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Gene Review

RRM2  -  ribonucleotide reductase M2

Homo sapiens

Synonyms: R2, RR2, RR2M, Ribonucleoside-diphosphate reductase subunit M2, Ribonucleotide reductase small chain, ...
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Disease relevance of RRM2


Psychiatry related information on RRM2

  • The differential equation consisting of two parallel reactions was solved to predict the concentration of RR2 at any reaction time with very good agreements [5].

High impact information on RRM2

  • Expression of p53R2, but not R2, was induced by ultraviolet and gamma-irradiation and adriamycin treatment in a wild-type p53-dependent manner [6].
  • It is composed of two different dimeric proteins R1 and R2 (refs 3-5) [7].
  • Iron-free R2, apoR2, is a precursor of active R2 and folds into a stable protein which is transformed into active R2 by ferrous ions and molecular oxygen [7].
  • R2 subunits contain buried iron-centres with each centre formed by two ferric ions coordinated by four carboxylates and two histidine ligands [7].
  • We also show that RRM2 of SF2/ASF plays an important role in alternative splicing specificity: deletion of this domain results in a protein that, although active in alternative splicing, has altered specificity in 5' splice site selection [8].

Chemical compound and disease context of RRM2

  • In order to assess target down-regulation by GTI-2040, RRM2 mRNA expression levels were analyzed in pre- and post-treatment samples from a phase II clinical trial of GTI-2040 combined with capecitabine in patients with metastatic breast cancer [9].
  • TNFalpha, R1 and R2 serum levels measured in MS patients did not differ from those measured in healthy individuals and did not correlate with (a) clinical relapses, (b) presence of gadolinium-enhancing brain-magnetic resonance imaging (MRI) lesions, and (c) bioactivity of TNFalpha [10].
  • These results bear a strong resemblance to the spectra of Escherichia coli ribonucleotide reductase (R2), and density functional theory calculations were conducted on the W48F/D84E R2 mutant in order to determine the energetics of formation of a monodentate end-on-bound O2 to one iron in the binuclear site [11].
  • RESULTS: Circulating adiponectin was negatively associated, whereas AdipoR1/R2 mRNA levels were positively associated with obesity, glucose and lipid levels, and insulin resistance [12].
  • BACKGROUND: This study of GTI-2040, a 20-mer phosphorothioate oligonucleotide complementary to the messenger ribonucleic acid (mRNA) of the R2 subunit of ribonucleotide reductase (RNR), was conducted to determine the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD) of the agent in patients with advanced solid tumors or lymphoma [13].

Biological context of RRM2


Anatomical context of RRM2

  • No significant change in the expression of RRM2 was observed in either cell line, although both gemcitabine-resistant cell lines had an approximate 3-fold increase in p53R2 protein [18].
  • In contrast, hRRM2 was up-regulated by UV in both PC3 cells and KB cells. hRRM2 and p53R2 mRNA levels were assessed by Northern blot, and the results paralleled that of the Western blot [19].
  • These results indicated that DNA damage resulted in elevated levels of the R2 protein and dNTPs and, consequently, enhanced the survival of p53(-/-) HCT-116 cells [3].
  • By analysis of their electron paramagnetic resonance spectra, an increased level of the R2 protein was observed in the K562-DFMOr cells as compared to the wild type K562 cells [4].
  • Previously, we have demonstrated that, among the three RRMs of La protein, the RRM2 interacts with HCV internal ribosome entry site (IRES) around the GCAC motif near the initiator AUG present in the stem region of stem-loop IV (SL IV) (Pudi, R., Abhiman, S., Srinivasan, N., and Das S. (2003) J. Biol. Chem. 278, 12231-12240) [20].

Associations of RRM2 with chemical compounds

  • The genes for the M2 subunit of ribonucleotide reductase (RRM2), ornithine decarboxylase (ODC1), and 55,000-Daltons protein (P5), are amplified in hydroxyurea-resistant hamster and human cell lines [2].
  • PSF comprises an N-terminal proline- and glutamine-rich domain, two RRMs (RRM1 and RRM2), and a C-terminal region that contains two nuclear localization signals, both of which are required for complete nuclear localization [21].
  • Triapine, a new RR inhibitor, was equally potent for p53R2 and hRRM2 [22].
  • Of interest, p53R2 was 158-fold more susceptible to the iron chelator deferoxamine mesylate than hRRM2, although the iron content of the two proteins determined by atomic absorption spectrometer was almost the same [22].
  • The increase in sensitivity to cisplatin and RNR inhibitors was correlated with the suppression of dATP and dGTP levels caused by stable expression of R2-targeted short interference RNA [3].

Physical interactions of RRM2

  • In the present study, we have characterized the functional domains of GRSF-1 and mapped the RNA binding activity of GRSF-1 to RRM 2 (amino acids 194 to 275) with amino-terminal deletion glutathione S-transferase (GST)-GRSF-1 proteins [23].
  • The protein is inactive (specific activity 1 x 10(-4) that of wt-R2), which permitted a determination of the pK(a) of the NO(2)Y in the R1/R2 complex in the presence of substrate and effectors [24].

Enzymatic interactions of RRM2

  • Mutational analysis indicated that R2 phosphorylated the threonine residue within the T-loop of CDK2 and Cdc2Os1 [25].
  • In cells infected with HSV-1 or HSV-2, RR1 had auto- and transphosphorylating activity for the small subunit of HSV ribonucleotide reductase (RR2) and immunoglobulin G (IgG) [26].

Regulatory relationships of RRM2

  • When R2 was expressed in budding yeast CAK mutant, the suppression activity in terms of temperature-sensitivity was enhanced by co-expression with Os;cycH;1 [27].
  • Peptidomimetic inhibitors that mimic the C-terminal amino acids of R2 inhibit HSV RR by preventing the association of R1 and R2 [28].

Other interactions of RRM2

  • Thus, we hypothesize that hRRM2 complements p53R2 to form RR holoenzyme and maintain RR activity in PC3 cells after UV treatment [19].
  • RESULTS: RRM1 expression was significantly correlated with PTEN and RRM2 expression in tumor tissue [29].
  • Deletion of RRM2 led to a complete loss of speckle localization and resulted in diffuse accumulation of PSF in the nucleus, indicating that RRM2 is required for subnuclear localization [21].
  • Truncation of TIAR indicated that the high affinity DNA-binding site overlaps with the RNA-binding site involving RNA recognition motif 2 (RRM2) [30].
  • CONCLUSIONS: Taken collectively, TS, USP10, survivin and RRM2 may be useful as prognostic indicators and/or in the development of rationally designed treatment protocols [31].

Analytical, diagnostic and therapeutic context of RRM2

  • We demonstrate the ability of systemically administered RRM2 siRNA to suppress tumoral RRM2 expression in an orthotopic xenograft model of pancreatic adenocarcinoma [1].
  • The RR activity is consistent with the expression of hRRM2 seen in the Western blots [19].
  • Confocal microscopy further confirmed that these findings were not due to translocation of hRRM2 and p53R2 from the cytoplasm to the nucleus [19].
  • PCR analysis of the hRRM2 gene promoter confirmed the amplification [32].
  • Data are presented from a patient for whom both biopsy and PBMC samples were available, demonstrating applicability of this reproducible, highly sensitive real-time RT-PCR method for the detection and quantification of mRNAs for RRM2 in human WBC and tissue samples [9].


  1. RNA interference targeting the M2 subunit of ribonucleotide reductase enhances pancreatic adenocarcinoma chemosensitivity to gemcitabine. Duxbury, M.S., Ito, H., Zinner, M.J., Ashley, S.W., Whang, E.E. Oncogene (2004) [Pubmed]
  2. Amplification of N-myc and ornithine decarboxylase genes in human neuroblastoma and hydroxyurea-resistant hamster cell lines. Tonin, P.N., Yeger, H., Stallings, R.L., Srinivasan, P.R., Lewis, W.H. Oncogene (1989) [Pubmed]
  3. Stable suppression of the R2 subunit of ribonucleotide reductase by R2-targeted short interference RNA sensitizes p53(-/-) HCT-116 colon cancer cells to DNA-damaging agents and ribonucleotide reductase inhibitors. Lin, Z.P., Belcourt, M.F., Cory, J.G., Sartorelli, A.C. J. Biol. Chem. (2004) [Pubmed]
  4. Development of resistance to hydroxyurea during treatment of human myelogenous leukemia K562 cells with alpha-difluoromethylornithine as a result of coamplification of genes for ornithine decarboxylase and ribonucleotide reductase R2 subunit. Ask, A., Persson, L., Rehnholm, A., Frostesjö, L., Holm, I., Heby, O. Cancer Res. (1993) [Pubmed]
  5. Modeling of photodecoloration of azo dye in a cocktail photolysis system. Chu, W., Tsui, S.M. Water Res. (2002) [Pubmed]
  6. A ribonucleotide reductase gene involved in a p53-dependent cell-cycle checkpoint for DNA damage. Tanaka, H., Arakawa, H., Yamaguchi, T., Shiraishi, K., Fukuda, S., Matsui, K., Takei, Y., Nakamura, Y. Nature (2000) [Pubmed]
  7. Unusual clustering of carboxyl side chains in the core of iron-free ribonucleotide reductase. Aberg, A., Nordlund, P., Eklund, H. Nature (1993) [Pubmed]
  8. Role of the modular domains of SR proteins in subnuclear localization and alternative splicing specificity. Cáceres, J.F., Misteli, T., Screaton, G.R., Spector, D.L., Krainer, A.R. J. Cell Biol. (1997) [Pubmed]
  9. Analysis of ribonucleotide reductase M2 mRNA levels in patient samples after GTI-2040 antisense drug treatment. Juhasz, A., Vassilakos, A., Chew, H.K., Gandara, D., Yen, Y. Oncol. Rep. (2006) [Pubmed]
  10. Tumor necrosis factor alpha and its receptors in relapsing-remitting multiple sclerosis. Martino, G., Consiglio, A., Franciotta, D.M., Corti, A., Filippi, M., Vandenbroeck, K., Sciacca, F.L., Comi, G., Grimaldi, L.M. J. Neurol. Sci. (1997) [Pubmed]
  11. Spectroscopic and computational studies of the de novo designed protein DF2t: correlation to the biferrous active site of ribonucleotide reductase and factors that affect O2 reactivity. Wei, P.P., Skulan, A.J., Wade, H., DeGrado, W.F., Solomon, E.I. J. Am. Chem. Soc. (2005) [Pubmed]
  12. Circulating adiponectin and expression of adiponectin receptors in human skeletal muscle: associations with metabolic parameters and insulin resistance and regulation by physical training. Blüher, M., Bullen, J.W., Lee, J.H., Kralisch, S., Fasshauer, M., Klöting, N., Niebauer, J., Schön, M.R., Williams, C.J., Mantzoros, C.S. J. Clin. Endocrinol. Metab. (2006) [Pubmed]
  13. A phase I study of antisense oligonucleotide GTI-2040 given by continuous intravenous infusion in patients with advanced solid tumors. Desai, A.A., Schilsky, R.L., Young, A., Janisch, L., Stadler, W.M., Vogelzang, N.J., Cadden, S., Wright, J.A., Ratain, M.J. Ann. Oncol. (2005) [Pubmed]
  14. Suppression of lung tumor formation by the regulatory subunit of ribonucleotide reductase. Gautam, A., Bepler, G. Cancer Res. (2006) [Pubmed]
  15. Contributions of the individual domains in human La protein to its RNA 3'-end binding activity. Ohndorf, U.M., Steegborn, C., Knijff, R., Sondermann, P. J. Biol. Chem. (2001) [Pubmed]
  16. Identification of domains in apobec-1 complementation factor required for RNA binding and apolipoprotein-B mRNA editing. Mehta, A., Driscoll, D.M. RNA (2002) [Pubmed]
  17. Ribonucleotide reductase M2 subunit sequences mapped to four different chromosomal sites in humans and mice: functional locus identified by its amplification in hydroxyurea-resistant cell lines. Yang-Feng, T.L., Barton, D.E., Thelander, L., Lewis, W.H., Srinivasan, P.R., Francke, U. Genomics (1987) [Pubmed]
  18. An increase in the expression of ribonucleotide reductase large subunit 1 is associated with gemcitabine resistance in non-small cell lung cancer cell lines. Davidson, J.D., Ma, L., Flagella, M., Geeganage, S., Gelbert, L.M., Slapak, C.A. Cancer Res. (2004) [Pubmed]
  19. The human ribonucleotide reductase subunit hRRM2 complements p53R2 in response to UV-induced DNA repair in cells with mutant p53. Zhou, B., Liu, X., Mo, X., Xue, L., Darwish, D., Qiu, W., Shih, J., Hwu, E.B., Luh, F., Yen, Y. Cancer Res. (2003) [Pubmed]
  20. La protein binding at the GCAC site near the initiator AUG facilitates the ribosomal assembly on the hepatitis C virus RNA to influence internal ribosome entry site-mediated translation. Pudi, R., Srinivasan, P., Das, S. J. Biol. Chem. (2004) [Pubmed]
  21. An RNA recognition motif (RRM) is required for the localization of PTB-associated splicing factor (PSF) to subnuclear speckles. Dye, B.T., Patton, J.G. Exp. Cell Res. (2001) [Pubmed]
  22. In vitro characterization of enzymatic properties and inhibition of the p53R2 subunit of human ribonucleotide reductase. Shao, J., Zhou, B., Zhu, L., Qiu, W., Yuan, Y.C., Xi, B., Yen, Y. Cancer Res. (2004) [Pubmed]
  23. Selective translation of eukaryotic mRNAs: functional molecular analysis of GRSF-1, a positive regulator of influenza virus protein synthesis. Kash, J.C., Cunningham, D.M., Smit, M.W., Park, Y., Fritz, D., Wilusz, J., Katze, M.G. J. Virol. (2002) [Pubmed]
  24. Generation of the R2 subunit of ribonucleotide reductase by intein chemistry: insertion of 3-nitrotyrosine at residue 356 as a probe of the radical initiation process. Yee, C.S., Seyedsayamdost, M.R., Chang, M.C., Nocera, D.G., Stubbe, J. Biochemistry (2003) [Pubmed]
  25. A rice homolog of Cdk7/MO15 phosphorylates both cyclin-dependent protein kinases and the carboxy-terminal domain of RNA polymerase II. Yamaguchi, M., Umeda, M., Uchimiya, H. Plant J. (1998) [Pubmed]
  26. The novel protein kinase of the RR1 subunit of herpes simplex virus has autophosphorylation and transphosphorylation activity that differs in its ATP requirements for HSV-1 and HSV-2. Peng, T., Hunter, J.R., Nelson, J.W. Virology (1996) [Pubmed]
  27. Activation of CDK-activating kinase is dependent on interaction with H-type cyclins in plants. Yamaguchi, M., Fabian, T., Sauter, M., Bhalerao, R.P., Schrader, J., Sandberg, G., Umeda, M., Uchimiya, H. Plant J. (2000) [Pubmed]
  28. Resistance of herpes simplex virus type 1 to peptidomimetic ribonucleotide reductase inhibitors: selection and characterization of mutant isolates. Bonneau, A.M., Kibler, P., White, P., Bousquet, C., Dansereau, N., Cordingley, M.G. J. Virol. (1996) [Pubmed]
  29. RRM1 and PTEN as prognostic parameters for overall and disease-free survival in patients with non-small-cell lung cancer. Bepler, G., Sharma, S., Cantor, A., Gautam, A., Haura, E., Simon, G., Sharma, A., Sommers, E., Robinson, L. J. Clin. Oncol. (2004) [Pubmed]
  30. Novel DNA-binding properties of the RNA-binding protein TIAR. Suswam, E.A., Li, Y.Y., Mahtani, H., King, P.H. Nucleic Acids Res. (2005) [Pubmed]
  31. Increased Expression of Thymidylate Synthetase (TS), Ubiquitin Specific Protease 10 (USP10) and Survivin is Associated with Poor Survival in Glioblastoma Multiforme (GBM). Grunda, J.M., Nabors, L.B., Palmer, C.A., Chhieng, D.C., Steg, A., Mikkelsen, T., Diasio, R.B., Zhang, K., Allison, D., Grizzle, W.E., Wang, W., Gillespie, G.Y., Johnson, M.R. J. Neurooncol. (2006) [Pubmed]
  32. Human ribonucleotide reductase M2 subunit gene amplification and transcriptional regulation in a homogeneous staining chromosome region responsible for the mechanism of drug resistance. Zhou, B., Mo, X., Liu, X., Qiu, W., Yen, Y. Cytogenet. Cell Genet. (2001) [Pubmed]
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