Atlas of Genetics and Cytogenetics in Oncology and Haematology

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RRM1 (ribonucleotide reductase M1)

Identity

Other namesR1
RIR1
RR1
HGNC (Hugo) RRM1
LocusID (NCBI) 6240
Location 11p15.4
Location_base_pair Starts at 4115924 and ends at 4160106 bp from pter ( according to hg19-Feb_2009)  [Mapping]
Local_order STIM1-RRM1-OR55B1P-LOC643244.
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

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.
  

External links

Nomenclature
HGNC (Hugo)RRM1   10451
Entrez_Gene (NCBI)RRM1  6240  ribonucleotide reductase M1
Cards
AtlasRRM1ID42174ch11p15
GeneCards (Weizmann)RRM1
Ensembl (Hinxton)ENSG00000167325 [Gene_View]  chr11:4115924-4160106 [Contig_View]  RRM1 [Vega]
AceView (NCBI)RRM1
Genatlas (Paris)RRM1
SOURCE (Stanford)NM_001033
Genomic and cartography
GoldenPath (UCSC)RRM1  -  11p15.4   chr11:4115924-4160106 +  11p15.5   [Description]    (hg19-Feb_2009)
EnsemblRRM1 - 11p15.5 [CytoView]
Mapping of homologs : NCBIRRM1 [Mapview]
OMIM180410   
Gene and transcription
Genbank (Entrez)AK222786 AK297988 AK299629 AK301891 AK301922
RefSeq transcript (SRS)NM_001033
RefSeq transcript (Entrez)NM_001033
RefSeq genomic (SRS)AC_000143 NC_000011 NC_018922 NG_027992 NT_009237 NW_001838018 NW_004078070
RefSeq genomic (Entrez)AC_000143 NC_000011 NC_018922 NG_027992 NT_009237 NW_001838018 NW_004078070
Consensus coding sequences : CCDS (NCBI)RRM1
Cluster EST : UnigeneHs.445705 [ SRS ] Hs.445705 [ NCBI ]
CGAP (NCI)Hs.445705
Alternative Splicing : Fast-db (Paris)GSHG0004560
Alternative Splicing GalleryENSG00000167325
Gene ExpressionRRM1 [ NCBI-GEO ]   RRM1 [ EBI - ARRAY_EXPRESS ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP23921 (SRS) P23921 (Uniprot)
NextProtP23921
With graphics : InterProP23921
Splice isoforms : SwissVarP23921(Swissvar)
Domaine pattern : Prosite (SRS)ATP_CONE (PS51161)    RIBORED_LARGE (PS00089)   
Domaine pattern : Prosite (Expaxy)ATP_CONE (PS51161)    RIBORED_LARGE (PS00089)   
Domains : Interpro (SRS)ATP-cone    NrdE_NrdA    RNR_lg_C    RNR_lsu_N    RNR_R1-su_N   
Domains : Interpro (EBI)ATP-cone    NrdE_NrdA    RNR_lg_C    RNR_lsu_N    RNR_R1-su_N   
Related proteins : CluSTrP23921
Domain families : Pfam (SRS)ATP-cone (PF03477)    Ribonuc_red_lgC (PF02867)    Ribonuc_red_lgN (PF00317)   
Domain families : Pfam (Sanger)ATP-cone (PF03477)    Ribonuc_red_lgC (PF02867)    Ribonuc_red_lgN (PF00317)   
Domain families : Pfam (NCBI)pfam03477    pfam02867    pfam00317   
DMDM6240
Blocks (Seattle)P23921
PDB (SRS)2WGH    3HNC    3HND    3HNE    3HNF   
PDB (PDBSum)2WGH    3HNC    3HND    3HNE    3HNF   
PDB (IMB)2WGH    3HNC    3HND    3HNE    3HNF   
PDB (RSDB)2WGH    3HNC    3HND    3HNE    3HNF   
Human Protein AtlasENSG00000167325
HPRD01588
IPIIPI00013871   IPI00979136   IPI01018616   IPI00943207   IPI01016072   IPI00979995   IPI01008934   IPI00976088   IPI00978090   IPI00979327   
Protein Interaction databases
DIP (DOE-UCLA)P23921
IntAct (EBI)P23921
FunCoupENSG00000167325
REACTOMERRM1
Protein Interaction Database6240
BioGRIDRRM1
InParanoidP23921
Interologous Interaction database P23921
IntegromeDBRRM1
Polymorphism : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)RRM1
SNP (GeneSNP Utah)RRM1
SNP : HGBaseRRM1
Genetic variants : HAPMAPRRM1
Somatic Mutations in Cancer : COSMICRRM1 
CONAN: Copy Number AnalysisRRM1 
Mutations and Diseases : HGMDRRM1
OMIM180410   
GENETests180410   
Disease Genetic AssociationRRM1
Huge Navigator RRM1 [HugePedia]  RRM1 [HugeCancerGEM]
Genomic VariantsRRM1  RRM1 [DGVbeta]
snp3D : Map Gene to Disease6240
General knowledge
Homologs : HomoloGeneRRM1
Homology/Alignments : Family Browser (UCSC)RRM1
Phylogenetic Trees/Animal Genes : TreeFamRRM1
Catalytic activity : Enzyme1.17.4.1 [ Enzyme-Expasy ]   1.17.4.1 [ Enzyme-SRS ]   1.17.4.1 [ IntEnz-EBI ]   1.17.4.1 [ BRENDA ]   1.17.4.1 [ KEGG ]   
Chemical/Protein Interactions : CTD6240
Chemical/Pharm GKB GenePA298
Clinical trialRRM1
Cancer Resource (Charite)ENSG00000167325
Ontology : AmiGOribonucleoside-diphosphate reductase activity, thioredoxin disulfide as acceptor  ribonucleoside-diphosphate reductase activity, thioredoxin disulfide as acceptor  protein binding  ATP binding  nucleoplasm  cytosol  ribonucleoside-diphosphate reductase complex  DNA replication  DNA replication  deoxyribonucleotide biosynthetic process  nucleobase-containing small molecule interconversion  small molecule metabolic process  protein heterotetramerization  nucleobase-containing small molecule metabolic process  
Ontology : EGO-EBIribonucleoside-diphosphate reductase activity, thioredoxin disulfide as acceptor  ribonucleoside-diphosphate reductase activity, thioredoxin disulfide as acceptor  protein binding  ATP binding  nucleoplasm  cytosol  ribonucleoside-diphosphate reductase complex  DNA replication  DNA replication  deoxyribonucleotide biosynthetic process  nucleobase-containing small molecule interconversion  small molecule metabolic process  protein heterotetramerization  nucleobase-containing small molecule metabolic process  
Pathways : KEGGPyrimidine metabolismPurine metabolism
Other databases
Probes
Litterature
PubMed81 Pubmed reference(s) in Entrez
PubGeneRRM1
iHOPRRM1

Bibliography

Reduction of ribonucleotides.
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PMID 382982
 
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PMID 3894352
 
Characterization of a mouse cell line selected for hydroxyurea resistance by a stepwise procedure: drug-dependent overproduction of ribonucleotide reductase activity.
McClarty GA, Chan AK, Wright JA.
Somat Cell Mol Genet. 1986 Mar;12(2):121-31.
PMID 3515584
 
Gene for M1 subunit of ribonucleotide reductase is amplified in hydroxyurea-resistant hamster cells.
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PMID 3299747
 
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PMID 3551113
 
The structural gene for the M1 subunit of ribonucleotide reductase maps to chromosome 11, band p15, in human and to chromosome 7 in mouse.
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PMID 3275546
 
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.
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PMID 2832057
 
Immunocytochemical evidence for the cytoplasmic localization and differential expression during the cell cycle of the M1 and M2 subunits of mammalian ribonucleotide reductase.
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PMID 3049070
 
Comparison of the cellular pharmacokinetics and toxicity of 2',2'-difluorodeoxycytidine and 1-beta-D-arabinofuranosylcytosine.
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Cancer Res. 1988 Jul 15;48(14):4024-31.
PMID 3383195
 
Ribonucleotide reductase M1 subunit in cellular proliferation, quiescence, and differentiation.
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PMID 3044582
 
Differential DNA sequence deletions from chromosomes 3, 11, 13, and 17 in squamous-cell carcinoma, large-cell carcinoma, and adenocarcinoma of the human lung.
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Inhibition of ribonucleotide reduction in CCRF-CEM cells by 2',2'-difluorodeoxycytidine.
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PMID 2233693
 
Amplification of the genes for both components of ribonucleotide reductase in hydroxyurea resistant mammalian cells.
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PMID 2178608
 
Evidence that mammalian ribonucleotide reductase is a nuclear membrane associated glycoprotein.
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PMID 2205248
 
Allelic loss on the short arm of chromosome 11 in non-small-cell lung cancer.
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PMID 1682278
 
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PMID 1840662
 
Sequence analysis of the large and small subunits of human ribonucleotide reductase.
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Three tumor-suppressor regions on chromosome 11p identified by high-resolution deletion mapping in human non-small-cell lung cancer.
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PMID 7805035
 
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PMID 8674040
 
The R1 component of mammalian ribonucleotide reductase has malignancy-suppressing activity as demonstrated by gene transfer experiments.
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Delineation of the centromeric and telomeric chromosome segment 11p15.5 lung cancer suppressor regions LOH11A and LOH11B.
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PMID 9115960
 
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PMID 9413155
 
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PMID 9466044
 
A 1.4-Mb high-resolution physical map and contig of chromosome segment 11p15.5 and genes in the LOH11A metastasis suppressor region.
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Characterization of a dCTP transport activity reconstituted from human mitochondria.
Bridges EG, Jiang Z, Cheng YC.
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PMID 9988697
 
Lung cancer and the human gene for ribonucleotide reductase subunit M1 (RRM1).
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PMID 10441745
 
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
 
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
 
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.
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PMID 10716435
 
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
 
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
 
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-induced metastasis suppression through PTEN-regulated pathways.
Gautam A, Li ZR, Bepler G.
Oncogene. 2003 Apr 10;22(14):2135-42.
PMID 12687015
 
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
 
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.
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Contributor(s)

Written06-2009Scott N Freeman, Gerold Bepler
Department of Thoracic Oncology, Experimental Therapeutics Program and Lung Cancer Program, H Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA

Citation

This paper should be referenced as such :
Freeman SN, Bepler G . RRM1 (ribonucleotide reductase M1). Atlas Genet Cytogenet Oncol Haematol. June 2009 .
URL : http://AtlasGeneticsOncology.org/Genes/RRM1ID42174ch11p15.html

This paper is referenced by INIST as such :
http://documents.irevues.inist.fr/bitstream/2042/44758/1/06-2009-RRM1ID42174ch11p15.pdf   [ Bibliographic record ]

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