984). It is reduced more efficiently by the glutathione-glutaredoxin system than by thioredoxin (PMID:31266802). Loss-of-function and dominant C-terminal RRM2B mutations cause human mitochondrial DNA depletion syndromes, progressive external ophthalmoplegia, and Kearns-Sayre syndrome through impaired R1/p53R2 RNR assembly and mtDNA maintenance (PMID:17486094, PMID:19664747, PMID:21378381, PMID:22847445), and in mice Rrm2b loss produces chromosomal instability that activates ATM–IKK–NF-κB–IL-6–STAT3 signaling driving inflammation-associated disease (PMID:23643536).

Mechanistic history

Synthesis pass · year-by-year structured walk · 30 steps
  1. 2001 High

    Established that p53R2 is a genuine RNR small subunit, resolving whether the p53-inducible protein had catalytic function rather than merely regulatory activity.

    Evidence In vitro reconstitution of RNR activity with purified recombinant p53R2 and R1, EPR detection of an iron-tyrosyl radical, and reporter assays in serum-starved fibroblasts

    PMID:11517226

    Open questions at the time
    • Did not define affinity differences from R2
    • In vivo requirement not yet shown
  2. 2001 Medium

    Connected p53R2 to the DNA damage response by showing damage-induced nuclear accumulation and its requirement for RNR activity opposing apoptosis.

    Evidence Nuclear/cytoplasmic fractionation, RNR activity assay, and site-directed mutagenesis in gamma-irradiated cancer cells

    PMID:11719458

    Open questions at the time
    • Mechanism of nuclear import undefined
    • Single cell-line mutation analysis
  3. 2003 High

    Demonstrated in vivo that p53R2 is required for dNTP supply and genome stability in resting cells, linking its loss to mutation and organismal lethality.

    Evidence Rrm2b-null mice with dNTP pool, mutation frequency, TUNEL and p53 target readouts

    PMID:12858174

    Open questions at the time
    • Mitochondrial versus nuclear contribution not separated at this stage
  4. 2003 Medium

    Placed p53R2 in a p53-dependent regulatory circuit by showing p53 sequesters it until DNA damage triggers dissociation and nuclear translocation with R1.

    Evidence Co-immunoprecipitation, confocal colocalization, and in vivo RNR assay after UV in WT versus mutant p53 cells

    PMID:12615712

    Open questions at the time
    • Direct binding interface with p53 not mapped
    • Single lab, reciprocal but not structural
  5. 2004 High

    Quantified the biochemical distinction between p53R2 and R2, showing shared R1-binding heptapeptide but lower affinity, lower activity, and distinct iron-chelator/hydroxyurea sensitivities.

    Evidence In vitro CDP reduction, heptapeptide competition, atomic absorption, EPR, and inhibitor studies

    PMID:14729598

    Open questions at the time
    • Structural basis of affinity difference not resolved here
  6. 2005 High

    Confirmed in a eukaryotic expression system that R2 and p53R2 compete for the same R1 site and that allosteric ATP/dATP regulation is subunit-independent.

    Evidence Reconstitution of purified eukaryotic subunits with CDP reduction, heptapeptide competition, and allosteric assays

    PMID:16376858

    Open questions at the time
    • In-cell competition dynamics not addressed
  7. 2006 High

    Revealed an unexpected antioxidant function: p53R2 has catalase-like activity that lowers ROS and protects mitochondrial membrane potential, mapped to specific tyrosines.

    Evidence Cell-free ROS and catalase assays with purified protein, mitochondrial membrane potential assay, and tyrosine mutagenesis

    PMID:16488986

    Open questions at the time
    • Relationship between catalase and RNR activities mechanistically entangled via shared tyrosines
  8. 2006 High

    Characterized the diiron active site spectroscopically, defining a biferrous center with high Fe(II) affinity distinct from R2.

    Evidence CD, MCD, VTVH-MCD, EPR, and Fe(II) titration

    PMID:17115699

    Open questions at the time
    • Functional consequence of high Fe affinity for in vivo regulation inferred not tested
  9. 2007 High

    Identified mitochondrial DNA maintenance as a primary in vivo role, establishing RRM2B mutations as a cause of human mtDNA depletion.

    Evidence RRM2B sequencing in patients and mtDNA copy-number quantification in human tissues and Rrm2b-/- mice

    PMID:17486094

    Open questions at the time
    • Cell-type specificity of mtDNA depletion not fully resolved
  10. 2007 High

    Showed flux through the R1-p53R2 complex constitutes a complete de novo dNTP pathway in quiescent cells serving mtDNA replication.

    Evidence Isotope tracer incorporation in confluent quiescent human fibroblasts with dNTP pool and export measurement

    PMID:17416930

    Open questions at the time
    • Salvage pathway interplay not quantified
  11. 2007 Medium

    Linked p53R2 to cell cycle arrest machinery via a defined interaction with p21 modulating p21 nuclear accumulation during repair.

    Evidence Co-IP, mammalian two-hybrid domain mapping, and confocal microscopy with RNR assay after UV

    PMID:17210678

    Open questions at the time
    • Functional significance for arrest not genetically tested
    • Single lab
  12. 2008 High

    Defined the ATM-MDM2 axis controlling p53R2 stability, explaining how genotoxic stress rapidly stabilizes the protein.

    Evidence ATM Co-IP, S72A mutagenesis, ubiquitination and protein stability assays with ATM inhibitor

    PMID:19015526

    Open questions at the time
    • Structural basis of phosphorylation-protected MDM2 interface unknown
  13. 2009 Medium

    Mapped the molecular consequence of a dominant C-terminal truncation, linking loss of R1 binding to autosomal-dominant PEO with mtDNA deletions.

    Evidence Linkage mapping, RRM2B sequencing, NMD and truncation analysis, family segregation

    PMID:19664747

    Open questions at the time
    • Dominant-negative versus gain-of-function not biochemically distinguished
  14. 2009 High

    Determined the human p53R2 crystal structure, explaining its distinct iron handling and radical transfer relative to R2.

    Evidence X-ray crystallography at 2.6 Å

    PMID:19728742

    Open questions at the time
    • Holoenzyme R1-p53R2 complex structure not determined
  15. 2009 High

    Defined the mechanism by which gemcitabine diphosphate inactivates the alpha/p53R2 complex through covalent active-site modification.

    Evidence Radiolabeled F2CDP incorporation, SDS-PAGE crosslinking, and alpha-subunit active-site mutagenesis

    PMID:19899807

    Open questions at the time
    • In-cell relevance to gemcitabine therapy not addressed
  16. 2009 Medium

    Uncovered a non-canonical role linking p53R2 to MEK-ERK signaling and tumor cell invasion through a direct MEK2 interaction.

    Evidence Co-IP with domain mapping, immunofluorescence, siRNA/overexpression with invasion and anchorage-independent growth assays

    PMID:19398949

    Open questions at the time
    • Whether this is RNR-dependent unclear
    • Single lab
  17. 2011 Medium

    Showed that defective R1/p53R2 RNR holoenzyme assembly underlies disease, even when p53R2 protein levels appear normal.

    Evidence BN-PAGE of RNR complex with Western blot and sequencing in Kearns-Sayre patient cells

    PMID:21378381

    Open questions at the time
    • Structural defect in assembly not resolved
  18. 2011 High

    Provided mechanistic proof in patient cells that p53R2-dependent ribonucleotide reduction is specifically needed for mtDNA maintenance and repair in quiescence, rescuable by deoxynucleosides.

    Evidence Ethidium bromide depletion/recovery, FADU repair assay, γH2AX, dNTP pools, and deoxynucleoside supplementation

    PMID:22847445

    Open questions at the time
    • Therapeutic durability of deoxynucleoside rescue not assessed
  19. 2012 High

    Established a causal inflammatory pathway whereby Rrm2b loss-driven chromosomal instability activates ATM-IKK-NF-κB-IL-6-STAT3 signaling.

    Evidence Rrm2b knockout cytogenetics, phosphorylation assays, IL-6 ELISA, IL-6 genetic rescue, and lifespan analysis

    PMID:23643536

    Open questions at the time
    • Direct sensing event linking instability to ATM not detailed
  20. 2012 Medium

    Demonstrated that p53R2 supports mitochondrial bioenergetics and homeostasis beyond dNTP supply.

    Evidence siRNA/overexpression with mtDNA quantification, ATP synthesis, COX activity, membrane potential and ROS assays

    PMID:21640705

    Open questions at the time
    • No in vivo validation
    • Secondary versus direct effects unresolved
  21. 2012 Medium

    Linked p53R2 to senescence control, showing its silencing triggers premature senescence via ROS and p38MAPK/p53.

    Evidence siRNA in IMR90 fibroblasts and Rrm2b-/- MEFs with senescence, ROS, membrane potential assays and p38 inhibition

    PMID:23139867

    Open questions at the time
    • Single lab
    • Causality of ROS versus dNTP depletion not separated
  22. 2012 Medium

    Showed MEK2 directly regulates RNR activity through p53R2, integrating mitogenic signaling with nucleotide production.

    Evidence Co-IP domain mapping, MEK2 siRNA/inhibitor, and RNR activity assays after serum or ionizing radiation

    PMID:22895183

    Open questions at the time
    • Mechanism by which MEK2 binding alters RNR catalysis unknown
  23. 2014 Medium

    Identified FOXO3 as a p53-independent transcriptional activator of RRM2B, broadening its regulatory inputs.

    Evidence ChIP, promoter luciferase, FOXO3 overexpression with RT-PCR and Western blot

    PMID:24947616

    Open questions at the time
    • Physiological conditions invoking FOXO3 regulation not defined
  24. 2015 High

    Defined how apoptosis inactivates p53R2 through caspase-3/8 cleavage at Asp342 removing the R1-binding heptapeptide.

    Evidence In vitro cleavage with purified caspases, cleavage-site mapping, and caspase siRNA in apoptotic cells

    PMID:25878246

    Open questions at the time
    • Physiological impact of dNTP loss during apoptosis not quantified
  25. 2016 Medium

    Identified PYCR1/PYCR2 as functional partners required for p53R2-mediated antioxidant protection.

    Evidence Flag-RRM2B complex purification with mass spectrometry and PYCR1/2 shRNA with oxidative stress assays

    PMID:26733354

    Open questions at the time
    • Biochemical mechanism of the collaboration unresolved
  26. 2016 Medium

    Showed p53R2 interacts with and stimulates mitochondrial TrxR2, connecting it to the mitochondrial antioxidant system.

    Evidence Co-IP, in vitro TrxR activity assay, siRNA/overexpression, and UV stimulation

    PMID:27866984

    Open questions at the time
    • Structural basis of TrxR2 stimulation unknown
    • Single lab
  27. 2019 High

    Defined the preferred electron-donor system for R1-p53R2, showing GSH-glutaredoxin is more efficient than thioredoxin.

    Evidence In vitro RNR activity kinetics comparing Grx and Trx1 systems with GSH reductase dependency

    PMID:31266802

    Open questions at the time
    • In-cell reductant usage not measured
  28. 2021 Low

    Proposed S-glutathionylation as a redox regulatory modification of p53R2 reversed by Grx1.

    Evidence In vitro S-glutathionylation and Grx1 deglutathionylation with anti-glutathione Western blot

    PMID:34599703

    Open questions at the time
    • No functional activity assay after glutathionylation
    • In vitro only, single method
  29. 2023 Medium

    Defined CK2-mediated Ser20 phosphorylation as an activating switch coupling p53R2 dNTP supply to CtIP stability and homologous recombination, with therapeutic implications for PARP inhibitors.

    Evidence CK2 kinase assay, phospho-specific antibody, p53R2 siRNA, CtIP ubiquitination, HR reporter, and PARP inhibitor sensitivity in vitro and in vivo

    PMID:37620447

    Open questions at the time
    • Direct structural effect of Ser20 phosphorylation on RNR undefined
    • Single lab
  30. 2025 Medium

    Explained why RRM2B loss selectively depletes dATP and dGTP, attributing the asymmetry to SAMHD1 degradation preference and lower RNR output.

    Evidence Rrm2b knockout mouse dNTP pool measurement in non-dividing tissues with SAMHD1 substrate analysis

    PMID:40244665

    Open questions at the time
    • Direct in vivo demonstration of SAMHD1 epistasis not performed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple post-translational and protein-interaction inputs (ATM/Ser72, CK2/Ser20, MEK2, p21, redox modifications) are integrated to tune p53R2 activity in specific physiological contexts, and the structure of the assembled R1-p53R2 holoenzyme, remain unresolved.
  • No holoenzyme structure
  • Integration of competing regulatory signals not modeled
  • In-cell electron-donor and redox regulation not directly measured

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140098 catalytic activity, acting on RNA 4 GO:0016491 oxidoreductase activity 3 GO:0016209 antioxidant activity 2 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005739 mitochondrion 3 GO:0005634 nucleus 2 GO:0005829 cytosol 2
Pathway
R-HSA-1643685 Disease 4 R-HSA-73894 DNA Repair 4 R-HSA-69306 DNA Replication 3 R-HSA-1430728 Metabolism 2 R-HSA-8953897 Cellular responses to stimuli 2
Partners
ATMCDKN1AMAP2K2PYCR1PYCR2RRM1TP53TXNRD2
Complex memberships
Ribonucleotide reductase (R1/p53R2 holoenzyme)

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 Recombinant human and mouse p53R2 proteins contain an iron-tyrosyl free radical center and form an active ribonucleotide reductase (RNR) complex with the R1 protein, demonstrating that R1 is the functional partner of p53R2 and that the R1-p53R2 complex can supply resting cells with deoxyribonucleotides for DNA repair. In vitro reconstitution of RNR activity with purified recombinant proteins; EPR spectroscopy to detect iron-tyrosyl radical; UV irradiation of serum-starved G0/G1 mouse fibroblasts with R1 promoter-luciferase reporter The Journal of biological chemistry High 11517226
2001 p53R2 protein accumulates in the nucleus after DNA damage (gamma-irradiation), whereas R2 remains cytoplasmic; nuclear accumulation of p53R2 correlates with elevated RNR-dependent DNA synthesis activity after DNA damage. A point mutation in p53R2 in the HCT116 cancer cell line abolishes RNR activity, leading to enhanced p53AIP1-mediated apoptosis. Western blot of nuclear/cytoplasmic fractions; RNR activity assay; site-directed mutagenesis; gamma-irradiation of cells Cancer research Medium 11719458
2003 Rrm2b-null mice show severe dNTP pool attenuation in mouse embryonic fibroblasts under oxidative stress, increased spontaneous mutation frequency in kidneys, p53 activation, and early death from renal failure, establishing that p53R2 is required in vivo for dNTP supply for DNA repair in resting cells. Rrm2b knockout mouse generation; dNTP pool measurement; TUNEL staining; spontaneous mutation assay; p53 target gene transcription analysis Nature genetics High 12858174
2003 Wild-type p53 directly interacts with both p53R2 and hRRM2 subunits (but not hRRM1) in co-immunoprecipitation experiments. After UV irradiation, p53R2 and hRRM2 dissociate from p53 and translocate with hRRM1 to the nucleus, where increased RNR activity is detected. This nuclear translocation and p53 dissociation are deficient in cells expressing mutant p53. Co-immunoprecipitation; confocal microscopy for colocalization; in vivo RNR activity assay; UV irradiation Cancer research Medium 12615712
2004 Purified recombinant p53R2 forms active RNR with hRRM1 via a C-terminal heptapeptide binding site shared with hRRM2, but with 4.76-fold lower binding affinity for hRRM1 than hRRM2. p53R2-containing RNR has ~20–50% lower kinetic activity than hRRM2-containing RNR. p53R2 is 158-fold more susceptible to the iron chelator deferoxamine mesylate than hRRM2, whereas it is 2.5-fold less sensitive to hydroxyurea; the iron center and tyrosyl radical are required for RNR activity. In vitro [3H]CDP reduction assay; synthetic heptapeptide competition assay; atomic absorption spectrometry for iron content; EPR for tyrosyl radical; deferoxamine and hydroxyurea inhibition studies Cancer research High 14729598
2007 Loss-of-function mutations in RRM2B (nonsense, missense, splice-site, in-frame deletions) cause severe mitochondrial DNA (mtDNA) depletion in humans, and Rrm2b-/- mice show severe mtDNA depletion in multiple tissues, demonstrating that p53R2 is required for dNTP supply for mtDNA synthesis. RRM2B sequencing in human patients; Southern blot/quantitative PCR for mtDNA copy number in human tissues and Rrm2b-/- mouse tissues Nature genetics High 17486094
2007 In quiescent human fibroblasts lacking R2, the R1-p53R2 complex supports a complete de novo deoxyribonucleotide synthesis pathway (including thymidylate synthesis), with the primary function of providing dNTPs for mitochondrial DNA replication rather than nuclear DNA synthesis. Isotope incorporation with [5-3H]cytidine, [6-3H]deoxycytidine, [CH3-3H]thymidine in confluent quiescent human fibroblasts; measurement of dNTP pools and nucleoside export The Journal of biological chemistry High 17416930
2007 p53R2 physically interacts with p21 in vivo; the N-terminal region (aa 1–113) of p53R2 interacts with the N-terminal region (aa 1–93) of p21. In response to UV, p53R2 dissociates from p21, facilitates nuclear accumulation of p21, and RNR activity increases, suggesting p53R2 cooperates with p21 during G1 DNA repair arrest. Co-immunoprecipitation; mammalian two-hybrid assay; confocal microscopy; UV irradiation; RNR activity assay Cancer research Medium 17210678
2008 ATM phosphorylates p53R2 at Ser72 within 30 minutes of genotoxic stress, and p53R2 and its partner RRM1 are associated with ATM in vivo. Ser72 phosphorylation stabilizes p53R2 by preventing MDM2-mediated ubiquitination and degradation; the S72A mutant shows hyperubiquitination, reduced stability, and impaired DNA damage resistance. In vivo co-immunoprecipitation of p53R2/RRM1 with ATM; site-directed mutagenesis (S72A); ubiquitination assay; Western blot for protein stability; ATM kinase inhibitor treatment Proceedings of the National Academy of Sciences of the United States of America High 19015526
2009 A heterozygous truncating mutation in RRM2B (p.R327X) removes 25 highly conserved C-terminal amino acids essential for interaction with the R1 subunit of ribonucleotide reductase, causing autosomal-dominant progressive external ophthalmoplegia with multiple mtDNA deletions, consistent with a dominant-negative or gain-of-function mechanism. Genetic linkage mapping; RRM2B sequencing; nonsense-mediated decay analysis; protein truncation assessment; family segregation analysis American journal of human genetics Medium 19664747
2009 Gemcitabine 5'-diphosphate (F2CDP) is a substoichiometric inactivator of the human RNR alpha/p53R2 (beta') complex; inactivation results in covalent attachment of ~0.5 equiv sugar to alpha subunit and release of cytosine, with cross-linking observed by SDS-PAGE. Active site mutants (C444S/A, C218S/A, E431Q/D) do not bind the sugar label, establishing that inactivation requires the catalytic active site of the alpha (R1) subunit. In vitro [1'-3H]-F2CDP and [5-3H]-F2CDP radiolabel incorporation; SDS-PAGE; size exclusion chromatography; active site mutagenesis of alpha subunit; Sephadex G-50 reisolation Biochemistry High 19899807
2009 The 2.6 Å X-ray crystal structure of human p53R2 reveals monomers with mono- and binuclear iron occupancy; pronounced structural differences at three regions from hRRM2 explain differences in iron assimilation, mobility/accessibility of the radical iron center, and radical transfer pathways between the two enzymes. X-ray crystallography at 2.6 Å resolution Biochemistry High 19728742
2009 p53R2 interacts physically with MEK2 (ERK kinase 2) in co-immunoprecipitation and immunofluorescence assays; the p53R2 segment aa 161–206 is critical for this interaction. p53R2 negatively modulates serum-induced MEK-ERK signaling: knockdown of p53R2 augments MEK1/2 and ERK1/2 phosphorylation, while overexpression attenuates it. MEK2 is required for p53R2 knockdown-enhanced invasion and anchorage-independent growth. Co-immunoprecipitation; immunofluorescence; siRNA knockdown; overexpression; phosphorylation assay by Western blot; Matrigel invasion assay Oncogene Medium 19398949
2011 In quiescent (but not cycling) patient fibroblasts carrying a lethal missense mutation in p53R2, mtDNA synthesis is defective after ethidium bromide depletion and recovery, and UV-induced DNA repair is impaired (delayed dsDNA recovery, prolonged γH2AX phosphorylation). Supplementation with deoxynucleosides restored dNTP pools, mtDNA synthesis, and DNA repair, confirming that p53R2-dependent ribonucleotide reduction is specifically required for mtDNA maintenance and DNA repair in quiescent cells. Ethidium bromide depletion/recovery assay for mtDNA; fluorometric analysis of DNA unwinding (FADU) for repair; γH2AX Western blot; dNTP pool measurement; deoxynucleoside supplementation Proceedings of the National Academy of Sciences of the United States of America High 22847445
2011 In Kearns-Sayre syndrome caused by two novel RRM2B missense mutations, Blue-native PAGE demonstrates reduced heterotetrameric R1/p53R2 RNR levels despite normal steady-state p53R2 on Western blot, establishing that defective R1/p53R2 RNR assembly is a disease mechanism. Western blot; Blue-native polyacrylamide gel electrophoresis (BN-PAGE); RRM2B DNA sequencing Journal of medical genetics Medium 21378381
2006 Purified recombinant p53R2 has catalase activity (breaks down H2O2) and reduces intracellular ROS while protecting mitochondrial membrane potential against oxidative stress, in contrast to hRRM2 which increases ROS. Site-directed mutagenesis identified Y331, Y285, Y49, and Y241 as critical residues for antioxidant activity; these mutations also negatively correlated with RNR enzymatic activity. Cell-free ROS assay with carboxy-H2DCFDA; catalase activity assay with purified protein; mitochondrial membrane potential assay; site-directed mutagenesis; overexpression in cells Cancer research High 16488986
2012 Rrm2b gene loss causes severe numerical and structural chromosomal abnormalities leading to ATM activation, which induces IKKγ/NEMO phosphorylation at pSer85, activating IKK and NF-κB, resulting in sustained IL-6 expression and constitutive STAT3 activation. Genetic ablation of IL-6 suppressed STAT3 and delayed disease onset in Rrm2b-/- mice, establishing this pathway as causal for inflammation-associated tumorigenesis. Rrm2b knockout mouse; cytogenetic analysis; ATM and IKK phosphorylation assays; NF-κB and STAT3 activation; IL-6 ELISA; IL-6 genetic knockout cross; mouse lifespan analysis Cell reports High 23643536
2012 p53R2 overexpression reduces intracellular ROS, maintains mtDNA content, and supports cytochrome c oxidase activity and ATP synthesis; siRNA knockdown of p53R2 reduces mtDNA content, impairs mitochondrial function (ATP synthesis, COX activity, membrane potential), and increases ROS, establishing a role for p53R2 in mitochondrial homeostasis beyond dNTP synthesis. siRNA knockdown; overexpression; mtDNA quantification by PCR; ATP synthesis assay; cytochrome c oxidase activity assay; mitochondrial membrane potential assay; ROS measurement Biochemical and biophysical research communications Medium 21640705
2012 RRM2B is highly induced in a p53-dependent manner during senescence; silencing RRM2B increases ROS, induces mitochondrial membrane depolarization, and causes premature senescence in a p38MAPK- and p53-dependent manner. Senescence is accelerated in Rrm2b-deficient MEFs. RRM2B siRNA knockdown in IMR90 fibroblasts; senescence assays; ROS measurement; mitochondrial membrane potential assay; p38MAPK inhibitor treatment; Rrm2b-/- MEFs Scientific reports Medium 23139867
2012 MEK2 regulates RNR activity through a direct interaction with p53R2; the MEK2 segment aa 65–171 is critical for p53R2 binding. Inhibition of MEK2 (by siRNA or pharmacological inhibitor) dramatically decreases serum-stimulated RNR activity, and p53R2 siRNA (but not R2 siRNA) inhibits this activity, indicating specific MEK2-p53R2 regulation. Ionizing radiation activates MEK1/2 and increases RNR activity, which is attenuated by MEK2 or p53R2 siRNA. Co-immunoprecipitation; MEK2 siRNA; MEK inhibitor; RNR activity assay; ionizing radiation Cell cycle Medium 22895183
2016 PYCR1 and PYCR2 were identified by mass spectrometry as components of RRM2B complexes. Silencing of both PYCR1 and PYCR2 abolished the antioxidant activity of RRM2B overexpression, demonstrating a functional collaboration between RRM2B, PYCR1, and PYCR2 in protecting cells from oxidative stress. Large-scale Flag-tagged RRM2B complex purification; mass spectrometry; shRNA silencing of PYCR1/PYCR2; oxidative stress assays; mitochondrial network analysis Scientific reports Medium 26733354
2014 FOXO3 directly binds to the RRM2B promoter and transcriptionally activates RRM2B expression at RNA and protein levels independently of p53, establishing FOXO3 as a novel p53-independent regulator of RRM2B. Chromatin immunoprecipitation (ChIP); promoter luciferase assay; FOXO3 overexpression; Western blot and RT-PCR; cancer cell proliferation assay Oncotarget Medium 24947616
2019 The glutathione-glutaredoxin (GSH-Grx) system is 4–6 times more catalytically efficient than the thioredoxin-1 (Trx1) system as electron donor for mammalian R1-p53R2 RNR, with Vmax for Grx strongly dependent on GSH concentration. GSH reductase is essential for this reaction. This identifies the C-terminal swinging-arm dithiol/disulfide of R1 as having a crucial catalytic role in reduction for p53R2-containing RNR. In vitro RNR activity assay with mouse R1-p53R2; comparison of Grx vs Trx1 electron donor systems; Vmax/Km kinetic measurements; GSH reductase dependency assay The Journal of biological chemistry High 31266802
2016 p53R2 interacts with mitochondrial thioredoxin reductase 2 (TrxR2) and stimulates TrxR enzymatic activity in vitro. TrxR2 activity is significantly lower in p53R2 knockdown cells and increased upon p53R2 overexpression in a p53-independent manner; p53R2 knockdown also suppresses UV-induced TrxR activity. Co-immunoprecipitation; in vitro TrxR activity assay; siRNA knockdown; overexpression; UV irradiation Biochemical and biophysical research communications Medium 27866984
2015 During apoptosis, p53R2 is cleaved in a caspase-dependent manner (by caspase-3 and caspase-8) between Asp342 and Asn343, releasing a C-terminal 9-residue peptide containing the conserved heptapeptide essential for R1 binding, rendering the cleaved p53R2 inactive. R1 is not degraded during apoptosis. Cell treatment with Bcr-Abl inhibitors and TNF-α/cycloheximide; Western blot for cleavage products; in vitro cleavage by purified caspase-3 and -8; caspase-specific siRNA knockdown; cleavage site mapping The Journal of biological chemistry High 25878246
2006 Circular dichroism and magnetic circular dichroism spectroscopy of p53R2 revealed a biferrous active site with one five-coordinate and one four-coordinate iron weakly antiferromagnetically coupled through mu-1,3-carboxylate bridges; both human and mouse p53R2 have high Fe(II) affinity, distinct from mouse R2, potentially reflecting differences in regulation of enzymatic activity. Circular dichroism (CD); magnetic circular dichroism (MCD); variable-temperature variable-field MCD; EPR spectroscopy; Fe(II) titration for metal binding affinity Biochemistry High 17115699
2023 CK2 (casein kinase II) phosphorylates p53R2 at Ser20, activating RNR for dNTP production. Loss of p53R2 impairs homologous recombination (HR) repair by reducing CtIP levels through dNTP shortage-induced ubiquitination of CtIP. Pharmacologic inhibition of CK2-mediated p53R2 Ser20 phosphorylation compromises HR repair in BRCA1/2-WT cancer cells and sensitizes them to PARP inhibitors. CK2 kinase assay; phospho-specific antibody; siRNA depletion of p53R2; ubiquitination assay for CtIP; HR repair reporter assay; PARP inhibitor sensitivity assay in vitro and in vivo Oncogene Medium 37620447
2021 p53R2 (and R2) subunits of mammalian RNR can be S-glutathionylated in vitro, and the Grx1 system efficiently deglutathionylates the S-glutathionylated p53R2, suggesting S-glutathionylation as a redox regulatory mechanism for p53R2 activity. In vitro S-glutathionylation assay; Grx1-mediated deglutathionylation assay; Western blot with anti-glutathione antibody Molecular biology reports Low 34599703
2025 In Rrm2b knockout mouse tissues, RRM2B deficiency selectively depletes dATP and dGTP pools while dCTP and dTTP remain stable or increase. Mechanistically, this is attributed to preferred degradation of dATP and dGTP by the dNTPase SAMHD1 combined with lower RNR production rate of dATP. Rrm2b knockout mouse model; dNTP pool measurement in non-dividing tissues; SAMHD1 substrate preference analysis; comparison with hydroxyurea-treated controls Proceedings of the National Academy of Sciences of the United States of America Medium 40244665
2005 In vitro reconstitution using eukaryotically expressed and purified hRRM1, hRRM2, and p53R2 confirmed that both hRRM2 and p53R2 interact with hRRM1 to form functional RNR holoenzyme; hRRM2 and p53R2 share the same binding site on hRRM1 (competitive C-terminal heptapeptide), but hRRM1 has higher affinity for hRRM2 than p53R2. ATP and dATP allosteric regulation of hRRM1 is independent of which small subunit is present. Eukaryotic expression and purification of RNR subunits; [3H]CDP reduction assay; synthetic C-terminal heptapeptide competition assay; allosteric regulation assay with ATP/dATP Biochemical and biophysical research communications High 16376858

Source papers

Stage 0 corpus · 95 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion. Nature genetics 435 17486094
2001 Mammalian p53R2 protein forms an active ribonucleotide reductase in vitro with the R1 protein, which is expressed both in resting cells in response to DNA damage and in proliferating cells. The Journal of biological chemistry 169 11517226
2003 Impaired function of p53R2 in Rrm2b-null mice causes severe renal failure through attenuation of dNTP pools. Nature genetics 120 12858174
2001 p53R2-dependent pathway for DNA synthesis in a p53-regulated cell cycle checkpoint. Cancer research 116 11719458
2003 Wild-type p53 regulates human ribonucleotide reductase by protein-protein interaction with p53R2 as well as hRRM2 subunits. Cancer research 108 12615712
2012 Mammalian ribonucleotide reductase subunit p53R2 is required for mitochondrial DNA replication and DNA repair in quiescent cells. Proceedings of the National Academy of Sciences of the United States of America 101 22847445
2009 A heterozygous truncating mutation in RRM2B causes autosomal-dominant progressive external ophthalmoplegia with multiple mtDNA deletions. American journal of human genetics 93 19664747
2009 Mitochondrial neurogastrointestinal encephalopathy due to mutations in RRM2B. Archives of neurology 91 19667227
2004 In vitro characterization of enzymatic properties and inhibition of the p53R2 subunit of human ribonucleotide reductase. Cancer research 82 14729598
2007 p53R2-dependent ribonucleotide reduction provides deoxyribonucleotides in quiescent human fibroblasts in the absence of induced DNA damage. The Journal of biological chemistry 79 17416930
2003 The human ribonucleotide reductase subunit hRRM2 complements p53R2 in response to UV-induced DNA repair in cells with mutant p53. Cancer research 75 14583450
2008 Mitochondrial DNA depletion syndrome due to mutations in the RRM2B gene. Neuromuscular disorders : NMD 68 18504129
2016 PYCR1 and PYCR2 Interact and Collaborate with RRM2B to Protect Cells from Overt Oxidative Stress. Scientific reports 66 26733354
2012 Adults with RRM2B-related mitochondrial disease have distinct clinical and molecular characteristics. Brain : a journal of neurology 64 23107649
2008 ATM-mediated serine 72 phosphorylation stabilizes ribonucleotide reductase small subunit p53R2 protein against MDM2 to DNA damage. Proceedings of the National Academy of Sciences of the United States of America 55 19015526
2009 A novel homozygous RRM2B missense mutation in association with severe mtDNA depletion. Neuromuscular disorders : NMD 50 19138848
2007 Ribonucleotide reductase subunits M2 and p53R2 are potential biomarkers for metastasis of colon cancer. Clinical colorectal cancer 50 17311703
2006 Metastasis-suppressing potential of ribonucleotide reductase small subunit p53R2 in human cancer cells. Clinical cancer research : an official journal of the American Association for Cancer Research 46 17085643
2009 A novel mutation of the RRM2B gene in an infant with early fatal encephalomyopathy, central hypomyelination, and tubulopathy. Molecular genetics and metabolism 44 19616983
2009 Mechanism of inactivation of human ribonucleotide reductase with p53R2 by gemcitabine 5'-diphosphate. Biochemistry 44 19899807
2008 Impairment of the DNA repair and growth arrest pathways by p53R2 silencing enhances DNA damage-induced apoptosis in a p53-dependent manner in prostate cancer cells. Molecular cancer research : MCR 44 18505925
2008 p53-inducible ribonucleotide reductase (p53R2/RRM2B) is a DNA hypomethylation-independent decitabine gene target that correlates with clinical response in myelodysplastic syndrome/acute myelogenous leukemia. Cancer research 44 19010910
2011 p53R2 inhibits the proliferation of human cancer cells in association with cell-cycle arrest. Molecular cancer therapeutics 43 21216934
2014 The roles of p53R2 in cancer progression based on the new function of mutant p53 and cytoplasmic p21. Life sciences 42 24486301
2014 Akt and p53R2, partners that dictate the progression and invasiveness of cancer. DNA repair 41 25086499
2007 Ribonucleotide reductase small subunit p53R2 facilitates p21 induction of G1 arrest under UV irradiation. Cancer research 41 17210678
2008 Regulation of p53R2 and its role as potential target for cancer therapy. Cancer letters 40 18760875
2011 Kearns-Sayre syndrome caused by defective R1/p53R2 assembly. Journal of medical genetics 37 21378381
2005 The predictive value of p53, p53R2, and p21 for the effect of chemoradiation therapy on oesophageal squamous cell carcinoma. British journal of cancer 37 15655547
2004 Silencing of the p53R2 gene by RNA interference inhibits growth and enhances 5-fluorouracil sensitivity of oral cancer cells. Cancer letters 37 15890238
2009 2.6 A X-ray crystal structure of human p53R2, a p53-inducible ribonucleotide reductase . Biochemistry 36 19728742
2006 Transcriptional responses to ionizing radiation reveal that p53R2 protects against radiation-induced mutagenesis in human lymphoblastoid cells. Oncogene 35 16247478
2006 Structurally dependent redox property of ribonucleotide reductase subunit p53R2. Cancer research 34 16488986
2014 Tumor suppressor FOXO3 regulates ribonucleotide reductase subunit RRM2B and impacts on survival of cancer patients. Oncotarget 33 24947616
2012 RRM2B suppresses activation of the oxidative stress pathway and is up-regulated by p53 during senescence. Scientific reports 33 23139867
2011 Deoxyribonucleotide metabolism in cycling and resting human fibroblasts with a missense mutation in p53R2, a subunit of ribonucleotide reductase. The Journal of biological chemistry 31 21297166
2011 Exome sequencing identifies a novel missense variant in RRM2B associated with autosomal recessive progressive external ophthalmoplegia. Genome biology 30 21951382
2005 Rapid development of glomerular injury and renal failure in mice lacking p53R2. Pediatric nephrology (Berlin, Germany) 30 15723268
2003 Expression of p53R2, newly p53 target in oral normal epithelium, epithelial dysplasia and squamous cell carcinoma. Cancer letters 30 12565178
2009 Ribonucleotide reductase small subunit p53R2 suppresses MEK-ERK activity by binding to ERK kinase 2. Oncogene 27 19398949
2006 P53R2, p53 inducible ribonucleotide reductase gene, correlated with tumor progression of non-small cell lung cancer. Anticancer research 27 16619496
2002 Expression and mutation analyses of P53R2, a newly identified p53 target for DNA repair in human gastric carcinoma. International journal of cancer 27 11920641
2006 Disruption of the p53-p53r2 DNA repair system in ulcerative colitis contributes to colon tumorigenesis. International journal of cancer 26 16206288
2019 Glutathione-glutaredoxin is an efficient electron donor system for mammalian p53R2-R1-dependent ribonucleotide reductase. The Journal of biological chemistry 25 31266802
2012 Akt phosphorylation in human chondrocytes is regulated by p53R2 in response to mechanical stress. Osteoarthritis and cartilage 25 22954457
2013 Chromosomal instability triggered by Rrm2b loss leads to IL-6 secretion and plasmacytic neoplasms. Cell reports 23 23643536
2019 miR-942 promotes proliferation and metastasis of hepatocellular carcinoma cells by inhibiting RRM2B. OncoTargets and therapy 21 31632084
2021 RRM2B Is Frequently Amplified Across Multiple Tumor Types: Implications for DNA Repair, Cellular Survival, and Cancer Therapy. Frontiers in genetics 20 33868369
2005 Characterization of enzymatic properties of human ribonucleotide reductase holoenzyme reconstituted in vitro from hRRM1, hRRM2, and p53R2 subunits. Biochemical and biophysical research communications 20 16376858
2016 Novel regulators and molecular mechanisms of p53R2 and its disease relevance. Biochimie 18 26796884
2015 RRM2B-Mediated Regulation of Mitochondrial Activity and Inflammation under Oxidative Stress. Mediators of inflammation 18 26089597
2006 Circular dichroism and magnetic circular dichroism studies of the active site of p53R2 from human and mouse: iron binding and nature of the biferrous site relative to other ribonucleotide reductases. Biochemistry 18 17115699
2019 The natural history of infantile mitochondrial DNA depletion syndrome due to RRM2B deficiency. Genetics in medicine : official journal of the American College of Medical Genetics 16 31462754
2011 Ribonucleotide reductase subunit p53R2 regulates mitochondria homeostasis and function in KB and PC-3 cancer cells. Biochemical and biophysical research communications 16 21640705
2008 Redox property of ribonucleotide reductase small subunit M2 and p53R2. Methods in molecular biology (Clifton, N.J.) 16 19082948
2007 Improvement in radiosensitivity using small interfering RNA targeting p53R2 in esophageal squamous cell carcinoma. Oncology reports 16 17671702
2008 Ribonucleotide reductase small subunit p53R2 promotes oral cancer invasion via the E-cadherin/beta-catenin pathway. Oral oncology 14 18804405
2017 Phenotypic and Genotypic Heterogeneity of RRM2B Variants. Neuropediatrics 13 29241262
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
2008 Upregulation of the p53R2 ribonucleotide reductase subunit by nitric oxide. Nitric oxide : biology and chemistry 13 18474260
2013 Infantile peripheral neuropathy, deafness, and proximal tubulopathy associated with a novel mutation of the RRM2B gene: case study. Croatian medical journal 12 24382854
2008 Reprimo 824 G>C and p53R2 4696 C>G single nucleotide polymorphisms and colorectal cancer: a case-control disease association study. International journal of colorectal disease 12 18197409
2019 Rrm2b deletion causes mitochondrial metabolic defects in renal tubules. Scientific reports 10 31519977
2016 p53R2 regulates thioredoxin reductase activity through interaction with TrxR2. Biochemical and biophysical research communications 10 27866984
2022 A novel RRM2B mutation associated with mitochondrial DNA depletion syndrome. Molecular genetics and metabolism reports 9 35756861
2015 Differential Expressions of p53, p53R2, hRRM2 and PBR in Chronic Lymphocytic Leukemia: A Correlation with Intracellular Cholesterol. Indian journal of clinical biochemistry : IJCB 9 27382207
2012 MEK2 regulates ribonucleotide reductase activity through functional interaction with ribonucleotide reductase small subunit p53R2. Cell cycle (Georgetown, Tex.) 9 22895183
2010 Molecular analysis and functions of p53R2 in zebrafish. Gene 9 21194559
2015 Caspase-dependent Proteolysis of Human Ribonucleotide Reductase Small Subunits R2 and p53R2 during Apoptosis. The Journal of biological chemistry 8 25878246
2020 Prediction of the Impact of Deleterious Nonsynonymous Single Nucleotide Polymorphisms on the Human RRM2B Gene: A Molecular Modeling Study. BioMed research international 7 32775440
2019 Congenital cochlear deafness in mitochondrial diseases related to RRM2B and SERAC1 gene defects. A study of the mitochondrial patients of the CMHI hospital in Warsaw, Poland. International journal of pediatric otorhinolaryngology 7 30909120
2018 A homozygous variant in RRM2B is associated with severe metabolic acidosis and early neonatal death. European journal of medical genetics 7 30439532
2001 Polymorphic insertion of additional repeat within an area of direct 8 bp tandem repeats in the 5'-untranslated region of the p53R2 gene and cancer risk. Mutagenesis 7 11682647
2017 Novel RRM2B Mutation and Severe Mitochondrial DNA Depletion: Report of 2 Cases and Review of the Literature. Neuropediatrics 6 28482374
2017 RRM2B: An oxygen-requiring protein with a role in hypoxia. Molecular & cellular oncology 5 29057303
2004 Infrequent alteration in the p53R2 gene in human transitional cell carcinoma of the urinary tract. Pathobiology : journal of immunopathology, molecular and cellular biology 5 14707445
2002 The discovery and confirmation of single nucleotide polymorphisms in the human p53R2 gene by EST database analysis. Mutagenesis 5 12202622
2020 Renal dysfunction, rod-cone dystrophy, and sensorineural hearing loss caused by a mutation in RRM2B. Human mutation 4 32827185
2020 The single nucleotide variant at c.662A>G in human RRM2B is a loss-of-function mutation. Molecular genetics & genomic medicine 4 32931159
2005 Novel genetic variations of the p53R2 gene in patients with colorectal adenoma and controls. World journal of gastroenterology 4 16127747
2025 RRM2B deficiency causes dATP and dGTP depletion through enhanced degradation and slower synthesis. Proceedings of the National Academy of Sciences of the United States of America 3 40244665
2023 Targeting CK2-mediated phosphorylation of p53R2 sensitizes BRCA-proficient cancer cells to PARP inhibitors. Oncogene 3 37620447
2023 Identification of two novel RRM2B variants associated with autosomal recessive progressive external ophthalmoplegia in a family with pseudodominant inheritance pattern. Journal of human genetics 2 36959467
2021 Ribonucleotide reductase: In-vitro S-glutathionylation of R2 and p53R2 subunits of mammalian class I ribonucleotide reductase protein. Molecular biology reports 2 34599703
2012 Synergism between clofarabine and decitabine through p53R2: a pharmacodynamic drug-drug interaction modeling. Leukemia research 2 22884950
2023 Effect of siRNA-mediated silencing of p53R2 gene on sensitivity of T-ALL cellsto Daunorubicin. Gene 1 37419428
2014 Investigation of the association of hRRM1 and p53R2 gene polymorphisms in head and neck squamous cell carcinomas. Medical oncology (Northwood, London, England) 1 24861915
2026 A Novel Truncating Pathogenic Variant in RRM2B in a Kurdish Family With Autosomal-Dominant Chronic Progressive External Ophthalmoplegia Plus (PEOA5). Journal of clinical neuromuscular disease 0 41766080
2026 Roles of RRM2 and RRM2B in pyrimidine stress responses and differentiation of acute myeloid leukemia cells. Cell death discovery 0 42031709
2026 Harmane induces apoptosis through RRM2B and suppresses colorectal cancer progression. mSystems 0 42262096
2025 Deoxynucleoside supplementation ameliorates the disease associated phenotypes in a zebrafish model of RRM2B mtDNA depletion syndrome. Human molecular genetics 0 40211788
2025 Genetic dissection of Huntington's disease modification by variation at RRM2B. Human molecular genetics 0 41092345
2024 Creatine kinase elevation in chronic hepatitis B patients with telbivudine therapy: influence of telbivudine plasma concentration and single nucleotide polymorphisms of TK2, RRM2B, and NME4. European journal of clinical pharmacology 0 38502357
2024 Case Report: A novel RRM2B variant in a Chinese infant with mitochondrial DNA depletion syndrome and collective analyses of RRM2B variants for disease etiology. Frontiers in pediatrics 0 38737634
2022 [Clinical characteristics and genetic analysis of a Chinese pedigree affected with mitochondrial DNA depletion syndrome due to compound heterozygous variants of RRM2B gene]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 0 34964961

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