Biosci. Rep. (2010) / 30 / 135–148 (Printed in Great Britain) / doi 10.1042/BSR20090057
Queuosine modification of tRNA: its divergent role
in cellular machinery
Manjula VINAYAK1 and Chandramani PATHAK2
Biochemistry and Molecular Biology Laboratory, Centre of Advanced Study in Zoology, Banaras Hindu University, Varanasi 221005, India
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Synopsis
tRNAs possess a high content of modified nucleosides, which display an incredible structural variety. These modified nucleosides are conserved in their sequence and have important roles in tRNA functions. Most often, hypermodified nucleosides are found in the wobble position of tRNAs, which play a direct role in maintaining translational
efficiency and fidelity, codon recognition, etc. One of such hypermodified base is queuine, which is a base analogue of
guanine, found in the first anticodon position of specific tRNAs (tyrosine, histidine, aspartate and asparagine tRNAs).
These tRNAs of the ‘Q-family’ originally contain guanine in the first position of anticodon, which is post-transcriptionally
modified with queuine by an irreversible insertion during maturation. Queuine is ubiquitously present throughout the
living system from prokaryotes to eukaryotes, including plants. Prokaryotes can synthesize queuine de novo by a
complex biosynthetic pathway, whereas eukaryotes are unable to synthesize either the precursor or queuine. They
utilize salvage system and acquire queuine as a nutrient factor from their diet or from intestinal microflora. The tRNAs
of the Q-family are completely modified in terminally differentiated somatic cells. However, hypomodification of Q-tRNA
(queuosine-modified tRNA) is closely associated with cell proliferation and malignancy. The precise mechanisms of
queuine- and Q-tRNA-mediated action are still a mystery. Direct or indirect evidence suggests that queuine or Q-tRNA
participates in many cellular functions, such as inhibition of cell proliferation, control of aerobic and anaerobic metabolism, bacterial virulence, etc. The role of Q-tRNA modification in cellular machinery and the signalling pathways
involved therein is the focus of this review.
Key words: antioxidant defence system, cell signalling, glycolytic metabolism, queuine, queuosine-modified tRNA
(Q-tRNA)
&
INTRODUCTION
The presence of modified nucleosides is a distinctive structural
feature of tRNA which leads to structural variety [1]. An important function of the modified nucleosides is in structural formation
and stabilization of functional RNAs [2]. The degree of modification varies with the source of tRNA and appears to increase
in amount with the evolutionary development of the organism.
Maximum number of modified bases are found in human tRNA,
whereas they appear much less in bacterial tRNA [3]. Currently,
the structure of more than 93 modified nucleosides is well known
[4]. The role of all the modified nucleosides is still not clear,
although their importance is slowly emerging.
Modified bases in tRNA influence or modulate its activity at
various levels, such as the rate of initiation of protein synthesis
[5,6], in vitro peptide elongation [7,8], kinetics of aminoacyl-
%
ation [9], recognition by aminoacyl tRNA synthetase [10], tRNA–
ribosome interaction [11], stabilization of tRNA conformation
and resistance towards nucleases [12,13], modulation of translation [14,15], codon recognition [5,8], translational frameshifting
[16], metabolism [17], signal transduction [18], bacterial virulence [19], regulation of cell proliferation [20,21], etc. tRNAs,
apart from the function as adaptor molecules in protein synthesis,
are also involved in many other cellular processes, such as protein modification, cell-wall biosynthesis, viral infection, RNA
metabolism and the regulation of gene expression [22–24].
tRNA MODIFICATION
A subset of the modified nucleosides, including D, , Um, ac4 C,
Cm, m1 G, m7 G, Gm, m1 A, t6 A and I, are present in tRNA from
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Abbreviations used: D-loop, dihydrouridine loop; EGF, epidermal growth factor; EGFR, EGF receptor; epoxyQ, 2,3-epoxy-4,5-dihydroxycyclopentyl-7-aminomethyl-7-deazaguanosine;
LDH, lactate dehydrogenase; PDGF, platelet-derived growth factor; preQ0 , 7-cyano-7-deazaguanine; preQ1 , 7-aminomethyl-7-deazaguanine; Q-tRNA, queuosine-modified tRNA; ROS,
reactive oxygen species; SAM:TRTase, S-adenosylmethionine:tRNA ribosyltransferase; TGTase, tRNA guanine transglycosylase
1 To whom correspondence should be addressed (email [email protected]).
2 Present address: National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India.
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M. Vinayak and C. Pathak
all the phylogenic domains, namely archaea, bacteria and eukaryotes [25]. Some are even present at comparative position in
tRNA from all three phylogenic domains, for example, 13,
Cm32, m1 G37, t6 A37, 38, 39, 55 and m1 A58 [26]. The
distribution of modified nucleosides in tRNA in the different
phylogenic domains supports the concept that there are three
different lines of descent from a common ancestor [27]. Some
modified nucleosides are specific to archaea, bacteria or eukaryotes, suggesting that these modified nucleosides have evolved
after the three phylogenic domains divided [28,29].
The most characteristic feature of tRNAs is presence of hypermodified nucleosides in the anticodon loop and stem (positions
27–40). They contribute to the decoding properties (efficiency
and accuracy) of tRNA molecules during translation [8,30,31]. A
majority of hypermodified nucleosides, such as queuosine, 2-Omethylguanosine and inosine, are present at position 34 of anticodon loop, whereas others, such as m6 t6 A, ms2 I6 A and Y base,
are present at position 37 (3 adjacent to the anticodon). Other
modified nucleosides, such as , Gm, Um, s2 C, m3 C and m5 C,
are present elsewhere in the anticodon branch. They are needed
to modulate the flexibility and preferential 3 stacking conformation adopted by the anticodon loop when it binds to complementary codon [32,33]. The presence of modified nucleosides in the
anticodon loop is important for modulation of codon–anticodon
interactions and helps to maintain the correct reading frame
during translation [34]. They may not be essential for viability, but play an important role in fine-tuning of tRNA activities
[35].
The two most important hypermodified nucleosides that are
known to occur in tRNA are queuosine and archaeosine, both of
which are characterized by a 7-deazaguanosine core structure.
They are rigorously segregated with respect to phyla and location in tRNAs. Queuosine is ubiquitously present throughout
living systems, where it occurs specifically at a wobble position
in specific tRNAs; however, archaeosine is found exclusively in
archaea, where it is found in majority of known archaeal tRNAs
at position 15 of the D-loop (dihydrouridine loop), which exhibits
many important developmental and cellular functions in the cells
[36].
QUEUINE
In 1968, a previously undescribed nucleic acid base was identified in Escherichia coli tRNATyr hydrolysate that could not be
matched with the established standards. It was given the designation as ‘Q’. The base form of Q was named queuine and
nucleoside queuosine. Queuosine was first discovered in the first
position of anticodon loop (position 34) of E. coli tRNATyr . Later,
it was found that queuosine is also present in the same position
in E. coli tRNAHis , tRNAAsn and tRNAAsp [37]. The structure of
queuosine was determined by gas chromatography/MS and elucidated by X-ray crystallography [38,39]. Queuosine was identified as a hypermodified guanosine analogue. The N-7 position
of purine ring is substituted with a C-7 in queuosine, which is
the site of attachment for aminomethyl ether to a dihydroxycyclopentenediol ring (Figure 1). The basic queuosine molecule
is defined as 7-(3,4-trans-4,5-cis-dihydroxy-1-cyclopenten-3-ylaminomethyl)-7-deazaguanosine [40,41].
QUEUOSINE MODIFICATION OF
tRNA: TGTase (tRNA-GUANINE
TRANSGLYCOSYLASE)
tRNA is post-transcriptionally modified to Q-tRNA with the help
of key enzyme TGTase (EC 2.4.2.29), which catalyses the baseexchange reaction in which guanine is replaced with queuine or
its precursor at the anticodon position 34 of cognate tRNAs (histidine, asparagine, aspartate and tyrosine tRNAs) [42,43]. This
replacement of genetically encoded base guanine with a modified base queuine is found across the three domains of life, including archaea, eubacteria and eukaryotes [44–46]. Queuosine
modification of tRNA is evolutionarily conserved, but the process of modification is significantly different in prokaryotes and
eukaryotes [36,44,47–49]. In prokaryotes, queuosine modification of tRNA is achieved by multi-step de novo biosynthesis,
whereas the modification of tRNA is a single step of enzymatic
reaction in the case of eukaryotes. Its phylogenic segregation is
correlated with unique modified base substrate specificity and
disparate tRNA recognition element [47,50,51]. The prokaryotic
TGTase catalyses a post-transcriptional trans-glycosylation reaction during incorporation of the modified base queuine into specific tRNAs [52,53]. It reversibly incorporates the partially modified base preQ1 (7-aminomethyl-7-deazaguanine) as a primary
substrate into tRNA by a base-exchange reaction [54]. This baseexchange reaction does not require cleavage of phosphodiester
backbone of the polynucleotide, nor does it require energy input, for example, ATP hydrolysis [43,55]. On the other hand,
the eukaryotic TGTase utilizes the completely modified base
queuine as a substrate and irreversibly incorporates it at position 34 of specific tRNAs by a base-exchange reaction [14]. In
contrast, archaeal TGTase incorporates archaeosine at position
15 of the D-loop of many tRNAs to maintain their structure
[51,55]. From sequence databases, all three classes of TGTase
(eubacteria, eukaryotes and archaea) share a high degree of sequence similarity (approx. 40 %) in domain-specific structural
properties [47]. The prokaryotic TGTase has been characterized
in a number of studies. It is a monomeric protein of approx. 43–
46 kDa [52,56,57]. A crystallographic study of E. coli TGTase
suggests that it is a zinc metalloenzyme. Structurally, TGTase is
TIM (triose-phosphate isomerase)-like (β/α)8 barrel protein (Figure 2). Eukaryotic TGTase, purified from bovine liver [58], rat
liver [59] and rabbit erythrocytes [60], was shown to be a heterodimer complex of 100–104 kDa protein, comprising a putative
60–66 kDa regulatory subunit and 34–45 kDa catalytic subunit.
However, catalytic subunits of TGTase are structurally well conserved [44]. Recently, the eukaryotic TGTase was reported to be
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Figure 1
Structure of tRNA showing queuosine modification site
(a) Clover-leaf structure of tRNA showing position of G34 in anticodon loop. (b) L-shaped three-dimensional structure of
tRNA. (c) Structure of queuine that replaces G34 in queuosine-modified tRNA.
a heterotrimeric protein which weakly interacts with the mitochondrial outer membrane [61].
Queuosine modification of tRNA in the prokaryotic
system
The mechanism of queuosine modification of tRNA in prokaryotes has been identified in E. coli, Salmonella typhimurium and
Zymomonas mobilis [42,54,57]. Reader et al. [62] have reported
that four genes (queC, queD, queE and queF) are essential for
synthesis of the intermediates preQ0 (7-cyano-7-deazaguanine)
or preQ1 in bacteria, which are subsequently transferred into the
appropriate tRNA in a guanine-exchange reaction that catalysed
by TGTase. Queuosine is formed by a multi-step intracellular
pathway, which involves de novo enzymatic synthesis on an intact tRNA. Biosynthesis of queuosine includes modification and
incorporation of the intracellular substrate into tRNA, which is
controlled by transcriptional access and regulation of key enzymes [63].
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M. Vinayak and C. Pathak
Figure 2
Structure of prokaryotic TGTase and its interaction with cognate tRNA
Left-hand panel: ribbon model showing α/β barrel fold structure of TGTase. Reproduced with permission from [180].
Right-hand panel: interaction between TGTase and tRNA. Reprinted by permission from Macmillan Publishers Ltd: EMBO
Journal, Romier, C., Reuter, K., Suck, D. and Ficner, R. Crystal structure of tRNA-guanine transglycosylase: RNA modification
c 1996.
by base exchange, vol. 15, pp. 2850–2857, The first step of queuosine synthesis involves the conversion of a GTP molecule into a preQ1 or a preQ0 derivative
of the guanine base [50,64]. This step is performed by GTPcyclohydrolase-like enzyme, which involves removal of both
the N-7 and C-8 atoms of the nucleotide base and incorporation of either an aminopropyl or cyanopropyl group respectively
to re-form the ring [62,65]. The preQ1 base is further inserted into the first anticodon position of Q-family tRNAs by a
base-to-base exchange reaction. This reaction is catalysed by
the prokaryotic TGTase enzyme [52,66]. The TGTase enzyme
appears to utilize guanine, preQ0 or preQ1 as a substrate for incorporation into tRNAs with low K m values in the nanomolar
range [67]. The incorporation reaction for guanine and perQ0 are
completely reversible; however, the reaction involving preQ1 is
irreversible. The irreversibility of the reaction and relative abundance of the incorporation of preQ1 is due to the low K m value,
suggesting that this compound serves as the natural substrate
for this enzyme [42]. The incorporated preQ1 is further modified by SAM:TRTase (S-adenosylmethionine:tRNA ribosyltransferase) into epoxyQ (2,3-epoxy-4,5-dihydroxycyclopentyl-7aminomethyl-7-deazaguanosine). S-Adenosylmethionine plays
an important role as a ribose donor for formation of queuosine which usually functions as a methionyl or methyl group
donor. It serves as a substrate for SAM:TRTase in the attachment of the cyclic ring to the end of the 7-aminomethyl side
chain of the incorporated 7-deazaguanosine residue and produces
modified epoxyQ [63,68–70]. Finally, epoxyQ is converted into
queuosine by an unknown mechanism which requires coenzyme
B12 (Figure 3). The formation of queuosine appears to be regulated by the availability of the metabolic substrates GTP, Sadenosylmethionine and vitamin B12 , as well as the co-ordinated
expression of the modification enzymes from the queuine operon [41,71–73]. After synthesis of fully formed queuosine, the
modified tRNA participates in normal cellular functions until
it is degraded by natural tRNA turnover. The resulting queu-
osine nucleoside, nucleotide and queuine base are not salvaged
by prokaryotes after degradation of tRNA. Queuine and queuosine are lost to the surrounding environment as metabolic waste
products [55,74,75].
Queuosine modification of tRNA in the eukaryotic
system
Eukaryotes are unable to synthesize queuine itself. They obtain
it from diet or intestinal microflora [62,76]. Queuine is directly
incorporated in place of guanine at first position of anticodon
loop of specific tRNAs of the Q-family, i.e. His, Asn, Asp and
Tyr tRNAs, by a single-step enzymatic reaction catalysed by
eukaryotic TGTase [58,77,78] (Figures 4 and 5).
Germ-free mice fed with a queuine-free diet are found to be
deficient in queuosine modification of tRNA, whereas exogenous
administration of queuine improves queuosine modification level
in tRNA [79,80]. The nematode Caenorhabditis elegans, fed with
queuine-deficient E. coli, showed an absence of queuine modification of tRNA [81]. The queuosine modification system in mammalian cells may depend on three steps: uptake of queuine base
into the cells by a queuine-specific membrane transport system,
incorporation of queuine into the first position of the anticodon
loop of tRNA by an enzymatic reaction catalysed by TGTase and
salvage of queuine from queuosine 5 -monophosphate, resulting
from tRNA degradation. All these three steps are potential points
for deficiency in cellular queuosine modification level of tRNA
[82,83]. The mammalian queuosine modification system maintains a specific cellular membrane uptake mechanism to move
queuine from extracellular space into the cytosol and incorporates it into intact tRNA post-transcriptionally [84]. The cellular
uptake of queuine and its incorporation is modulated by phosphorylation of the modifying enzyme TGTase [83]. Activation of
protein kinase C by a phorbol ester elevates both the rate of transport and incorporation [85]. Protein kinase C activates TGTase
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Figure 3
Queuosine modification of tRNA in prokaryotes
GTP is modified to preQ1 and is inserted at position 34 of unmodified tRNA, replacing G. The partially modified nucleotide
undergoes complete modification while remaining attached to tRNA. The modification is done in multiple steps involving
a number of enzymes. PreQ1 , preQ1 -tRNA, epoxy-Q-tRNA are precursors of Q-tRNA. In the case of archaea, tRNA is
modified to archeosine-tRNA by a similar pathway. GTP is modified to preQo and is inserted at position 15 of unmodified
tRNA, replacing G. The partially modified nucleotide undergoes complete modification while remaining attached to tRNA.
The modification process and the enzymes involved are not known. Reproduced with permission from The American
Society for Biochemistry and Molecular Biology: Journal of Biological Chemistry, Bai, Y., Fox, D.T., Lacy, J.A., Van-Lanen,
S.G. and Reuyl, D.I. Hypermodification of tRNA in thermophilic archaeal: cloning, overexpression and characterization of
c 2000.
tRNA-guanine transglycosylase from Methanococcus jannaschi, vol. 275, pp. 28731–28738 activity, as well as the cellular uptake mechanism for queuine, and
supports complete modification of tRNA with queuine [59,84].
Morris et al. [83] have reported that protein kinase C and protein phosphatase modulate the rate of queuine uptake into the cell
and subsequent incorporation into the anticodon of tRNAs; therefore aberrant kinase activity and/or phosphatase activity may also
affect queuosine modification of tRNAs. Eukaryotic cells have
the ability to salvage this base from tRNA turnover products
to maintain the cytosolic level of queuine under conditions of
dietary queuine deprivation [74,75].
OCCURRENCE OF Q-tRNA
In biological systems, the queuine base is known to exist in
four forms: free queuosine base, free nucleoside, free nucleotide and nucleoside incorporated into tRNA (Q-tRNA). Under normal physiological conditions, tRNAs of the Q-family are
completely modified in terminally differentiated somatic cells.
However, queuosine modification of tRNA is often incomplete
in undifferentiated rapidly growing cells, embryonic tissues and
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M. Vinayak and C. Pathak
Figure 4
Quenine modification of tRNA in eukaryotes involves the salvage pathway as well as uptake of queuine from
dietary source
Reprinted from Molecular Genetics and Metabolism, vol. 68, Morris, R.C., Galicia, M.C., Clase, K.L. and Elliott, M.S.
c 1999, with permission
Determination of queuosine modification system deficiencies in cultured human cells, pp. 56–67, from Elsevier.
Figure 5 Single step of queuosine modification of tRNAs in eukaryotes showing replacement of G34 by quenine in the anticodon
triplet by the enzymatic reaction
regenerating hepatocytes [86,87]. Similarly queuosine deficiency
in tRNAs is observed in human placenta [88]. Alteration in the
level of queuosine in tRNA has been observed during differentiation and development in Dictyostelium discoideum [89,90],
Drosophila melanogaster [91] and during the development and
aging of rats [92]. Variations in the modification level of tRNAs
occur in eukaryotes from organ to organ [93].
BIOLOGICAL FUNCTION OF QUEUINE
Owing to the presence of queuine at the wobble position of several tRNAs, studies have investigated its role in codon–anticodon
pairing. Meier et al. [94] have reported that tRNAHis (G34) clearly
prefers the histidine codon CAC to the codon CAU, whereas
tRNA His (Q34) has little preference for the codon CAU. Furthermore, queuosine-modified tRNAs have been shown to suppress stop codons as tRNATyr (G34) allows stop codon readthrough,
whereas tRNATyr (Q34) prevents it [95–99]. However, there is no
direct evidence providing a link between hypomodification of
tRNA and frameshifting. Queuosine modification of tRNA has
been correlated with low-level translation of a bacterial (Shigella)
virulence protein mRNA [100,101].
PHYSIOLOGICAL ROLE OF QUEUINE
The precise physiological role of queuine has not been established to date. When a queuine-free diet was fed to germ-free
mice, the mice did not show any pathological symptoms in a
stressless environment, suggesting that the role of queuine may
be to protect organisms against stress [102,103]. A correlation
between queuine abundance and stress tolerance has been reported by Gaur et al. [73].
Queuine plays an important role in tyrosine biosynthesis in
mammals [104]. In absence of queuine, tyrosine becomes an essential amino acid for normal development of mouse. Similarly
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TGTase, the enzyme responsible for modification of Q-tRNA,
has been recognized as one of the key enzyme in the regulation of bacterial virulence in Shigella flexneri. A strong reduction
in virulence is achieved by reduction or loss of TGTase activity [105,106], suggesting it as a putative target for drug design
[107,108].
ROLE OF QUEUINE IN THE CELLULAR
ANTIOXIDANT DEFENCE SYSTEM
Organisms have developed an intricately regulated antioxidant defence system to protect against toxic effects of ROS
and to modulate the physiological effects of ROS. Endogenous
antioxidants are enzymatic and non-enzymatic in action. The
major antioxidant enzymes are catalase, superoxide dismutase
and glutathione peroxidase, and non-enzymatic antioxidants are
thiol, glutathione, ascorbate, urate etc., which protect against oxidative stress by preventing the uncontrolled formation of free
radicals and activated oxygen species. De-regulation of the balance between production of ROS by normal cellular processes
and their removal by antioxidant enzymes in favour of the oxidants causes oxidative stress [109], which leads to various pathological conditions, including metabolic dysfunction and cardiovascular diseases, such as atherosclerosis, pulmonary fibrosis
and neurodegenerative diseases, as well as malignancy.
Queuine promotes the activity of the antioxidant enzymes,
such as catalase, superoxide dismutase, glutathione reductase,
glutathione transferase, etc., suggesting that queuine improves the
antioxidant defence system [110]. Thus queuine may be regarded
as an antioxidant compound to protect the antioxidant defence
system.
REGULATION OF GLYCOLYTIC
METABOLISM BY QUEUINE
The free-base queuine or Q-tRNAs play an essential role in adaptive regulation of glycolytic metabolism, depending upon anaerobic or aerobic conditions [17]. Proliferating and cancer cells
maintain a high rate of glycolysis, even under aerobic conditions,
leading to high rate of lactate formation [111–113]. Alterations in
expression of different LDH (lactate dehydrogenase) isoenzymes
are associated with clinical diseases, such as cancer [114–117],
myocardial infarction [118] and liver disorders [119]. Elevated
level of LDH-A is associated with proliferation and a variety of
malignancies [120–123]. The major anoxic stress protein LDHk/6
is highly expressed in various human cancer and transformed
cells [124,125]. LDHk/6 activity is suppressed by the modified
base queuine [126]. Specific changes in LDH level and isoenzyme pattern by queuine are observed in D. discoidium [127] and
in cancerous mice [128,129] to down-regulate anaerobic metabolism. Queuine protects HeLa cells from hypoxic stress and
improves metabolic adaptation [18,130].
EFFECT OF QUEUINE ON CELL
PROLIFERATION
Queuine may act as a positive or a negative modulator of cell proliferation, depending on the aerobic or glycolytic state of cells and
on the availability of free queuine base. It is not directly related
to the presence or absence of Q-tRNA [21]. Queuine inhibits cell
proliferation of a number of cell lines, including Colo-DM320,
PC-12, C3H, U87, HepG2, ascite tumour, transformed NIH 3T3
and EGF (epidermal growth factor)-supported proliferation of
HeLa cells [131,132]. The inhibition is co-related with an increase in apoptosis. However, proliferation is stimulated in the
case of HeLa S3, A-431 and HL-60 cells [18]. Queuine induces
cell differentiation in cancerous cells [133].
QUEUOSINE DEFICIENCY OF tRNA
AND CANCER
The lack of queuine in the first position of anticodons is found
in tRNAs of Q-family from various tumour cells [54,75,134].
tRNAs, isolated from neoplastic tissues and transformed cells,
are hypomodified with queuosine to various degrees. The level
of queuosine deficiency of tRNA is high in lung cancer as compared with normal tissue [135]. The degree of hypomodification
is related to the severity of malignancy in human lymphoma, leukaemia, lung cancer, ovarian carcinoma and brain tumour [74]. A
correlation between the level of queuosine modification of tRNA
in cancerous tissues of human and grade of malignancy has been
reported by several laboratories [23,135–137], which are of value
for the prognosis of various cancers. The level of quenine-lacking
tRNA is substantially greater in high-grade malignant lymphomas and immunoblastic lymphomas compared with low-grade
malignancies [23]. The amount of queuosine-deficient tRNA is
strongly correlated to the histopathological grade of malignancy.
There is a positive correlation between the level of queuosine
modification of tRNA and survival of the patients [23]. Queuosine
deficiency of tRNA increases in metastastic ovarian malignant tumours compared with primary ovarian malignancies [137]. The
level of queuine deficiency in tRNA is found to be significantly
higher in astrocytomas (malignant brain tumours) than in meningiomas (benign brain tumours) [136]. tRNA isolated from liver
of cancerous mouse is hypomodified with respect to queuosine,
as compared with normal mouse liver [138]. Queuine administration leads to Q-tRNA modification, along with a decrease in
the proliferation capacity of tissues [132].
Okada et al. [93] have reported that the presence of hypomodified tRNA in transformed cells is not simply due to their
high growth rate, but closely related to state of differentiation.
tRNA isolated from mitochondria of Morris hepatoma (5123D)
has been found to lack queuosine, suggesting that a queuosine
defect may develop at an early stage of carcinogenesis and may
be directly associated with abnormalities of mitochondria [139].
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Queuosine hypomodification of tRNA in cancer might be due to
one or a number of different causative factors, such as a decrease
in incorporation of modified base queuine due to inactivation of
the enzyme or loss of queuine uptake regulated by protein kinase
C, by aberrant kinase or phosphatase activity [140] or loss of
the ability to salvage queuine from the tRNA turnover process
[74,75]. An elevated level of tRNA turnover and urinary excretion
of modified nucleosides is characteristic feature of malignancies
[141,142]. It may be possible that queuine is not salvaged completely and excreted with urine due to the high turnover rate of
tRNA or to inactivation of TGTase. DNA methylation is known
to be high in cancer cells. The presence of methylated purines
in cancer cells inhibits TGTase activity and queuosine modification of tRNAs [143]. These factors ultimately target TGTase and
make it inactive. Hypomodification of tRNA in cancerous tissues
is correlated with the loss of TGTase activity [140].
QUEUINE AND CELL SIGNALLING
The most important extracellular signalling molecules regulating cell proliferation are growth factors, which provide increased
survival response to cancer cells. The binding of ligands to receptors results in autophosphorylation of multiple tyrosine residues
in the cytoplasmic domains of the growth factor receptors,
which, in turn, activates intracellular signal transduction, enhances transcription of growth-related genes and promotes cell
growth [144]. An abnormal level of phosphorylation of membrane or nuclear proteins is associated with malignancy [145].
An increased level of EGFR (EGF receptor) mRNA and protein
has also been found in a variety of human cancers [146,147].
Queuine modulates the proliferation of HeLa cells in presence
of EGF and PDGF (platelet-derived growth factor), acting as
an antagonist to EGF, but as a synergist with PDGF [148].
Queuine has been shown to modulate mitotic signalling initiated by EGFR in vitro by tyrosine phosphorylation of specific
membrane-associated proteins [130,149,150]. The addition of
queuine to queuine-starved cells or in an in vitro system affects
protein synthesis and protein phosphorylation [151,152]. Thus
queuine is proposed to have important role in mitotic signalling.
transiently induced in a wide range of cell types in response to a
variety of extracellular stimuli, including serum, growth factors
and cytokines [156,157]. Expression of c-fos is also regulated
post-transcriptionally. It is short-lived and degraded by ubiquitinmediated proteolysis [158]. Overexpression of c-fos is associated with transformation of cells and tumorigenesis [159,160].
Similarly, c-myc targets a wide range of genes that co-ordinate
cell-cycle progression and cell growth, which sensitize the cell
to apoptotic stimuli [161,162]. Elevated expression of c-myc is
found in various human cancers, including lymphoma [163,164],
lung cancer [165], breast cancer [166,167], colon cancer [168]
and hepatocellular carcinoma [169–171]. c-Myc is a transcriptional regulator and key component in controlling cell growth
[172,173]. An increase in activity of the LDH-A isoenzyme is associated with activation of c-myc proto-oncogenes [174,175]. The
LDH-A promoter is reported to contain two consensus Myc/Maxbinding sites or E-boxes CACGTG (located at −78 to −83 and
−175 to −180 from the transcriptional start site) that are conserved in both mouse and human. It has been suggested that
c-Myc may be able to regulate transcription of LDH-A, leading
to enhanced glycolytic metabolism [176,177].
Queuine-dependent down-regulation of c-myc and c-fos expression has been observed in HeLa cells [151], as well as in cancerous mouse liver [130]. On the other hand, the proto-oncogene
bcl-2 and its family are involved in the regulation of cell death and
survival, without affecting cell proliferation [178]. The product
of the bcl-2 family, acting in the apoptotic pathway has both
pro- and anti-apoptotic properties. The regulation of apoptosis is
mediated by a dynamic balance between the cell death repressor
proteins Bcl-2 and Bcl-xL and death-activator proteins, such as
Bax and Bcl-xs . Up-regulation of bax or down-regulation of bcl-2
facilitate apoptosis [179]. Queuine is possibly involved in the regulation of apoptosis by decreasing bcl-2 gene expression [132].
The available evidence suggest that queuine suppresses malignancy by down-regulation of proto-oncogenes, by up-regulation
of apoptosis, by inhibiting anaerobic metabolism of tumours and
by checking oxidative stress. Queuine also helps in stress tolerance. The available knowledge regarding the physiological role
of queuine provides a basis to propose queuine as an anticarcinogenic agent.
The overview of the impact of queuine base and/ or Q-tRNA
on cellular and physiological functions that are known to date exposes the unknown steps followed by them in signalling pathways
to execute the overall response (Figure 6).
EFFECT OF QUEUINE ON
PROTO-ONCOGENES
FUTURE PROSPECTS
The precise regulation between cell proliferation and cell death in
multicellular organism is critical for tissue homoeostasis. Protooncogenes regulate normal cell proliferation and differentiation,
but their mutant forms contribute in neoplastic transformation.
The cellular proto-oncogenes induced in response to growth
factors or mitogens play an important role in regulation of the
cell cycle and mitogenic responses [153–155]. The c-fos protooncogene is an immediate early response gene that is rapidly and
Insufficiently defined signalling pathways adopted by queuine
and/or Q-tRNA pose a challenge for the workers in this field.
Further research is needed to ascertain whether the biological actions are all executed by Q-tRNA, or both by the queuine base and
Q-tRNA. Similarly, the basic role of queuosine modification of
tRNA in the modulation of codon–anticodon recognition is poorly
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potential of queuosine-modified tRNA to modulate translational
efficiency, strong experimental evidence for a unified theme of its
molecular function is still lacking. Therefore serious efforts are
needed to explore the holistic action of queuine or Q-tRNA in the
cellular machinery that contributes towards normal physiology.
ACKNOWLEDGEMENT
We thank Dr C. Romier for his permission to reproduce the ribbon
structure of TGTase shown in Figure 2.
FUNDING
The work of M.V. is supported by the Department of Science and
Technology, India.
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Figure 6 Overview of the physiological role of queuine/Q-tRNA
Blue arrows indicate known steps and black arrows show unknown
steps. Red arrows show down-regulation and the green arrow shows
up-regulation. CAT, catalase; GFR, growth factor receptor; GPx, glutathione peroxidase; GR, glutathione reductase; GST, glutathione transferase; RTK, receptor tyrosine kinase; SOD, superoxide dismutase.
2
3
4
5
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6
7
CONCLUSIONS
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The presence of queuine or Q-tRNA has been correlated with
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Received 12 May 2009/3 August 2009; accepted 28 August 2009
Published on the Internet 23 November 2009, doi 10.1042/BSR20090057
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