Atlas of Genetics and Cytogenetics in Oncology and Haematology


Home   Genes   Leukemias   Solid Tumours   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NA

RRM1 (ribonucleotide reductase M1)

Written2009-06Scott N Freeman, Gerold Bepler
Department of Thoracic Oncology, Experimental Therapeutics Program, Lung Cancer Program, H Lee Moffitt Cancer Center, Research Institute, Tampa, Florida, USA

(Note : for Links provided by Atlas : click)

Identity

Alias_namesribonucleotide reductase M1 polypeptide
Other aliasR1
RIR1
RR1
HGNC (Hugo) RRM1
LocusID (NCBI) 6240
Atlas_Id 42174
Location 11p15.4  [Link to chromosome band 11p15]
Location_base_pair Starts at 4115915 and ends at 4160155 bp from pter ( according to hg19-Feb_2009)  [Mapping RRM1.png]
Local_order STIM1-RRM1-OR55B1P-LOC643244.
Fusion genes
(updated 2016)
PHF23 (17p13.1) / RRM1 (11p15.4)RRM1 (11p15.4) / RRM1 (11p15.4)RRM1 (11p15.4) / STIM1 (11p15.4)
Note The RRM1 gene is oriented on the plus strand. The chromosomal region containing the RRM1 gene locus displays frequent loss of heterozygosity (LOH) in lung cancer and is amplified in some instances of acquired resistance to gemcitabine and hydroxyurea.

DNA/RNA

Description The RRM1 gene consists of 44182 base pairs which encode 19 exons.
Transcription The mature RRM1 mRNA is 3234 ribonucleotides in length and harbors an open reading frame of 2379 ribonucleotides.
Pseudogene There are no reported human RRM1 pseudogenes.

Protein

Note The RRM1 protein functions in a heterodimeric tetramer with either RRM2 (RRM2a) or p53R2 (RRM2b) in the ribonucleotide reductase holoenzyme. While this interaction is essential for the de novo synthesis of deoxyribonucleotides, it is unclear whether this association is necessary for other biological activities ascribed to RRM1.
Description The RRM1 protein is 792 amino acids in length and has a calculated molecular weight of 90 kDa. Analysis of the human RRM1 protein via the NCBI Conserved Domains program reveals an N-terminal ATP-cone domain and a Ribonucleotide Reductase (RNR) Class I domain which spans the majority of the protein. The RNR Class I domain harbors the all-alpha domain, the barrel domain, as well as regions and residues comprising the active site, the allosteric effector dTTP-binding site, the RRM2 peptide-binding site and the dimer interface.
Expression While the RRM2 subunit of the ribonucleotide reductase holoenzyme is regulated in a cell cycle-specific manner, RRM1 expression remains relatively constant in actively proliferating cells. However, expression of RRM1 is significantly decreased upon exit from the cell cycle to G0 or terminal differentiation. This decreased level of RRM1 expression in non-dividing cells is essential for the supply of dNTPs for mitochondrial DNA replication. Upregulation of RRM1 occurs when cells are stimulated to re-enter the cell cycle from G0.
Localisation Depending on the experimental technique employed, the cell line or tissue sample, the cellular state and the antibody source, RRM1 can be detected within the nucleus, the cytoplasm or both. In quantitative immunofluorescent staining of non-small-cell lung cancer (NSCLC) cell lines and tumor samples, RRM1 protein is predominantly nuclear. The method of analyzing nuclear RRM1 expression in resected NSCLC tumor samples can be used for survival prognostication. This is in agreement with fractionation of NSCLC cell lines, where RRM1 is detected almost exclusively in the nuclear fraction. In contrast, studies utilizing various experimental methods to examine RRM1 in mouse and human lung fibroblasts find RRM1 to be cytoplasmic. This is in line with other studies that find RRM1 localized in cytoplasmic compartments in mouse fibroblasts, as well as cytoplasmic RRM1 immunoreactivity in various rat tissues. Still, another study demonstrates both nuclear and cytoplasmic RRM1 in multiple cell lines and finds RRM1 localized to the nuclear membrane, while others report a DNA damage-dependent relocalization of RRM1 from the cytoplasm to the nucleus. Given the current evidence, it is likely that RRM1 localization is dependent on cell type, tissue of origin, and cellular state. It is also evident that variables such as the antibody and experimental technique employed obscure a conclusive answer as to the true localization characteristics of RRM1.
Function The RRM1 protein is implicated in deoxyribonucleotide (dNTP) synthesis, DNA damage response and repair and tumor suppression. In dNTP synthesis, RRM1 serves as the regulatory subunit of the ribonucleotide reductase (RR) holoenzyme, which catalyzes the de novo synthesis of dNTPs from ribonucleotide precursors. Synthesis of dNTPs via this pathway is reported to occur in the cytosol, with dNTPs re-localizing to the nucleus through diffusion and to the mitochondria via transport mechanisms. The RR enzyme primarily exists as a heterodimeric tetramer of RRM1 and RRM2, the primary catalytic subunit. While RRM1 expression remains relatively constant in cycling cells, RRM2 is regulated in a cell cycle-specific manner and is degraded upon exit from mitosis and absent in quiescent cells. Given this, the RRM2 subunit is the primary regulator of RR enzymatic activity. RRM1 can alternatively associate with the p53R2 subunit in substitution for RRM2. Unlike RRM2, p53R2 is present in quiescent cells and as such associates with RRM1 under this context to provide dNTPs for mitochondrial DNA (mtDNA) replication in cells which are not actively dividing. Additionally, the expression of p53R2 is induced by the DNA damage response proteins p53 and p73, stabilized by ATM-mediated phosphorylation and is reported to be involved in the supply of dNTPs by RR for mtDNA replication and DNA damage repair. The role of RRM1 in the synthesis of dNTPs is also manifested as upregulation in cases of acquired resistance to gemcitabine and hydroxyurea, which directly inhibit the RR holoenzyme.
In the context of DNA damage response and repair, stable overexpression of RRM1 in lung adenocarcinoma cells results in an increased fraction of cells arrested in G2/M. This coincides with increased expression of the GADD45 G2 checkpoint protein, which is thought to mediate this arrest. In response to DNA-damaging agents, overexpression of RRM1 promotes the efficient repair of DNA damage. Additionally, RRM1-overexpressing cells have an increased level of apoptosis. When subjected to a murine chemical carcinogenesis protocol, mice transgenic for RRM1 (tg+) have significantly reduced lung tumor formation, and splenocytes derived from tg+ mice repair hydrogen peroxide-induced DNA damage more efficiently than those from tg- littermates. While the exact mechanism by which RRM1 contributes to DNA damage response and repair in unclear, it may involve its association with the p53R2 RR subunit. This subunit is induced by the DNA damage responsive p53 and p73 transcription factors, is stabilized by ATM-mediated phosphorylation and can substitute for RRM2 in the RR complex. Current data indicates a role for p53R2 in providing dNTPs during DNA damage repair and may explain the involvement of RRM1 in DNA damage response and repair.
With regard to tumor suppression, overexpression of RRM1 in human and mouse lung cancer cell lines, as well as ras-transformed mouse fibroblasts, inhibits metastasis, tumorigenicity and motility. It also suppresses metastasis formation and increases survival in a syngeneic murine lung cancer model. Evidence points to reduced phosphorylation of focal adhesion kinase (FAK) and increased PTEN expression as mediators of these effects. Mice transgenic for RRM1 subjected to a murine chemical carcinogenesis protocol display significantly decreased lung tumor development and survive significantly longer than tg- littermates. Additionally, multiple clinical studies show correlations between increased intratumoral RRM1 expression in surgically resected tumor tissue and increased survival (NSCLC, pancreatic cancer, bladder cancer). As previously noted, reduced FAK phosphorylation and increased PTEN expression are thought to be the primary mediators of the tumor suppressor function of RRM1; however, the ability of RRM1 to contribute to DNA damage response and repair may also play a role.
Homology The RRM1 protein is highly conserved from human to many lower organisms. Human RRM1 protein shares 99.7% similarity and 97.6% identity with mouse (M. musculus) RRM1 and 88.2% similarity and 69.1% identity with that of fission yeast (S. pombe). It does not harbor significant homology to other human proteins.

Mutations

Germinal At this point, there are no described germline mutations within the RRM1 gene. There are a total of 272 reported single nucleotide polymorphisms (SNPs) for the RRM1 gene. Nine are in the coding region of RRM1, and four result in amino acid alterations which consist of: G249A, A768C, T821G and T2565C. We sequenced the genomic region of RRM1 and deposited this data in GenBank (AF107045), which provided for the reference for some of the reported SNPs. In addition, we described SNPs in the RRM1 promoter region that have a substantial effect on in vitro reporter gene transcription.
Somatic RRM1 resides at 11p15.5, a frequent region of allele loss in cancer. Additionally, amplification of RRM1 has been observed in acquired resistance to gemcitabine and hydroxyurea.

Implicated in

Note
  
Entity Non-small cell lung cancer (NSCLC)
Note Overexpression of RRM1 in human and mouse lung cancer cell lines inhibits motility in cell culture and decreases metastasis and tumorigenicity in a syngeneic mouse lung cancer model. Increased survival is also noted upon RRM1 overexpression in the same model. Mice transgenic for RRM1 subjected to a chemical carcinogenesis protocol display significantly decreased lung tumor development and survive significantly longer than tg- littermates.
Since gemcitabine works in part through the inhibition of ribonucleotide reductase, RRM1 is a key molecule involved in the therapeutic response. Multiple NSCLC clinical studies demonstrate that while decreased intratumoral RRM1 is indicative of sensitivity to gemcitabine, elevated levels are predictive of poor response to gemcitabine. In NSCLC cell lines, depletion of RRM1 results in sensitivity to gemcitabine, and vice versa increased RRM1 expression results in resistance to gemcitabine. Gemcitabine-resistant NSCLC cells display upregulation of RRM1, and depletion of RRM1 in these cells restores gemcitabine sensitivity. Additionally, a 2464G>A RRM1 polymorphism was reported to be associated with gemcitabine sensitivity in cancer cell lines of various origins, while NSCLC patients harboring a combination of the RR37AC and RR524CT promoter polymorphisms, the haplotype associated with decreased promoter activity, show greater response to gemcitabine.
Disease NSCLC is the most frequently diagnosed type of lung cancer and refers to malignant neoplasms of the lung which are histologically distinct from small cell lung cancer. NSCLC cases are classified as adenocarcinoma, large cell carcinoma or squamous (epidermoid) carcinoma. The National Cancer Institute (NCI) estimates that there were 215,020 new cases of lung cancer and 161,840 deaths in 2008.
Prognosis Loss of the chromosomal region harboring RRM1 in NSCLC is associated with increased metastatic spread and decreased overall survival (OS) in patients with stage I or stage II disease. RRM1 mRNA derived from surgically resected NSCLC tumors indicates that high levels of RRM1 expression are associated with longer survival. This result was confirmed in a study where an elevated level of intratumoral RRM1 protein was prognostic of favorable survival. In addition to RRM1 expression, promoter polymorphisms at positions -37 and -524 (RR37AC and RR524CT), which regulate RRM1 expression in in vitro models, are associated with survival.
Cytogenetics The RRM1 gene resides at 11p15.5, a region frequently associated with allele loss in NSCLC. This is exemplified in primary lung cancer tissue as well as lung cancer cell lines. The region of minimal allele loss in NSCLC is mapped to a 310 kb region which contains the complete coding sequence for the RRM1 and SSA/Ro52 genes. Of these two genes, RRM1 is identified as the putative tumor suppressor within this region of LOH.
  
  
Entity Pancreatic cancer
Note Increased RRM1 expression is indicative of resistance to gemcitabine in pancreatic cancer. RRM1 is the most highly upregulated gene observed in the 81-fold gemcitabine-resistant MiaPaCa2 derived cell line MiaPaCa2-RG, and siRNA depletion of RRM1 expression in this resistant cell line restores gemcitabine sensitivity. During the acquisition of gemcitabine resistance in pancreatic cell lines, progressive upregulation of RRM1 is observed.
Disease The term pancreatic cancer refers to malignant neoplasms of the pancreas. Tumors of the pancreas can originate from either exocrine or endocrine pancreatic cells, with exocrine pancreatic cancer being the predominant form. The majority of exocrine pancreatic cancers are adenocarcinomas. The NCI estimates that there will be 42,470 new cases of pancreatic cancer and 35,240 deaths in 2009.
  
  
Entity Biliary tract cancer
Note Depletion of RRM1 expression via siRNA in the G-415 biliary tract carcinoma cell line increases sensitivity to gemcitabine and enhances gemcitabine-induced apoptosis. Tumor tissue derived from biliary tract carcinoma patients treated with gemcitabine shows a tendency toward elevated RRM1 expression associating with progressive disease (PD) and decreased RRM1 expression associating with partial response (PR), although these tendencies were not statistically significant. These results suggest that RRM1 expression may be a useful tool for predicting response to gemcitabine in patients with cancer of the biliary tract.
Disease Biliary tract cancer refers to malignant neoplasms of the gallbladder and/or bile duct. Cancers of the bile duct are referred to as cholangiocarcinomas, while other cancers of the biliary system include gallbladder cancers and cancer of the ampulla of Vater. Biliary tract malignancies are relatively rare.
  

Bibliography

Significance of RRM1 and ERCC1 expression in resectable pancreatic adenocarcinoma.
Akita H, Zheng Z, Takeda Y, Chiwan K, Kittaka N, Kobayashi S, Marubashi S, Takemasa I, Nagano H, Dono K, Nakamori S, Monden M, Mori M, Doki Y, Bepler G.
Oncogene. 2009: in press.
 
Association of chromosome 11 locus D11S12 with histology, stage, and metastases in lung cancer.
Bepler G, Fong KM, Johnson BE, O'Briant KC, Daly LA, Zimmerman PV, Garcia-Blanco MA, Peterson B.
Cancer Detect Prev. 1998;22(1):14-9.
PMID 9466044
 
Prognostic significance of molecular genetic aberrations on chromosome segment 11p15.5 in non-small-cell lung cancer.
Bepler G, Gautam A, McIntyre LM, Beck AF, Chervinsky DS, Kim YC, Pitterle DM, Hyland A.
J Clin Oncol. 2002 Mar 1;20(5):1353-60.
PMID 11870179
 
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 Oct 10;24(29):4731-7. Epub 2006 Sep 11.
PMID 16966686
 
A 1.4-Mb high-resolution physical map and contig of chromosome segment 11p15.5 and genes in the LOH11A metastasis suppressor region.
Bepler G, O'briant KC, Kim YC, Schreiber G, Pitterle DM.
Genomics. 1999 Jan 15;55(2):164-75.
PMID 9933563
 
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 May 15;22(10):1878-85.
PMID 15143080
 
Clinical efficacy and predictive molecular markers of neoadjuvant gemcitabine and pemetrexed in resectable non-small cell lung cancer.
Bepler G, Sommers KE, Cantor A, Li X, Sharma A, Williams C, Chiappori A, Haura E, Antonia S, Tanvetyanon T, Simon G, Obasaju C, Robinson LA.
J Thorac Oncol. 2008 Oct;3(10):1112-8.
PMID 18827606
 
Ribonucleotide reductase M1 gene promoter activity, polymorphisms, population frequencies, and clinical relevance.
Bepler G, Zheng Z, Gautam A, Sharma S, Cantor A, Sharma A, Cress WD, Kim YC, Rosell R, McBride C, Robinson L, Sommers E, Haura E.
Lung Cancer. 2005 Feb;47(2):183-92.
PMID 15639717
 
In vivo induction of resistance to gemcitabine results in increased expression of ribonucleotide reductase subunit M1 as the major determinant.
Bergman AM, Eijk PP, Ruiz van Haperen VW, Smid K, Veerman G, Hubeek I, van den Ijssel P, Ylstra B, Peters GJ.
Cancer Res. 2005 Oct 15;65(20):9510-6.
PMID 16230416
 
Tumor BRCA1, RRM1 and RRM2 mRNA expression levels and clinical response to first-line gemcitabine plus docetaxel in non-small-cell lung cancer patients.
Boukovinas I, Papadaki C, Mendez P, Taron M, Mavroudis D, Koutsopoulos A, Sanchez-Ronco M, Sanchez JJ, Trypaki M, Staphopoulos E, Georgoulias V, Rosell R, Souglakos J.
PLoS ONE. 2008;3(11):e3695. Epub 2008 Nov 11.
PMID 19002265
 
Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletion.
Bourdon A, Minai L, Serre V, Jais JP, Sarzi E, Aubert S, Chretien D, de Lonlay P, Paquis-Flucklinger V, Arakawa H, Nakamura Y, Munnich A, Rotig A.
Nat Genet. 2007 Jun;39(6):776-80. Epub 2007 May 7.
PMID 17486094
 
Characterization of a dCTP transport activity reconstituted from human mitochondria.
Bridges EG, Jiang Z, Cheng YC.
J Biol Chem. 1999 Feb 19;274(8):4620-5.
PMID 9988697
 
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 JE, Caras I, Thelander L, Francke U.
Exp Cell Res. 1988 Jan;174(1):302-8.
PMID 3275546
 
ERCC1 and RRM1 gene expressions but not EGFR are predictive of shorter survival in advanced non-small-cell lung cancer treated with cisplatin and gemcitabine.
Ceppi P, Volante M, Novello S, Rapa I, Danenberg KD, Danenberg PV, Cambieri A, Selvaggi G, Saviozzi S, Calogero R, Papotti M, Scagliotti GV.
Ann Oncol. 2006 Dec;17(12):1818-25. Epub 2006 Sep 15.
PMID 16980606
 
Controlled protein degradation regulates ribonucleotide reductase activity in proliferating mammalian cells during the normal cell cycle and in response to DNA damage and replication blocks.
Chabes A, Thelander L.
J Biol Chem. 2000 Jun 9;275(23):17747-53.
PMID 10747958
 
ATM-mediated serine 72 phosphorylation stabilizes ribonucleotide reductase small subunit p53R2 protein against MDM2 to DNA damage.
Chang L, Zhou B, Hu S, Guo R, Liu X, Jones SN, Yen Y.
Proc Natl Acad Sci U S A. 2008 Nov 25;105(47):18519-24. Epub 2008 Nov 17.
PMID 19015526
 
Molecular mechanisms of drug resistance involving ribonucleotide reductase: hydroxyurea resistance in a series of clonally related mouse cell lines selected in the presence of increasing drug concentrations.
Choy BK, McClarty GA, Chan AK, Thelander L, Wright JA.
Cancer Res. 1988 Apr 15;48(8):2029-35.
PMID 2832057
 
Gene for M1 subunit of ribonucleotide reductase is amplified in hydroxyurea-resistant hamster cells.
Cocking JM, Tonin PN, Stokoe NM, Wensing EJ, Lewis WH, Srinivasan PR.
Somat Cell Mol Genet. 1987 May;13(3):221-33.
PMID 3299747
 
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 JD, Ma L, Flagella M, Geeganage S, Gelbert LM, Slapak CA.
Cancer Res. 2004 Jun 1;64(11):3761-6.
PMID 15172981
 
Immunocytochemical evidence for the cytoplasmic localization and differential expression during the cell cycle of the M1 and M2 subunits of mammalian ribonucleotide reductase.
Engstrom Y, Rozell B.
EMBO J. 1988 Jun;7(6):1615-20.
PMID 3049070
 
The R1 component of mammalian ribonucleotide reductase has malignancy-suppressing activity as demonstrated by gene transfer experiments.
Fan H, Huang A, Villegas C, Wright JA.
Proc Natl Acad Sci U S A. 1997 Nov 25;94(24):13181-6.
PMID 9371820
 
Mitochondrial deoxynucleotide pool sizes in mouse liver and evidence for a transport mechanism for thymidine monophosphate.
Ferraro P, Nicolosi L, Bernardi P, Reichard P, Bianchi V.
Proc Natl Acad Sci U S A. 2006 Dec 5;103(49):18586-91. Epub 2006 Nov 21.
PMID 17124168
 
Microsatellite instability and other molecular abnormalities in non-small cell lung cancer.
Fong KM, Zimmerman PV, Smith PJ.
Cancer Res. 1995 Jan 1;55(1):28-30.
PMID 7805035
 
Suppression of lung tumor formation by the regulatory subunit of ribonucleotide reductase.
Gautam A, Bepler G.
Cancer Res. 2006 Jul 1;66(13):6497-502.
PMID 16818620
 
RRM1-induced metastasis suppression through PTEN-regulated pathways.
Gautam A, Li ZR, Bepler G.
Oncogene. 2003 Apr 10;22(14):2135-42.
PMID 12687015
 
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, Hakansson P, Voevodskaya N, Fridd S, Graslund A, Arakawa H, Nakamura Y, Thelander L.
J Biol Chem. 2001 Nov 2;276(44):40647-51. Epub 2001 Aug 21.
PMID 11517226
 
Regulation of mammalian ribonucleotide reduction and dNTP pools after DNA damage and in resting cells.
Hakansson P, Hofer A, Thelander L.
J Biol Chem. 2006 Mar 24;281(12):7834-41. Epub 2006 Jan 24.
PMID 16436374
 
RRM1 expression in muscle invasive locally advanced urothelial cancer may correlate with age.
Harshman LC, Bepler G, Zheng Z, Higgins JP, Allen GI, Srinivas S.
Proc Am Soc Clin Oncol. 2009: in press.
 
Inhibition of ribonucleotide reduction in CCRF-CEM cells by 2',2'-difluorodeoxycytidine.
Heinemann V, Xu YZ, Chubb S, Sen A, Hertel LW, Grindey GB, Plunkett W.
Mol Pharmacol. 1990 Oct;38(4):567-72.
PMID 2233693
 
Amplification of the genes for both components of ribonucleotide reductase in hydroxyurea resistant mammalian cells.
Hurta RA, Wright JA.
Biochem Biophys Res Commun. 1990 Feb 28;167(1):258-64.
PMID 2178608
 
Efficacy of gemcitabine in patients with non-small cell lung cancer according to promoter polymorphisms of the ribonucleotide reductase M1 gene.
Kim SO, Jeong JY, Kim MR, Cho HJ, Ju JY, Kwon YS, Oh IJ, Kim KS, Kim YI, Lim SC, Kim YC.
Clin Cancer Res. 2008 May 15;14(10):3083-8.
PMID 18483375
 
Impaired function of p53R2 in Rrm2b-null mice causes severe renal failure through attenuation of dNTP pools.
Kimura T, Takeda S, Sagiya Y, Gotoh M, Nakamura Y, Arakawa H.
Nat Genet. 2003 Aug;34(4):440-5.
PMID 12858174
 
Ribonucleotide reductase M1 (RRM1) 2464G>A polymorphism shows an association with gemcitabine chemosensitivity in cancer cell lines.
Kwon WS, Rha SY, Choi YH, Lee JO, Park KH, Jung JJ, Kim TS, Jeung HC, Chung HC.
Pharmacogenet Genomics. 2006 Jun;16(6):429-38.
PMID 16708051
 
Allelic loss on the short arm of chromosome 11 in non-small-cell lung cancer.
Ludwig CU, Raefle G, Dalquen P, Stulz P, Stahel R, Obrecht JP.
Int J Cancer. 1991 Nov 11;49(5):661-5.
PMID 1682278
 
Ribonucleotide reductase M1 subunit in cellular proliferation, quiescence, and differentiation.
Mann GJ, Musgrove EA, Fox RM, Thelander L.
Cancer Res. 1988 Sep 15;48(18):5151-6.
PMID 3044582
 
Elevated expression of M1 and M2 components and drug-induced posttranscriptional modulation of ribonucleotide reductase in a hydroxyurea-resistant mouse cell line.
McClarty GA, Chan AK, Engstrom Y, Wright JA, Thelander L.
Biochemistry. 1987 Dec 1;26(24):8004-11.
PMID 2827767
 
In situ protein expression of RRM1, ERCC1 and BRCA1 in metastatic breast cancer patients treated with gemcitabine-based chemotherapy.
Metro G, Zheng Z, Fabi A, Schell M, Antoniani B, Mottolese M, Monteiro AN, Vici P, Lara Rivera S, Boulware D, Cognetti F, Bepler G.
Cancer Invest. 2009: in press.
 
Involvement of ribonucleotide reductase M1 subunit overexpression in gemcitabine resistance of human pancreatic cancer.
Nakahira S, Nakamori S, Tsujie M, Takahashi Y, Okami J, Yoshioka S, Yamasaki M, Marubashi S, Takemasa I, Miyamoto A, Takeda Y, Nagano H, Dono K, Umeshita K, Sakon M, Monden M.
Int J Cancer. 2007 Mar 15;120(6):1355-63.
PMID 17131328
 
A ribonucleotide reductase gene is a transcriptional target of p53 and p73.
Nakano K, Balint E, Ashcroft M, Vousden KH.
Oncogene. 2000 Aug 31;19(37):4283-9.
PMID 10980602
 
Gemcitabine chemoresistance and molecular markers associated with gemcitabine transport and metabolism in human pancreatic cancer cells.
Nakano Y, Tanno S, Koizumi K, Nishikawa T, Nakamura K, Minoguchi M, Izawa T, Mizukami Y, Okumura T, Kohgo Y.
Br J Cancer. 2007 Feb 12;96(3):457-63. Epub 2007 Jan 16.
PMID 17224927
 
Ribonucleotide reductases.
Nordlund P, Reichard P.
Annu Rev Biochem. 2006;75:681-706. (REVIEW)
PMID 16756507
 
Growth inhibition of a human lung adenocarcinoma cell line by genetic complementation with chromosome 11.
O'Briant K, Jolicoeur E, Garst J, Campa M, Schreiber G, Bepler G.
Anticancer Res. 1997 Sep-Oct;17(5A):3243-51.
PMID 9413155
 
Delineation of the centromeric and telomeric chromosome segment 11p15.5 lung cancer suppressor regions LOH11A and LOH11B.
O'Briant KC, Bepler G.
Genes Chromosomes Cancer. 1997 Feb;18(2):111-4.
PMID 9115960
 
The determinants of sensitivity and acquired resistance to gemcitabine differ in non-small cell lung cancer: a role of ABCC5 in gemcitabine sensitivity.
Oguri T, Achiwa H, Sato S, Bessho Y, Takano Y, Miyazaki M, Muramatsu H, Maeda H, Niimi T, Ueda R.
Mol Cancer Ther. 2006 Jul;5(7):1800-6.
PMID 16891466
 
Down-regulation of deoxycytidine kinase enhances acquired resistance to gemcitabine in pancreatic cancer.
Ohhashi S, Ohuchida K, Mizumoto K, Fujita H, Egami T, Yu J, Toma H, Sadatomi S, Nagai E, Tanaka M.
Anticancer Res. 2008 Jul-Aug;28(4B):2205-12.
PMID 18751396
 
Ribonucleotide reductase subunit M1 is a possible chemoresistance marker to gemcitabine in biliary tract carcinoma.
Ohtaka K, Kohya N, Sato K, Kitajima Y, Ide T, Mitsuno M, Miyazaki K.
Oncol Rep. 2008 Aug;20(2):279-86.
PMID 18636187
 
Human M1 subunit of ribonucleotide reductase: cDNA sequence and expression in stimulated lymphocytes.
Parker NJ, Begley CG, Fox RM.
Nucleic Acids Res. 1991 Jul 11;19(13):3741.
PMID 1840662
 
Sequence analysis of the large and small subunits of human ribonucleotide reductase.
Pavloff N, Rivard D, Masson S, Shen SH, Mes-Masson AM.
DNA Seq. 1992;2(4):227-34.
PMID 1627826
 
Lung cancer and the human gene for ribonucleotide reductase subunit M1 (RRM1).
Pitterle DM, Kim YC, Jolicoeur EM, Cao Y, O'Briant KC, Bepler G.
Mamm Genome. 1999 Sep;10(9):916-22.
PMID 10441745
 
Ribonucleotide reduction is a cytosolic process in mammalian cells independently of DNA damage.
Pontarin G, Fijolek A, Pizzo P, Ferraro P, Rampazzo C, Pozzan T, Thelander L, Reichard PA, Bianchi V.
Proc Natl Acad Sci U S A. 2008 Nov 18;105(46):17801-6. Epub 2008 Nov 7.
PMID 18997010
 
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.
Reynolds C, Obasaju C, Schell MJ, Li X, Zheng Z, Boulware D, Caton JR, DeMarco LC, O'Rourke MA, Shaw Wright G, Boehm KA, Asmar L, Bromund J,Peng G, Monberg MJ, Bepler G.
J Clin Oncol. 2009: in press.
 
Targeted therapy in combination with gemcitabine in non-small cell lung cancer.
Rosell R, Crino L, Danenberg K, Scagliotti G, Bepler G, Taron M, Alberola V, Provencio M, Camps C, De Marinis F, Sanchez JJ, Penas R.
Semin Oncol. 2003 Aug;30(4 Suppl 10):19-25.
PMID 12917817
 
Ribonucleotide reductase messenger RNA expression and survival in gemcitabine/cisplatin-treated advanced non-small cell lung cancer patients.
Rosell R, Danenberg KD, Alberola V, Bepler G, Sanchez JJ, Camps C, Provencio M, Isla D, Taron M, Diz P, Artal A; Spanish Lung Cancer Group.
Clin Cancer Res. 2004 Feb 15;10(4):1318-25.
PMID 14977831
 
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 JJ, Maestre J.
Clin Cancer Res. 2004 Jun 15;10(12 Pt 2):4215s-4219s.
PMID 15217961
 
Evidence that mammalian ribonucleotide reductase is a nuclear membrane associated glycoprotein.
Sikorska M, Brewer LM, Youdale T, Richards R, Whitfield JF, Houghten RA, Walker PR.
Biochem Cell Biol. 1990 May;68(5):880-8.
PMID 2205248
 
Ribonucleotide reductase subunits M1 and M2 mRNA expression levels and clinical outcome of lung adenocarcinoma patients treated with docetaxel/gemcitabine.
Souglakos J, Boukovinas I, Taron M, Mendez P, Mavroudis D, Tripaki M, Hatzidaki D, Koutsopoulos A, Stathopoulos E, Georgoulias V, Rosell R.
Br J Cancer. 2008 May 20;98(10):1710-5. Epub 2008 Apr 15.
PMID 18414411
 
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 Mar 2;404(6773):42-9.
PMID 10716435
 
Ribonucleotide reductase from calf thymus. Separation of the enzyme into two nonidentical subunits, proteins M1 and M2.
Thelander L, Eriksson S, Akerman M.
J Biol Chem. 1980 Aug 10;255(15):7426-32.
PMID 6993487
 
Chromosomal assignment of amplified genes in hydroxyurea-resistant hamster cells.
Tonin PN, Stallings RL, Carman MD, Bertino JR, Wright JA, Srinivasan PR, Lewis WH.
Cytogenet Cell Genet. 1987;45(2):102-8.
PMID 3622008
 
Bexarotene (LGD1069, Targretin), a selective retinoid X receptor agonist, prevents and reverses gemcitabine resistance in NSCLC cells by modulating gene amplification.
Tooker P, Yen WC, Ng SC, Negro-Vilar A, Hermann TW.
Cancer Res. 2007 May 1;67(9):4425-33.
PMID 17483357
 
High-density marker analysis of 11p15.5 in non-small cell lung carcinomas reveals allelic deletion of one shared and one distinct region when compared to breast carcinomas.
Tran YK, Newsham IF.
Cancer Res. 1996 Jul 1;56(13):2916-21.
PMID 8674040
 
Differential DNA sequence deletions from chromosomes 3, 11, 13, and 17 in squamous-cell carcinoma, large-cell carcinoma, and adenocarcinoma of the human lung.
Weston A, Willey JC, Modali R, Sugimura H, McDowell EM, Resau J, Light B, Haugen A, Mann DL, Trump BF, et al.
Proc Natl Acad Sci U S A. 1989 Jul;86(13):5099-103.
PMID 2567993
 
Altered expression of ribonucleotide reductase and role of M2 gene amplification in hydroxyurea-resistant hamster, mouse, rat, and human cell lines.
Wright JA, Alam TG, McClarty GA, Tagger AY, Thelander L.
Somat Cell Mol Genet. 1987 Mar;13(2):155-65.
PMID 3551113
 
Wild-type p53 regulates human ribonucleotide reductase by protein-protein interaction with p53R2 as well as hRRM2 subunits.
Xue L, Zhou B, Liu X, Qiu W, Jin Z, Yen Y.
Cancer Res. 2003 Mar 1;63(5):980-6.
PMID 12615712
 
p53R2-dependent pathway for DNA synthesis in a p53-regulated cell cycle checkpoint.
Yamaguchi T, Matsuda K, Sagiya Y, Iwadate M, Fujino MA, Nakamura Y, Arakawa H.
Cancer Res. 2001 Nov 15;61(22):8256-62.
PMID 11719458
 
Transcript map and complete genomic sequence for the 310 kb region of minimal allele loss on chromosome segment 11p15.5 in non-small-cell lung cancer.
Zhao B, Bepler G.
Oncogene. 2001 Dec 6;20(56):8154-64.
PMID 11781830
 
DNA synthesis and repair genes RRM1 and ERCC1 in lung cancer.
Zheng Z, Chen T, Li X, Haura E, Sharma A, Bepler G.
N Engl J Med. 2007 Feb 22;356(8):800-8.
PMID 17314339
 
ERCC1 and non-small-cell lung cancer.
Zhou SF.
N Engl J Med. 2007 Jun 14;356(24):2540; author reply 2540-1.
PMID 17575590
 
Expression microarray analysis and oligo array comparative genomic hybridization of acquired gemcitabine resistance in mouse colon reveals selection for chromosomal aberrations.
van de Wiel MA, Costa JL, Smid K, Oudejans CB, Bergman AM, Meijer GA, Peters GJ, Ylstra B.
Cancer Res. 2005 Nov 15;65(22):10208-13.
PMID 16288008
 

Citation

This paper should be referenced as such :
Freeman, SN ; Bepler, G
RRM1 (ribonucleotide reductase M1)
Atlas Genet Cytogenet Oncol Haematol. 2010;14(5):473-478.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/RRM1ID42174ch11p15.html


Other Leukemias implicated (Data extracted from papers in the Atlas) [ 1 ]
  t(3;5)(p21;q32) RBM6/CSF1R


External links

Nomenclature
HGNC (Hugo)RRM1   10451
Cards
AtlasRRM1ID42174ch11p15
Entrez_Gene (NCBI)RRM1  6240  ribonucleotide reductase catalytic subunit M1
AliasesR1; RIR1; RR1
GeneCards (Weizmann)RRM1
Ensembl hg19 (Hinxton)ENSG00000167325 [Gene_View]  chr11:4115915-4160155 [Contig_View]  RRM1 [Vega]
Ensembl hg38 (Hinxton)ENSG00000167325 [Gene_View]  chr11:4115915-4160155 [Contig_View]  RRM1 [Vega]
ICGC DataPortalENSG00000167325
TCGA cBioPortalRRM1
AceView (NCBI)RRM1
Genatlas (Paris)RRM1
WikiGenes6240
SOURCE (Princeton)RRM1
Genetics Home Reference (NIH)RRM1
Genomic and cartography
GoldenPath hg19 (UCSC)RRM1  -     chr11:4115915-4160155 +  11p15.5   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)RRM1  -     11p15.5   [Description]    (hg38-Dec_2013)
EnsemblRRM1 - 11p15.5 [CytoView hg19]  RRM1 - 11p15.5 [CytoView hg38]
Mapping of homologs : NCBIRRM1 [Mapview hg19]  RRM1 [Mapview hg38]
OMIM180410   
Gene and transcription
Genbank (Entrez)AK222786 AK297988 AK299629 AK301891 AK301922
RefSeq transcript (Entrez)NM_001033 NM_001318064 NM_001318065
RefSeq genomic (Entrez)NC_000011 NC_018922 NG_027992 NT_009237 NW_004929378
Consensus coding sequences : CCDS (NCBI)RRM1
Cluster EST : UnigeneHs.445705 [ NCBI ]
CGAP (NCI)Hs.445705
Alternative Splicing GalleryENSG00000167325
Gene ExpressionRRM1 [ NCBI-GEO ]   RRM1 [ EBI - ARRAY_EXPRESS ]   RRM1 [ SEEK ]   RRM1 [ MEM ]
Gene Expression Viewer (FireBrowse)RRM1 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)6240
GTEX Portal (Tissue expression)RRM1
Protein : pattern, domain, 3D structure
UniProt/SwissProtP23921   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP23921  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP23921
Splice isoforms : SwissVarP23921
Catalytic activity : Enzyme1.17.4.1 [ Enzyme-Expasy ]   1.17.4.11.17.4.1 [ IntEnz-EBI ]   1.17.4.1 [ BRENDA ]   1.17.4.1 [ KEGG ]   
PhosPhoSitePlusP23921
Domaine pattern : Prosite (Expaxy)ATP_CONE (PS51161)    RIBORED_LARGE (PS00089)   
Domains : Interpro (EBI)ATP-cone_dom    NrdE_NrdA    RNR_lg_C    RNR_lsu_N    RNR_R1-su_N   
Domain families : Pfam (Sanger)ATP-cone (PF03477)    Ribonuc_red_lgC (PF02867)    Ribonuc_red_lgN (PF00317)   
Domain families : Pfam (NCBI)pfam03477    pfam02867    pfam00317   
Conserved Domain (NCBI)RRM1
DMDM Disease mutations6240
Blocks (Seattle)RRM1
PDB (SRS)2WGH    3HNC    3HND    3HNE    3HNF    4X3V    5D1Y   
PDB (PDBSum)2WGH    3HNC    3HND    3HNE    3HNF    4X3V    5D1Y   
PDB (IMB)2WGH    3HNC    3HND    3HNE    3HNF    4X3V    5D1Y   
PDB (RSDB)2WGH    3HNC    3HND    3HNE    3HNF    4X3V    5D1Y   
Structural Biology KnowledgeBase2WGH    3HNC    3HND    3HNE    3HNF    4X3V    5D1Y   
SCOP (Structural Classification of Proteins)2WGH    3HNC    3HND    3HNE    3HNF    4X3V    5D1Y   
CATH (Classification of proteins structures)2WGH    3HNC    3HND    3HNE    3HNF    4X3V    5D1Y   
SuperfamilyP23921
Human Protein AtlasENSG00000167325
Peptide AtlasP23921
HPRD01588
IPIIPI00013871   IPI00979136   IPI01018616   IPI00943207   IPI01016072   IPI00979995   IPI01008934   IPI00976088   IPI00978090   IPI00979327   
Protein Interaction databases
DIP (DOE-UCLA)P23921
IntAct (EBI)P23921
FunCoupENSG00000167325
BioGRIDRRM1
STRING (EMBL)RRM1
ZODIACRRM1
Ontologies - Pathways
QuickGOP23921
Ontology : AmiGOmitotic cell cycle  ribonucleoside-diphosphate reductase activity, thioredoxin disulfide as acceptor  ribonucleoside-diphosphate reductase activity, thioredoxin disulfide as acceptor  protein binding  ATP binding  nuclear envelope  nucleoplasm  cytoplasm  cytosol  ribonucleoside-diphosphate reductase complex  pyrimidine nucleobase metabolic process  DNA replication  male gonad development  deoxyribonucleotide biosynthetic process  deoxyribonucleotide biosynthetic process  response to ionizing radiation  nucleobase-containing small molecule interconversion  cell proliferation in forebrain  cell projection  neuronal cell body  protein heterotetramerization  oxidation-reduction process  retina development in camera-type eye  extracellular exosome  
Ontology : EGO-EBImitotic cell cycle  ribonucleoside-diphosphate reductase activity, thioredoxin disulfide as acceptor  ribonucleoside-diphosphate reductase activity, thioredoxin disulfide as acceptor  protein binding  ATP binding  nuclear envelope  nucleoplasm  cytoplasm  cytosol  ribonucleoside-diphosphate reductase complex  pyrimidine nucleobase metabolic process  DNA replication  male gonad development  deoxyribonucleotide biosynthetic process  deoxyribonucleotide biosynthetic process  response to ionizing radiation  nucleobase-containing small molecule interconversion  cell proliferation in forebrain  cell projection  neuronal cell body  protein heterotetramerization  oxidation-reduction process  retina development in camera-type eye  extracellular exosome  
Pathways : KEGGPurine metabolism    Pyrimidine metabolism    Glutathione metabolism   
REACTOMEP23921 [protein]
REACTOME Pathways499943 [pathway]   
NDEx NetworkRRM1
Atlas of Cancer Signalling NetworkRRM1
Wikipedia pathwaysRRM1
Orthology - Evolution
OrthoDB6240
GeneTree (enSembl)ENSG00000167325
Phylogenetic Trees/Animal Genes : TreeFamRRM1
HOVERGENP23921
HOGENOMP23921
Homologs : HomoloGeneRRM1
Homology/Alignments : Family Browser (UCSC)RRM1
Gene fusions - Rearrangements
Fusion : MitelmanRRM1/STIM1 [11p15.4/11p15.4]  
Fusion: TCGARRM1 11p15.4 STIM1 11p15.4 BRCA
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerRRM1 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)RRM1
dbVarRRM1
ClinVarRRM1
1000_GenomesRRM1 
Exome Variant ServerRRM1
ExAC (Exome Aggregation Consortium)RRM1 (select the gene name)
Genetic variants : HAPMAP6240
Genomic Variants (DGV)RRM1 [DGVbeta]
DECIPHER (Syndromes)11:4115915-4160155  ENSG00000167325
CONAN: Copy Number AnalysisRRM1 
Mutations
ICGC Data PortalRRM1 
TCGA Data PortalRRM1 
Broad Tumor PortalRRM1
OASIS PortalRRM1 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICRRM1  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDRRM1
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch RRM1
DgiDB (Drug Gene Interaction Database)RRM1
DoCM (Curated mutations)RRM1 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)RRM1 (select a term)
intoGenRRM1
NCG5 (London)RRM1
Cancer3DRRM1(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM180410   
Orphanet
MedgenRRM1
Genetic Testing Registry RRM1
NextProtP23921 [Medical]
TSGene6240
GENETestsRRM1
Huge Navigator RRM1 [HugePedia]
snp3D : Map Gene to Disease6240
BioCentury BCIQRRM1
ClinGenRRM1
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD6240
Chemical/Pharm GKB GenePA298
Clinical trialRRM1
Miscellaneous
canSAR (ICR)RRM1 (select the gene name)
Probes
Litterature
PubMed118 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineRRM1
EVEXRRM1
GoPubMedRRM1
iHOPRRM1
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

Search in all EBI   NCBI

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Tue Mar 14 13:48:50 CET 2017

Home   Genes   Leukemias   Solid Tumours   Cancer-Prone   Deep Insight   Case Reports   Journals  Portal   Teaching   

For comments and suggestions or contributions, please contact us

jlhuret@AtlasGeneticsOncology.org.