RRM2 (ribonucleotide reductase M2)
2014-04-01 Ali Afrasiabi, PhD , Hamid Fiuji , Reza Mirhafez , Amir Avan AffiliationIdentity
HGNC
LOCATION
2p25.1
LOCUSID
ALIAS
C2orf48,R2,RR2,RR2M
FUSION GENES
Abstract
Ribonucleotide reductase subunit M2 (RRM2) is located in chromosome-2 p25-p24, converts ribonucleotides to deoxynucleotides which is required for DNA polymerization and repair. It has been shown that RMM2 plays a key role in DNA synthesis, cell growth, and drug resistance of cancer cells. There is accumulating evidence that alteration in the expression level of RRM2 can have a substantial impact on the biological characteristics of cancer cells, including tumor initiation and progression, suggesting its role as a prognostic factor and a possible therapeutic target for cancer therapy. Therefore, this review highlights several recent and clinically relevant aspects of the expression and function of RRM2 in human cancer.
DNA/RNA
Table 1. Exons and introns of RRM2 gene. Figure 1. Ribonucleotide reductase subunit M2 (RRM2) is located in chr 2p25-p24. Synthesis of the encoded protein RRM2 is regulated in a cell-cycle dependent fashion and elevated to maximal levels during S-phase of cell cycle. RRM2 has two isoforms with different N-terminal lengths, variant 1 and 2, which contains 3452 and 3284 bp, respectively.
Description
RRM2 gene has ten exons, nine introns and alternative promoters (Table 1). The alternative promoters are resulting in two isoforms with different N-terminal lengths (variants 1 and 2; Figure 1). Variants 1 and 2 contain 3452 and 3284 bp, respectively. Variant 1 is the longest isoform with respect to the variant 2.
Transcription
Promoter of RRM2 gene has two transcription start sites, TATA box, three CCAAT boxes and several GC rich in 5 of the downstream transcription initiation site. Variant 2 has a shorter 5 UTR and uses a downstream translational start codon, compared to the variant 1. Regions of -204 to +1 and -659 to -257 act as a promoter for the variant 1 (1.65 kbp) and variant 2 (3.4 kbp), respectively. Several studies are currently ongoing for the role of the 3 UTR in the regulation of RRM2 expression. Moreover, three CCAAT boxes exist in the region between transcription initiating sites at positions -82, -109, -139 and -436. Also, the transcription of 1.65 kbp RRM2 mRNA initiates from +1, while 3.4 kbp mRNA RRM2 initiates at position -187 (Zhou and Yen, 2001).
Synthesis of the encoded protein (RRM2) is regulated in a cell-cycle dependent fashion and elevated to maximal levels during S-phase of cell cycle (Figure 1). RRM2 promoter has transcription factor binding sites for SP1, c-Ets, MZF1, E2F, Lyf-1, GATA-X, HSF2, AP-1, CdxA, IK-2, Sox-5, SRY, Brn-2, HNF-1, STATx, GATA-1, USF (c-Myc), Pbx-1, Oct-1, GATA-2, CRE-Bp and Nkx-2. 3.4 kbp RRM2 mRNA is the major form in kidney, placenta and lung, while 1.65 kbp RRM2 mRNA is the main form in small intestine, colon, testis and thymus. RRM2 gene expression level is high in small intestine, colon thymus and testis tissues. In addition RRM2 mRNA in heart is very higher with respect to other tissues. Conversely, the expression level of RRM2 gene is low in lung and liver tissues, and its level is very low level in prostate, skeletal muscle, brain and leukocyte tissues (Zhou and Yen, 2001; Park and Levine, 2000).
Synthesis of the encoded protein (RRM2) is regulated in a cell-cycle dependent fashion and elevated to maximal levels during S-phase of cell cycle (Figure 1). RRM2 promoter has transcription factor binding sites for SP1, c-Ets, MZF1, E2F, Lyf-1, GATA-X, HSF2, AP-1, CdxA, IK-2, Sox-5, SRY, Brn-2, HNF-1, STATx, GATA-1, USF (c-Myc), Pbx-1, Oct-1, GATA-2, CRE-Bp and Nkx-2. 3.4 kbp RRM2 mRNA is the major form in kidney, placenta and lung, while 1.65 kbp RRM2 mRNA is the main form in small intestine, colon, testis and thymus. RRM2 gene expression level is high in small intestine, colon thymus and testis tissues. In addition RRM2 mRNA in heart is very higher with respect to other tissues. Conversely, the expression level of RRM2 gene is low in lung and liver tissues, and its level is very low level in prostate, skeletal muscle, brain and leukocyte tissues (Zhou and Yen, 2001; Park and Levine, 2000).
Pseudogene
Related pseudogenes have been identified on chromosomes 1 and X (1p33→p31, 1q21→q23 and Xp21→p11).
Proteins
Description
The building blocks of DNA, deoxyribonucleotide triphosphates (dNTPs), is provided/generated by ribonucleotide reductases (RNR). In fact RNR have a vital role in preserving the appropriate amount of dNTPs (dATP, dGTP, dCTP, dTTP) pool for DNA replication and repair by converting ribonucleotide diphosphates (NDP) to deoxyribonucleotide diphosphates (dNDP). RNR enzymes are divided into three different classes: I, II and III. Human RNR belongs to the class I. Furthermore, RNR has two subunits, RRM1 and RRM2. RRM1 is the larger subunit of RNR with respect to the RRM2. RRM2 isoform 1 and 2 have 449 and 389 residues, respectively. In particular, isoform 1 has 60 residues more than isoform 2 inits N-terminal region. RRM2 interact with RRM1 through its C-terminus region (Nordlund and Reichard, 2006; Eklund et al., 2001; Thelander, 2007).
Expression
RRM2 protein expression is increased to maximal level during S-phase due to E2F, as an activator of DNA synthesizing enzymes, however, its exression is reduced during G1 by E2F4 (Eklund et al., 2001; Nordlund and Reichard, 2006).
Function
RRM2 contains a KEN-box on the N-terminus that is recognized during the mitosis by the Cdh1-anaphase-promoting complex and thereby becomes poly-ubiquitinated or depredates by proteasome (Nordlund and Reichard, 2006; Eklund et al., 2001; Thelander, 2007). RRM2 is responsible for producing a stable tyrosyl radical for the active site of RNR that is located in RRM1. In addition, p53R2 is 80% similar to RRM2, which can bind to RRM1 and form the active structure. According to the vital role of RNR in cell cycle and proliferation, RNRs can be considered as suitable targets for cancer treatment. Several studies have been demonstrated that inhibition of RRM2 can inhibit cancer cell growth and overcomes drug resistance (Aimiuwu et al., 2012; Zhou et al., 2013). In particular, Zhou and colleagues showed that inhibition of RRM2 by novel RNR inhibitor COH29 inhibited the proliferation of most cell lines in the human cancer panel, mostly ovarian cancer and leukemia. In mouse xenograft models of human cancer, COH29 treatment reduced tumor growth with respect to the control group (Zhou et al., 2013).
Homology
The RRM2 gene is conserved in Rhesus monkey, dog, chicken, cow, mouse, rat, K. lactis, fruit fly, mosquito, C. elegans, M. oryzae, S. cerevisiae, S. pombe, E. gossypii, N. crassa, and A. thaliana. Percentage of identity or homology of RRM2 in DNA and protein levels in eukaryots with respect to human is shown in Table 2.
Table 2. Percentage of identity/homology of RRM2 in DNA and protein levels in eukaryotes with respect to human.
Mutations
Note
More than 1215 single nucleotide variations (SNPs) have been reported in RRM2 gene (until 5th of March 2014, dbSNP), such as rs15516, rs1130609, rs1138727, rs1138728, rs1138729, rs4668664, etc.
Implicated in
Entity name
Pancreatic cancer
Note
Youns and colleagues recently showed that RRM2 is overexpressed in the pancreatic cancer cell lines. They performed a gene expression profiling to identify novel molecular targets modulating the growth inhibitory effects of COX-2 inhibitor NS-398 in pancreatic cancer. They found that RRM2 was down-regulated in BxPC-3, MiaPaCa-2 and ASPC-1 cell lines after treatment with NS-398. Moreover, they identified RRM2 as a biomarker for the chemo-preventive effect of NS-398 in pancreatic cancer cells (Youns et al., 2011). Previous study illustrated that over-expression of RRM2 was associated with resistance to gemcitabine in pancreatic cancer (Nakano et al., 2007). In this study the expression level of RRM2 was analysed by q-PCR in different subclones during the development of acquired resistance to gemcitabine. This analysis showed that the expression level of RRM2 enhanced during the development of gemcitabine resistance. Moreover, they also evaluated the expression levels of other genes, RRM1, dCK, hENT1. This results illustrated that expression ratio significantly correlated with gemcitabine sensitivity in eight pancreatic cancer cell lines, whereas no single gene expression level correlated with the sensitivity, indicating that the sensitivity of pancreatic cancer cells to gemcitabine is dependent on the ratio of four factors involved in gemcitabine transport and metabolism. On the one hand, the ratio of the four gene expression associated with acquired gemcitabine-resistance in pancreatic cancer cells (Nakano et al., 2007). Moreover, Duxbury et al., showed that small interfering RNA targeting RRM2 enhanced chemosensitivity to gemcitabine in pancreatic adenocarcinoma (Duxbury et al., 2004), suggesting its role as an attractive target for pancreatic cancer.
Entity name
Lung cancer
Note
Several studies have been shown that RRM2 is overexpressed in lung cancer. In particular, Souglakos and colleagues showed that patients with low level of RRM2 had a significantly higher response rate (60% vs 14.2%), time to progression (9.9 vs 2.3 months), and overall survival (15.4 vs 3.6 months) in metastatic lung adenocarcinoma patients treated with gemcitabine plus docetaxel with respect to the patients with high level of RRM2 (Souglakos et al., 2008). Furthermore, Boukovinas et al., evaluated the effect of RRM2 expression on outcome to gemcitabine plus docetaxel in advanced non-small-cell lung cancer (NSCLC) patients. RRM1, RRM2 and BRCA1 mRNA levels were determined by quantitative PCR and correlated with response, time to progression and survival. This study showed that the probability of response decreased (RRM2: Odds Ratio, 0.94; p
Entity name
Breast cancer
Note
It has been shown that RRM2 is overexpressed in human breast carcinoma tissue (DCIS, Jensen et al., 1994). Recently Kretschmer and colleagues identified molecular markers for the ductal carcinoma in situ using WAP-TNP8 mouse model. In particular, they identified seven marker genes (RRM2, MUC1, SPP1, FOXM1, EXO1, NUSAP1 and DEPDC1), which were overexpressed at a very early stage of premalignancy and preneoplasia of breast carcinomas (Kretschmer et al., 2011).
Entity name
Ovarian cancer
Note
Ferrandina and colleagues found a association between RRM2 expression level and relative risk of death in ovarian cancer. In this study they evaluated the mRNA expression levels of several genes involved in transportation and metabolism of gemcitabine, including RRM2, in 25 primary ovarian carcinomas using q-PCR. They showed that samples with high RRM2 expression had a less overall survival, OS, (median OS=19 months) with respect to the samples with low RRM2 level (median OS=36 months; Ferrandina et al., 2010).
Entity name
Note
Fellenberg et al., in 2007 investigated the prognostic value of eight genes including RRM2 in 35 formalin-fixed osteosarcoma biopsies. They observed a significant relation between RRM2 expression with overall survival of the patients. However, the prognostic value of this gene did not confirm by multivariate analysis and further studies are needed to evaluate the prognostic role of RRM2 in osteosarcoma (Fellenberg et al., 2007).
Entity name
Bladder cancer
Note
Lu and colleagues investigated whether global gene expression profiling can help in predecting the suitability of rodent models of bladder cancer for the detection of cancer-related genes and prediction of cancer prevention in human bladder cancer and carcinogen-induced rodent models. They found that 13~34% of whole genome were differentially expressed between tumor and normal tissues in humans, Fischer-344 rats, and B6D2F1 mice. Approximately 20% of these differentially expressed genes overlapped among species, corresponding to 2.6 to 4.8% of whole genes in the genome. A number of genes were consistently dysregulated in bladder tumors in both humans and rodents. Among these genes, RRM2 was up-regulated in tumor tissue across three species, suggesting its role as a potential factor in contributing to bladder carcinogenesis (Lu et al., 2010).
Entity name
Hepatocellular carcinoma
Disease
Patients with hepatocellular carcinoma (HCC) suffer from chronic hepatitis or liver cirrhosis. Satow and colleagues performed whole-genome RNA interference-based functional screening in order to identify genes that sensitize lung cancer cells to drug and genes required for proliferation and survival of HCC cells. In this study four genes (AKR1B10, HCAP-G, RRM2, and TPX2) were found to be expressed strongly in HCC, suggeting their role as potential therapeutic targets in hepatocellular carcinoma (Satow et al., 2010).
Entity name
Gastric cancer
Note
Morikawa et al., in 2010, explored the prognostic value of RRM2 in 112 gastric cancer samples using immunohistochemistry (Morikawa et al., 2010). They found that RRM2 expression was limited to the neck regions of gastric pits, in normal gastric mucosa. Moreover, they observed RRM2 overexpression in 72 cases (64.3%), among 112 gastric cancer tissues. In vitro analysis and inhibition of RRM2 systhesis by small interfering RNA, inhibited the growth of three gastric cancer cell lines, MKN-1, MKN-7, and SNU-719. Furthermore, they demonstarted that overexpression of RRM2 was associated with the gastric cancer progression and suppression of its function could be considered as a potential therapeutic strategy in gastric cancer (Morikawa et al., 2010).
Entity name
Parkinson disease
Note
The inhibitory effect of dopamine on RRM1/2 has been reported in Parkinson disease. Dopamine inhibits RNR through two pathways: (I) dopamine acts as an effective radical scavenger and scavenge the tyrosyl radical of RRM2, which is important for initiating of catalytic process in RRM1 active site and (II) chelates the iron center of RRM2 which acts as a chelator for iron and other metals. In addition nitric oxide induces dopaminergic neuronal cells through inhibiting RNR (Woldman et al,. 2005; Ebadi and Sharma, 2003).
Article Bibliography
| Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|
| 22517893 | 2012 | RNA-dependent inhibition of ribonucleotide reductase is a major pathway for 5-azacytidine activity in acute myeloid leukemia. | Aimiuwu J et al |
| 23335963 | 2013 | Differential processing of let-7a precursors influences RRM2 expression and chemosensitivity in pancreatic cancer: role of LIN-28 and SET oncoprotein. | Bhutia YD et al |
| 19002265 | 2008 | 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 et al |
| 15300189 | 2004 | RETRACTED: Retrovirally mediated RNA interference targeting the M2 subunit of ribonucleotide reductase: A novel therapeutic strategy in pancreatic cancer. | Duxbury MS et al |
| 12880486 | 2003 | Peroxynitrite and mitochondrial dysfunction in the pathogenesis of Parkinson's disease. | Ebadi M et al |
| 11796141 | 2001 | Structure and function of the radical enzyme ribonucleotide reductase. | Eklund H et al |
| 3049070 | 1988 | Immunocytochemical evidence for the cytoplasmic localization and differential expression during the cell cycle of the M1 and M2 subunits of mammalian ribonucleotide reductase. | Engström Y et al |
| 17660802 | 2007 | Prognostic significance of drug-regulated genes in high-grade osteosarcoma. | Fellenberg J et al |
| 19639316 | 2010 | Expression of nucleoside transporters, deoxycitidine kinase, ribonucleotide reductase regulatory subunits, and gemcitabine catabolic enzymes in primary ovarian cancer. | Ferrandina G et al |
| 10485455 | 1999 | Overexpression of ribonucleotide reductase as a mechanism of resistance to 2,2-difluorodeoxycytidine in the human KB cancer cell line. | Goan YG et al |
| 7937751 | 1994 | Identification of genes expressed in premalignant breast disease by microscopy-directed cloning. | Jensen RA et al |
| 21314937 | 2011 | Identification of early molecular markers for breast cancer. | Kretschmer C et al |
| 21139803 | 2010 | Cross-species comparison of orthologous gene expression in human bladder cancer and carcinogen-induced rodent models. | Lu Y et al |
| 20825972 | 2010 | Expression of ribonucleotide reductase M2 subunit in gastric cancer and effects of RRM2 inhibition in vitro. | Morikawa T et al |
| 17224927 | 2007 | Gemcitabine chemoresistance and molecular markers associated with gemcitabine transport and metabolism in human pancreatic cancer cells. | Nakano Y et al |
| 16756507 | 2006 | Ribonucleotide reductases. | Nordlund P et al |
| 10631117 | 2000 | Characterization of the promoter of the human ribonucleotide reductase R2 gene. | Park JB et al |
| 20388846 | 2010 | Combined functional genome survey of therapeutic targets for hepatocellular carcinoma. | Satow R et al |
| 18414411 | 2008 | Ribonucleotide reductase subunits M1 and M2 mRNA expression levels and clinical outcome of lung adenocarcinoma patients treated with docetaxel/gemcitabine. | Souglakos J et al |
| 10716435 | 2000 | A ribonucleotide reductase gene involved in a p53-dependent cell-cycle checkpoint for DNA damage. | Tanaka H et al |
| 17534360 | 2007 | Ribonucleotide reductase and mitochondrial DNA synthesis. | Thelander L et al |
| 24155212 | 2014 | Expression of RRM1 and RRM2 as a novel prognostic marker in advanced non-small cell lung cancer receiving chemotherapy. | Wang L et al |
| 15755480 | 2005 | Dopamine inhibits cell growth and cell cycle by blocking ribonucleotide reductase. | Woldman I et al |
| 20969859 | 2011 | Transcript profiling identifies novel key players mediating the growth inhibitory effect of NS-398 on human pancreatic cancer cells. | Youns M et al |
| 14583450 | 2003 | The human ribonucleotide reductase subunit hRRM2 complements p53R2 in response to UV-induced DNA repair in cells with mutant p53. | Zhou B et al |
| 24072748 | 2013 | A small-molecule blocking ribonucleotide reductase holoenzyme formation inhibits cancer cell growth and overcomes drug resistance. | Zhou B et al |
| 11978970 | 2001 | Characterization of the human ribonucleotide reductase M2 subunit gene; genomic structure and promoter analyses. | Zhou B et al |
Other Information
Locus ID:
NCBI: 6241
MIM: 180390
HGNC: 10452
Ensembl: ENSG00000171848
Variants:
dbSNP: 6241
ClinVar: 6241
TCGA: ENSG00000171848
COSMIC: RRM2
RNA/Proteins
Expression (GTEx)
Pathways
Protein levels (Protein atlas)
PharmGKB
| Entity ID | Name | Type | Evidence | Association | PK | PD | PMIDs |
|---|---|---|---|---|---|---|---|
| PA444760 | Leukemia, Myeloid, Acute | Disease | ClinicalAnnotation | associated | PD | 24024897 | |
| PA449027 | cladribine | Chemical | ClinicalAnnotation | associated | PD | 24024897 | |
| PA449177 | cytarabine | Chemical | ClinicalAnnotation | associated | PD | 24024897 |
References
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 38635758 | 2024 | A comprehensive analysis of ribonucleotide reductase subunit M2 for carcinogenesis in pan-cancer. | 0 |
| 38820515 | 2024 | IGF2BP3 regulates the expression of RRM2 and promotes the progression of rheumatoid arthritis via RRM2/Akt/MMP-9 pathway. | 0 |
| 38821625 | 2024 | RRM2 Is a CTNNB1 Transport Regulator Promoting Colon Cancer Progression. | 0 |
| 38635758 | 2024 | A comprehensive analysis of ribonucleotide reductase subunit M2 for carcinogenesis in pan-cancer. | 0 |
| 38820515 | 2024 | IGF2BP3 regulates the expression of RRM2 and promotes the progression of rheumatoid arthritis via RRM2/Akt/MMP-9 pathway. | 0 |
| 38821625 | 2024 | RRM2 Is a CTNNB1 Transport Regulator Promoting Colon Cancer Progression. | 0 |
| 36768895 | 2023 | NMR Analysis Suggests Synergy between the RRM2 and the Carboxy-Terminal Segment of Human La Protein in the Recognition and Interaction with HCV IRES. | 0 |
| 36882565 | 2023 | Ribonucleotide reductase subunit switching in hepatoblastoma drug response and relapse. | 2 |
| 37115505 | 2023 | MiR-17- 5p/RRM2 regulated gemcitabine resistance in lung cancer A549 cells. | 5 |
| 37196077 | 2023 | Ribonucleotide reductase regulatory subunit M2 drives glioblastoma TMZ resistance through modulation of dNTP production. | 9 |
| 37341611 | 2023 | USP12 promotes nonsmall cell lung cancer progression through deubiquitinating and stabilizing RRM2. | 2 |
| 37814947 | 2023 | Serum ribonucleotide reductase M2 is a potential biomarker for diagnosing and monitoring liver fibrosis in chronic hepatitis B patients. | 0 |
| 37863324 | 2023 | E2F8 exerts cancer-promoting effects by transcriptionally activating RRM2 and E2F8 knockdown synergizes with WEE1 inhibition in suppressing lung adenocarcinoma. | 1 |
| 38124207 | 2023 | Targeting of RRM2 suppresses DNA damage response and activates apoptosis in atypical teratoid rhabdoid tumor. | 0 |
| 36768895 | 2023 | NMR Analysis Suggests Synergy between the RRM2 and the Carboxy-Terminal Segment of Human La Protein in the Recognition and Interaction with HCV IRES. | 0 |
Citation
Ali Afrasiabi, PhD ; Hamid Fiuji ; Reza Mirhafez ; Amir Avan
RRM2 (ribonucleotide reductase M2)
Atlas Genet Cytogenet Oncol Haematol. 2014-04-01
Online version: http://atlasgeneticsoncology.org/gene/42175/rrm2-(ribonucleotide-reductase-m2)
