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Gene Section
Review
RRM1 (ribonucleotide reductase M1)
Scott 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 (SNF, GB)
Published in Atlas Database: June 2009
Online updated version : http://AtlasGeneticsOncology.org/Genes/RRM1ID42174ch11p15.html
DOI: 10.4267/2042/44758
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Description
Identity
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 dTTPbinding site, the RRM2 peptide-binding site and the
dimer interface.
Other names: R1; RIR1; RR1
HGNC (Hugo): RRM1
Location: 11p15.4
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.
Expression
DNA/RNA
Pseudogene
While the RRM2 subunit of the ribonucleotide
reductase holoenzyme is regulated in a cell cyclespecific 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.
There are no reported human RRM1 pseudogenes.
Localisation
Protein
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
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.
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.
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(5)
473
RRM1 (ribonucleotide reductase M1)
Freeman SN, Bepler G
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 tglittermates. 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.
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 ATMmediated 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
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(5)
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
474
RRM1 (ribonucleotide reductase M1)
Freeman SN, Bepler G
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.
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
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.
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.
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
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
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(5)
475
RRM1 (ribonucleotide reductase M1)
Freeman SN, Bepler G
2',2'-difluorodeoxycytidine
arabinofuranosylcytosine.
15;48(14):4024-31
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.
and
Cancer
Res.
1-beta-D1988
Jul
Mann GJ, Musgrove EA, Fox RM, Thelander L. Ribonucleotide
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Weston A, Willey JC, Modali R, Sugimura H, McDowell EM,
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DNA sequence deletions from chromosomes 3, 11, 13, and 17
in squamous-cell carcinoma, large-cell carcinoma, and
adenocarcinoma of the human lung. Proc Natl Acad Sci U S A.
1989 Jul;86(13):5099-103
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This article should be referenced as such:
Freeman SN, Bepler G. RRM1 (ribonucleotide reductase M1).
Atlas Genet Cytogenet Oncol Haematol. 2010; 14(5):473-478.
Kim SO, Jeong JY, Kim MR, Cho HJ, Ju JY, Kwon YS, Oh IJ,
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patients with non-small cell lung cancer according to promoter
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