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Gene Review

RRM1  -  ribonucleotide reductase M1

Homo sapiens

Synonyms: R1, RIR1, RR1, Ribonucleoside-diphosphate reductase large subunit, Ribonucleoside-diphosphate reductase subunit M1, ...
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Disease relevance of RRM1


High impact information on RRM1

  • It is composed of two different dimeric proteins R1 and R2 (refs 3-5) [5].
  • Consistent with such a requirement, a double point-mutation in RRM1 of SF2/ASF that impairs RNA binding prevents the protein from shuttling [6].
  • Kid cleaves specific mRNAs at UUACU sites to rescue the copy number of plasmid R1 [7].
  • The non- consensus RRM1 and the C-terminal glutamine-rich (Q) domain are required for association with U1 snRNP and to facilitate its recruitment to 5' ss [8].
  • Remarkably, no characterisitc of the ventricular tachycardia including beats per episode, episodes per day, rate, prematurity index (RR1/QT) of the initiating beat, or the occurrence of associated arrhythmias was important prognostically [9].

Chemical compound and disease context of RRM1

  • In the present study, we have examined the potential correlation and predictive value of ERCC1, RRM1, and XPD mRNA expression in resected specimens from 67 stage IIB, IIIA, and IIIB non-small cell lung cancer patients treated with neoadjuvant gemcitabine/platinum followed by surgery [10].
  • We carried out three different studies examining individually the role of ERCC1, RRM1, and then both, mRNA expression in paraffin-embedded pretreatment bronchial biopsies from gemcitabine/cisplatin-treated advanced non-small-cell lung cancer (NSCLC) patients [11].
  • In common with herpesviruses in the Varicellovirus genus of the alphaherpesvirus subfamily, FHV-1 RR1 lacks the N-terminal serine threonine protein kinase region present in herpes simplex virus (HSV)-1 and -2 [12].
  • The large subunit of the herpes simplex virus type 2 (HSV-2) ribonucleotide reductase (RR1) is demonstrated to possess serine/threonine-specific kinase activity [13].
  • EVM053 also exhibits a novel cis-proline (Pro53) in a loop that has been shown to contribute to R1-binding in Escherichia coli Grx-1 [14].

Biological context of RRM1


Anatomical context of RRM1

  • However, only the increased expression of ribonucleotide reductase subunit 1 (RRM1), which appeared in both resistant cell lines, met predefined analysis criteria for genes to investigate further [17].
  • UV irradiation of serum-starved, G0/G1-enriched mouse fibroblasts, stably transformed with an R1 promoter-luciferase reporter gene construct, caused a 3-fold increase in luciferase activity 24 h after irradiation, paralleled by an increase in the levels of R1 protein [18].
  • A methotrexate-resistant subline, CCRF-CEM/R1, was selected stepwise from the human leukemic lymphoblast T-cell line, CCRF-CEM, and maintained in 0.2 microM methotrexate [19].
  • In contrast, UK117,026 was a more potent inhibitor of 5 alpha-reductase activity in the prostate cancer cell lines and in COS cells expressing 5 alpha R1 [20].
  • AR and 5 alpha R1 mRNAs were expressed in all portions of the hair follicle [21].

Associations of RRM1 with chemical compounds


Physical interactions of RRM1

  • These results suggest that PC3 cells are deficient in both transcription of p53R2 and binding to hRRM1 in response to UV irradiation [27].
  • By using a new technique termed Gas-phase Electrophoretic-Mobility Macromolecule Analysis (GEMMA), we have found that the ATP/dATP-induced R1 oligomers have a defined size (hexamers) and can interact with the R2 dimer to form an enzymatically active protein complex (alpha(6)beta(2)) [28].

Enzymatic interactions of RRM1

  • 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) [29].

Regulatory relationships of RRM1

  • Peptidomimetic inhibitors that mimic the C-terminal amino acids of R2 inhibit HSV RR by preventing the association of R1 and R2 [30].

Other interactions of RRM1


Analytical, diagnostic and therapeutic context of RRM1

  • Quantitative PCR analysis demonstrated H358-G200 cells had a greater than 125-fold increase in RRM1 RNA expression [17].
  • Western blot analysis confirmed high levels of RRM1 protein in this line compared with the gemcitabine-sensitive parent [17].
  • RRM1 and PTEN expression in tumor tissue was highly predictive of overall (P =.011 and.018, respectively) and disease-free survival (P =.002 and.026, respectively) [1].
  • We analyzed RRM1 and ERCC1 mRNA expression in paraffin-embedded samples obtained from bronchoscopy by real-time quantitative reverse transcription-PCR [31].
  • Restriction mapping by pulsed-field electrophoresis indicates that GOK is located 1.7 kb telomeric of RRM1, and both genes are transcribed in the same direction [32].


  1. 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]
  2. RRM1-induced metastasis suppression through PTEN-regulated pathways. Gautam, A., Li, Z.R., Bepler, G. Oncogene (2003) [Pubmed]
  3. The 11p15.5 ribonucleotide reductase M1 subunit locus is not imprinted in Wilms' tumour and hepatoblastoma. Byrne, J.A., Smith, P.J. Hum. Genet. (1993) [Pubmed]
  4. Suppression of lung tumor formation by the regulatory subunit of ribonucleotide reductase. Gautam, A., Bepler, G. Cancer Res. (2006) [Pubmed]
  5. Unusual clustering of carboxyl side chains in the core of iron-free ribonucleotide reductase. Aberg, A., Nordlund, P., Eklund, H. Nature (1993) [Pubmed]
  6. A specific subset of SR proteins shuttles continuously between the nucleus and the cytoplasm. Cáceres, J.F., Screaton, G.R., Krainer, A.R. Genes Dev. (1998) [Pubmed]
  7. Kid cleaves specific mRNAs at UUACU sites to rescue the copy number of plasmid R1. Pimentel, B., Madine, M.A., de la Cueva-Méndez, G. EMBO J. (2005) [Pubmed]
  8. The splicing regulator TIA-1 interacts with U1-C to promote U1 snRNP recruitment to 5' splice sites. Förch, P., Puig, O., Martínez, C., Séraphin, B., Valcárcel, J. EMBO J. (2002) [Pubmed]
  9. Nonsustained ventricular tachycardia in ambulatory patients: characteristics and association with sudden cardiac death. Follansbee, W.P., Michelson, E.L., Morganroth, J. Ann. Intern. Med. (1980) [Pubmed]
  10. Gene expression as a predictive marker of outcome in stage IIB-IIIA-IIIB non-small cell lung cancer after induction gemcitabine-based chemotherapy followed by resectional surgery. Rosell, R., Felip, E., Taron, M., Majo, J., Mendez, P., Sanchez-Ronco, M., Queralt, C., Sanchez, J.J., Maestre, J. Clin. Cancer Res. (2004) [Pubmed]
  11. Pharmacogenomics and gemcitabine. Rosell, R., Cobo, M., Isla, D., Camps, C., Massuti, B. Ann. Oncol. (2006) [Pubmed]
  12. Sequences of the ribonucleotide reductase-encoding genes of felid herpesvirus 1 and molecular phylogenetic analysis. Willoughby, K., Bennett, M., Williams, R.A., McCracken, C., Gaskell, R.M. Virus Genes (1997) [Pubmed]
  13. Protein kinase activity associated with the large subunit of herpes simplex virus type 2 ribonucleotide reductase (ICP10). Chung, T.D., Wymer, J.P., Smith, C.C., Kulka, M., Aurelian, L. J. Virol. (1989) [Pubmed]
  14. Crystal Structures of a Poxviral Glutaredoxin in the Oxidized and Reduced States Show Redox-correlated Structural Changes. Bacik, J.P., Hazes, B. J. Mol. Biol. (2007) [Pubmed]
  15. The structural gene for the M1 subunit of ribonucleotide reductase maps to chromosome 11, band p15, in human and to chromosome 7 in mouse. Brissenden, J.E., Caras, I., Thelander, L., Francke, U. Exp. Cell Res. (1988) [Pubmed]
  16. Correlation of loss of heterozygosity at 11p with tumour progression and survival in non-small cell lung cancer. Fong, K.M., Zimmerman, P.V., Smith, P.J. Genes Chromosomes Cancer (1994) [Pubmed]
  17. 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]
  18. 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. Guittet, O., Håkansson, P., Voevodskaya, N., Fridd, S., Gräslund, A., Arakawa, H., Nakamura, Y., Thelander, L. J. Biol. Chem. (2001) [Pubmed]
  19. Molecular and karyological analysis of methotrexate-resistant and -sensitive human leukemic CCRF-CEM cells. Mini, E., Srimatkandada, S., Medina, W.D., Moroson, B.A., Carman, M.D., Bertino, J.R. Cancer Res. (1985) [Pubmed]
  20. 5 alpha-reductase expression by prostate cancer cell lines and benign prostatic hyperplasia in vitro. Smith, C.M., Ballard, S.A., Worman, N., Buettner, R., Masters, J.R. J. Clin. Endocrinol. Metab. (1996) [Pubmed]
  21. 5 alpha-reductase type 2 is constitutively expressed in the dermal papilla and connective tissue sheath of the hair follicle in vivo but not during culture in vitro. Asada, Y., Sonoda, T., Ojiro, M., Kurata, S., Sato, T., Ezaki, T., Takayasu, S. J. Clin. Endocrinol. Metab. (2001) [Pubmed]
  22. Transcripts in pretreatment biopsies from a three-arm randomized trial in metastatic non-small-cell lung cancer. Rosell, R., Scagliotti, G., Danenberg, K.D., Lord, R.V., Bepler, G., Novello, S., Cooc, J., Crinò, L., Sánchez, J.J., Taron, M., Boni, C., De Marinis, F., Tonato, M., Marangolo, M., Gozzelino, F., Di Costanzo, F., Rinaldi, M., Salonga, D., Stephens, C. Oncogene (2003) [Pubmed]
  23. 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]
  24. Analysis of the RNA recognition motifs of human neuronal ELAV-like proteins in binding to a cytokine mRNA. Sakai, K., Kitagawa, Y., Hirose, G. Biochem. Biophys. Res. Commun. (1999) [Pubmed]
  25. RRM1 Modulated In Vitro and In Vivo Efficacy of Gemcitabine and Platinum in Non-Small-Cell Lung Cancer. Bepler, G., Kusmartseva, I., Sharma, S., Gautam, A., Cantor, A., Sharma, A., Simon, G. J. Clin. Oncol. (2006) [Pubmed]
  26. Efficacy of gemcitabine in patients with non-small cell lung cancer according to promoter polymorphisms of the ribonucleotide reductase M1 gene. Kim, S.O., Jeong, J.Y., Kim, M.R., Cho, H.J., Ju, J.Y., Kwon, Y.S., Oh, I.J., Kim, K.S., Kim, Y.I., Lim, S.C., Kim, Y.C. Clin. Cancer Res. (2008) [Pubmed]
  27. 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]
  28. Enzymatically Active Mammalian Ribonucleotide Reductase Exists Primarily as an {alpha}6beta2 Octamer. Rofougaran, R., Vodnala, M., Hofer, A. J. Biol. Chem. (2006) [Pubmed]
  29. 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]
  30. 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]
  31. Ribonucleotide reductase messenger RNA expression and survival in gemcitabine/cisplatin-treated advanced non-small cell lung cancer patients. Rosell, R., Danenberg, K.D., Alberola, V., Bepler, G., Sanchez, J.J., Camps, C., Provencio, M., Isla, D., Taron, M., Diz, P., Artal, A. Clin. Cancer Res. (2004) [Pubmed]
  32. Molecular cloning of a novel human gene (D11S4896E) at chromosomal region 11p15.5. Parker, N.J., Begley, C.G., Smith, P.J., Fox, R.M. Genomics (1996) [Pubmed]
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