BioMol Concepts 2014; 5(5): 397–407

Review

Daniel L. Morris, Jr.*

DNA-bound metal ions: recent developments

Abstract: The affinity of metal ions for DNA is logical con- with its phosphate backbone, deoxyribose sugar with O
sidering that the structure of DNA includes a phosphate atoms, and bases containing N and O atoms, makes it a
backbone with a net-negative charge, a deoxyribose sugar natural target for metal ion binding. The ultimate effects
with O atoms, and purine and pyrimidine bases that con- and long-range consequences of DNA-metal interactions
tain O and N atoms. DNA-metal ion interactions encom- depend on many different factors, including the iden-
pass a large area of research that ranges from the most tity of the metal ion, its speciation, redox activity, and
fundamental characterization of DNA-metal ion bind- the actual site(s) of binding on the DNA macromolecule.
ing to the role of DNA-bound metal ions in disease and Normal pairing between bases of separate DNA strands
human health. Alternative DNA base pairing mediated comprises the secondary structure of DNA and arises from
by metal binding is also being investigated and manipu- hydrogen bonding between adenine (A) and thymine (T)
lated for applications in logic gates, molecular machines, bases, and between guanine (G) and cytosine (C) bases.
and nanotechnology. This review highlights recent work This base pairing produces the tertiary double-helical
aimed at understanding interactions of redox-active metal structure of double-stranded DNA that creates a small gap
ions with DNA that provides a better understanding of ‘minor groove’ that is AT rich and a larger ‘major groove’
the mechanisms by which various types of oxidative DNA that is GC rich. These grooves allow metal ions, small
damage (strand breakage and base modifications) occur. molecules, and complex ions to interact with DNA bases
Antioxidants that mitigate oxidative DNA damage by coor- directly. The structure of DNA and the various modes of
dinating metal ions that produce reactive oxygen species metal ion binding to the phosphate backbone, deoxyri-
are addressed, as well as recent work on the effect of DNA- bose sugar, and specific nucleobases have been reviewed
metal ion interactions and the efficacy of quinolone-based (1–3). Metal ion binding to the phosphate backbone (e.g.,
antibacterial drugs. Recent advances in metal-mediated Mg2+ ions) tends to stabilize the DNA double helix because
base pairing that triggers conformational changes in DNA this neutralizes the excess negative charge from the phos-
structure for use as selective metal ion sensors and novel phate groups. Outer-sphere complexes with metal ions
nanotechnology applications are also included. are formed when a fully hydrated metal ion is coordinated
with a ligand indirectly through water molecules, whereas
Keywords: antioxidants; DNA; metal ion binding; metal- inner-sphere coordination complexes are stronger inter-
mediated base pairing; oxidative DNA damage. actions in which coordinated water molecules with the
metal ion and/or ligand are displaced, allowing the ligand
DOI 10.1515/bmc-2014-0021
to coordinate directly with the metal ion. Transition metal
Received July 10, 2014; accepted August 14, 2014 ions tend to produce inner-sphere complexes with DNA
bases. It is generally accepted that metal ions bind to the
purine bases G and A through the N7 atom. The O6 atom
of G and the N1 atom of A are also metal ion binding sites.
Introduction The pyrimidine bases T and C bind metal ions through the
O2 and N3 atoms, respectively. Figure 1 shows the struc-
Metal ions are essential to numerous biomolecular pro- tures of the four DNA bases. The N and O atoms that par-
cesses. Mg2+ and Zn2+ are common examples that function ticipate in metal ion binding are numbered.
as cofactors in enzymatic reactions. The structure of DNA, Bound metal ions influence the nature and stability
of the secondary and tertiary structures of DNA, and DNA
is subject to modifications from subsequent reactions of
*Corresponding author: Daniel L. Morris, Jr., Rose-Hulman Institute
of Technology, Department of Chemistry and Biochemistry, these metal ions with other species. The importance of
5500 Wabash Avenue, Terre Haute, IN 47803-3920, USA, DNA-metal interactions and their relevance to disease
e-mail: [email protected] and medicine is a vast area, and they have the potential of
398 D.L. Morris: DNA-bound metal ions: recent developments

metal-mediated oxidative DNA damage (10–13). One of the

most common examples is Fe(II). Fe(II) in the presence
of H2O2, a product of aerobic metabolism, can react to
produce hydroxyl radical (.OH) through the Fenton reac-
tion (14):

Fe 2 + + H 2O2 → Fe 3+ + OH - + i OH.

Different metal ions give rise to different types and

degrees of oxidative DNA damage, and metal ions that
produce ROS through Fenton-like reactions with H2O2
include Fe(II), Cu(II), Cr(III), Cr(VI), V(III), Co(II), Ni(II),
Cd(II), and Zn (15). In the presence of reductants (e.g.,
Figure 1 Structures of the purine bases guanine (G) and adenine (A) ascorbate), Cu(II) is reduced to Cu(I), which can react
and the pyrimidine bases thymine (T) and cytosine (C). with H2O2 in a Fenton-like manner to produce Cu(II), OH-,
The N and O atoms that generally coordinate with metal ions are and .OH:
numbered.
Cu+ + H 2O2 →Cu2 + + OH - + i OH.

being harnessed for applications in several areas, includ-

ing metal-dependent DNAzymes for catalytic cleavage of However, even when reductants are not added, Cu(II)
DNA substrates and DNA-based sensors for metal ions (4– still reacts with H2O2 to produce ROS that behave very
7). This review focuses on recent advances in understand- similarly to .OH (15–18). The suggested mechanism of oxi-
ing fundamental aspects of metal-DNA interactions, their dative DNA damage arising from Cu(II) involves a process
relation to metal-mediated oxidative DNA damage, and in which Cu(II) is bound to a G-containing moiety in DNA
antioxidants that function by binding metal ions. Drugs and reduced to Cu(I) (16, 19–21). The ROS produced from
that are influenced by DNA-bound metal ions and some this mechanism are suggested to be Cu(I)-peroxide com-
recent developments in metal-dependent alternative DNA plexes, with reactivity similar to that of .OH, or singlet
base pairing are also addressed. oxygen (1O2) as opposed to hydroxyl radical (.OH) (19–21).

Base modifications
Metal-mediated oxidative DNA
damage The ability of DNA to bind metal ions that are capable of
producing ROS makes DNA-bound metal ions an impor-
Metal ions (such as K+, Na+, and Mg2+) are essential to DNA tant aspect of understanding the mechanism of ROS gen-
stability as they neutralize the net negative charge arising eration and the correlation of site-specific oxidative DNA
from the phosphate backbone (3). Many DNA-metal ion damage to diseases and disorders (13, 22–25). Oxidative
interactions are sequence specific and play vital roles in DNA damage from ROS ranges from single- and double-
the correct functioning of DNA-related enzymes (e.g., the strand breaks to modified DNA bases. Nucleobase modi-
frequent role of Mg2+ as an enzyme cofactor). However, fications can lead subsequently to DNA strand scission
these interactions can have adverse effects under certain (26), and these various forms of DNA damage are asso-
conditions. The cytotoxic effects of many metals arise ciated with numerous diseases and conditions, includ-
from metal ion binding to DNA bases. A prime example ing kidney disease and diabetes (27), certain types of
is Hg(II) ion and Hg(II) compounds, which disrupt the cancer (12, 28), hypertension (29), and aging (30, 31). In
hydrogen bonds between naturally occurring A-T base some cases, however, this damage is desirable, espe-
pairs and form T-Hg2+-T pairs (8, 9). Redox-active metal cially in chemopreventive and chemotherapeutic appli-
ions are receiving much attention because of their ubiq- cations if it can be targeted and controlled to prevent
uitous presence in biological systems and their abilities DNA from replicating in tumors (32–35). G is the most
to react with H2O2 and other endogenous oxidizing agents easily oxidized DNA base, and it exhibits the largest
to produce damaging reactive oxygen species (ROS), and degree of damage, producing several G-based derivatives
an important topic in metal toxicity and carcinogenesis is including the accepted oxidative DNA damage marker
 D.L. Morris: DNA-bound metal ions: recent developments 399

8-hydroxy-2′-deoxyguanosine (8-OH-dG) (17, 36–38). The = Base

structures of the mononucleoside 2′-deoxyguanosine (dG) = Metal ion
= Modified base
and the accepted oxidative damage marker 8-OH-dG and ROS

its keto form 8-oxo-2′-deoxyguanosine (8-oxo-dG) are pre- ROS

Double strand breaks
sented in Figure 2. The transition metal ions Fe(II), Cu(II),
Cr(III), and V(III) produce significant levels of 8-OH-dG in
the presence of H2O2 (15), and the Cu(I)/H2O2 system also ROS

yields significant 8-OH-dG levels (17). The reactive nature

of radical species suggests that they are generated close Single strand break

to the site at which they react. In general, single-strand

breaks are a form of generalized damage associated with
ROS generated free in solution, and double-strand breaks
are closely correlated with 8-OH-dG levels, suggesting that Figure 3 Illustration of ROS formation and oxidative DNA damage
they arise from ROS generated in close proximity to the G from metal ions free in solution and metal ions bound to the phos-
phate backbone and individual bases.
base (15, 18, 39). Figure 3 illustrates ROS production and
The strong correlation between site-specific modification of bases
the resulting types of damage from metal ions free in solu- (e.g., 8-OH-dG) and double-strand breaks suggests that both types
tion and those bound to the phosphate backbone and/or of damage result from ROS generated by DNA-bound metal ions.
individual bases of DNA. Characterizing the interactions Single-strand breaks are indicative of less site-specific ROS produc-
between metal ions and the nucleobases and phosphate tion (e.g., from metal ions free in solution).
groups of DNA, and correlating them with products that
result from oxidative DNA damage is ongoing. Nitrogen-15
nuclear magnetic resonance (NMR) spectrometry provides dG at the C5 position. Oxidation at the C8 position leads
insight into the formation of coordination and covalent to the accepted oxidative damage marker 8-oxo-dG (the
bonds between metal ions and N atoms on nucleobases keto form of 8-OH-dG). Coordination of Cu at the N7 posi-
(40), and this type of site-specific metal coordination is tion of dG appears to play a major role in both C5 and C8
expected to correlate closely with formation of very spe- oxidation. A Cu(III)-OH species at the N7 position is sug-
cific DNA base modifications (e.g., 8-OH-dG production). gested to yield a 5-OH-dG intermediate in C5 oxidation
Metal-mediated oxidation of DNA and the G base in (which leads to the major product d2lh) and the 8-OH-dG
particular is complicated. The products that result from tautomer in C8 oxidation. The product distribution also
the mononucleoside dG and single- and double-stranded contained species that arise from oxidation of the deoxy-
oligodeoxynucleotides when ROS are produced form ribose sugar with the identity of the reductant affecting
the Cu(II)/H2O2 system in the presence of the reduct- whether oxidation took place at the C5 or C8 carbons of
ants ascorbate and N-acetylcysteine were characterized dG or at the deoxyribose sugar (41).
recently by Fleming et al. They observed a total of 10 dif-
ferent dG oxidation products, including the G base itself.
They proposed mechanisms that account for their obser- Iron, copper, and chromium reactions
vation that the major oxidation product in this study was
5-carboxamido-5-formamido-2-iminohydantoin (d2lh), The metal ions Fe(II), Cu(I), Cu(II), and Cr(III) are often
which results from an overall two-electron oxidation of studied because of their abilities to produce significant
levels of the site-specific 8-OH-dG oxidative DNA damage
marker, and iron and copper are also interesting because
they are endogenous to living systems and exhibit dual
behaviors as essential elements and cytotoxic agents
depending on concentration. Extended X-ray absorption
fine structure spectroscopy of a solid Fe(II)-DNA complex
indicates that the inner coordination sphere of Fe(II) con-
tains five O atoms and one N atom, confirming that Fe(II)
interacts with nucleobases through N atoms. Values of the
Figure 2 Structures of the mononucleoside 2′-deoxyguanosine
(dG), the site-specific oxidative damage marker 8-hydroxy-
Fe-O and Fe-N distances in the inner coordination sphere
2′-deoxyguanosine (8-OH-dG), and its keto form 8-oxo-2′- were also reported (1.99 ± 0.02 and 2.22 ± 0.02 Å, respec-
deoxyguanosine (8-oxo-dG). tively) (42). Most studies indicate that Cu(II) interacts with
400 D.L. Morris: DNA-bound metal ions: recent developments

DNA primarily through N7 of the G base (43–46). Cu(II) reported that Cu(II) is preferentially bound to adjacent
has been reported to exhibit preferential binding at poly- G bases, and dopamine reduces Cu(II) to Cu(I), followed
guanosine sequences with at least two adjacent G bases by a conformational change in DNA to accommodate a
(16), and DNA-fiber electron paramagnetic resonance coordination geometry rearrangement. The oxidative DNA
(EPR) spectroscopy has demonstrated that aqueous Cu(II) damage marker 8-oxo-dG was produced when H2O2 was
can bind to DNA in both a mobile mode and a mode in introduced, supporting a Fenton-type reaction between
which the orientation of the coordination plane is fixed Cu(I) and H2O2 that produces .OH (51).
(47). Cr(III) is generally believed to bind to DNA through Solivio et al. report the formation of a lysine deriva-
the G base and an adjacent phosphate group (43, 48). tive of G when the mononucleoside dG is combined
Noblitt et al. employed the mononucleoside dG and the with an acylated lysine derivative in the presence of the
mononucleotide 2′-deoxyguanosine-5′-monophosphate Cu(II)/H2O2/ascorbate system. The proposed mechanism
(dGmp) as simple models to differentiate the interactions for forming the lysine-G adduct from dG begins with the
of the metal ions Fe(II), Cu(II), and Cr(III) with the dG base formation of 8-oxo-dG from .OH produced from the reac-
and/or the phosphate group that lead to the production tion between Cu(I) and H2O2. The same lysine-G derivative
of 8-OH-dG. Not surprisingly, the different metal ions pro- was also observed in reactions employing a 14-nucleo-
duced different levels of 8-OH-dG depending on whether tide duplex (oligonucleotide) and a larger 392-nucleotide
they interacted with the base only (the mononucleoside DNA substrate. The reactions involving the larger DNA
dG) or the base and/or the phosphate group (dGmp). The substrate demonstrate that adducts form predominately
level of 8-OH-dG production from Fe(II)/H2O2 was sub- at polyguanosine residues (specifically at a 5′-GGG posi-
stantially larger for the mononucleotide (dGmp) than the tion), and this study shows that the presence of Cu (free
mononucleoside (dG), suggesting a combined interaction or bound to DNA or proteins) can induce DNA-protein
of Fe(II) with N7 of the G base and the adjacent phosphate cross-link formation and other DNA modifications that
on the mononucleotide. No difference in the yields of can occur under oxidative conditions (52).
8-OH-dG from dG and dGmp was observed for Cu(II)/H2O2; Interactions between different metal ions also affect
however, the Cr(III)/H2O2 system produced higher levels of the degree and type of oxidative DNA damage (8-OH-dG
8-OH-dG formation from dG. It was concluded that Cu(II)- formation and strand breaks) from Fenton or Fenton-like
N7 and Cr(III)-N7 interactions with the G base favor the reactions. Moriwaki et al. studied the abilities of Fe(II),
production of 8-OH-dG (49). Cd(II), Ni(II), Cr(III), Cu(II), and binary mixtures thereof to
DNA-bound Cu(II) is reported to be responsible for produce 8-OH-dG and DNA strand breaks through Fenton-
enhancing 8-OH-dG formation in the presence of the type reactions. Notably, Fe(II) and Cu(II) exhibited fewer
sugars glucose and fructose. While glucose and fructose strand breaks and lower quantities of 8-OH-dG when com-
alone were shown to increase 8-OH-dG levels, a dramatic bined with Ni(II). Mixtures of Fe(II) and Cr(III) produced
increase was observed when Cu(II) was present. The fruc- an additive effect on 8-OH-dG formation, whereas Cu(II)
tose/Cu(II) system generated significantly more 8-OH-dG and Cr(III) together increased 8-OH-dG production in a
damage marker than the glucose/Cu(II) system. The synergistic manner. Interestingly, the degree of strand
enhanced ability of the fructose/Cu(II) system to cause breakage for the Fe(II)/Cr(III) and Cu(II)/Cr(III) systems
oxidative damage is suggested to proceed by a mechanism did not reflect the increases in 8-OH-dG yields. In most
where fructose (a reducing sugar) reduces DNA-bound cases, double-strand breaks were not observed with the
Cu(II) to produce a ·fructose (enediol radical anion)-DNA- exceptions being the Fe(II)/Cr(III) and Fe(II)/Cu(II) mix-
Cu+ complex. This complex can react subsequently with tures (53). These results reflect the various DNA binding
H2O2 to produce a DNA-Cu+-OOH complex, regenerating sites preferred by different metals, and confirm that DNA
fructose (50). This study is significant because it connects strand breaks and 8-OH-dG formation, although related,
DNA-bound Cu(II) with many of the observations associ- arise from different mechanisms.
ated with diabetes, including elevated fructose levels,
release of metal ions from intracellular stores [including
Cu(II)], and elevated levels of 8-OH-dG.
Recent interest in Cu(II)-DNA interactions is asso-
Antioxidants that coordinate metal
ciated with its role in neurodegenerative diseases, and ions
Ando et al. demonstrated the connection of Cu(II)-DNA
binding and the neurotransmitter dopamine in confor- Many antioxidants function as ROS scavengers by react-
mational DNA changes and oxidative DNA damage. It is ing sacrificially with ROS before surrounding structures
 D.L. Morris: DNA-bound metal ions: recent developments 401

are damaged. However, studies of antioxidants in the Sulfur compounds

realm of metal-mediated oxidative DNA damage suggest
that metal ion coordination is a critical part in the mech- The antioxidant activity of S-containing compounds in
anism of some antioxidants. Several sulfur (S) and sele- metal-mediated oxidative DNA damage studies also cor-
nium (Se) compounds function as antioxidants through a relates with their abilities to bind metal ions. Cystine,
mechanism that involves coordinating the metal ions that cysteine, methyl-cysteine, and methionine are all reported
produce ROS (54). However, metal ion coordination is only to form coordination complexes with Cu(I) and lower oxi-
one step in the mechanism, and many questions remain. dative DNA damage. The reduced and oxidized forms of
Recent work has attempted to address these questions. glutathione also lowered Cu(I)-induced oxidative DNA
damage through a mechanism that appears to involve
Cu(I) binding. The S compound 3-carboxypropyl disulfide
Selenium compounds showed no antioxidant activity toward Cu(I)/H2O2 oxida-
tive damage; however, it did lower Fe(II)-mediated damage
The organoselenium compounds selenocysteine and through a mechanism that appears to involve metal coor-
selenomethionine function as antioxidants in reactions dination (59). The S compounds methionine sulfoxide
involving Cu(I) through coordinating the Cu ions (55, 56). and methylcysteine sulfoxide also exhibited antioxidant
Methyl-selenocysteine exhibited the ability to minimize activity toward the Cu(I)/H2O2 system in a matter consist-
oxidative DNA damage by coordinating both Cu(I) and ent with Cu coordination; however, in this case, it appears
Fe(II), and whereas selenocystamine exhibited antioxi- that metal coordination alone does not account for all of
dant activity for reactions involving both Cu(I) and Fe(II), the antioxidant activity. Specifically, these results indicate
there was evidence that it formed a coordination complex that, in some cases, antioxidant activity may be a combi-
only with Fe(II) (56). The inorganic Se compounds Se nation of metal ion coordination and ROS scavenging (60).
dioxide (SeO2) and sodium selenite [Na2SeO3, which dis-
sociates in aqueous solution to produce the selenite ion
(SeO32-)], also appear to function as antioxidants in reac-
tions involving Fe(II), Cu(II), and Cr(III) by coordinating
DNA-metal ion binding and drug
these metal ions (57, 58). All of these compounds exhibit interactions
different levels of protection, and the extent of antioxi-
dant behavior also depends on the identity of the metal Metal-DNA interactions are the basis of numerous anti-
ion. Hart et al. investigated the abilities of SeO2 and SeO32- cancer drugs, antiviral drugs, and antibacterial agents.
to coordinate these metal ions before and after they had The majority of these species function by intercalating
the opportunity to bind to DNA by monitoring levels of into the DNA structure, and this behavior can be manipu-
the site-specific oxidative DNA damage marker 8-OH-dG lated by forming metal coordination complexes with the
(58). SeO2 and SeO32- lowered 8-OH-dG levels for reactions drug. Common metal centers for these drugs include Ru,
involving Fe(II) and Cu(II) even when the metal ions were Os, Co, Ni, Cu, and Zn. The discovery of the chemother-
first combined with DNA, and their effectiveness as anti- apeutic metal-based drug cisplatin is one of the prime
oxidants increased significantly for the Fe(II) and Cr(III) examples of the manipulation of metal-DNA interac-
reactions when these metal ions were preincubated with tions in fighting diseases. Cisplatin (cis-[PtCl2(NH3)2]) is a
the Se compounds before adding DNA. These results indi- metal complex, and the basis of its effectiveness involves
cate that SeO2 and SeO32- are capable of coordinating DNA- the ability of the Pt to coordinate with the N7 atom of the
bound Fe(II) and Cu(II) and lowering oxidative damage to G base to form numerous adducts. Several workers have
a limited extent. However, it is not clear from this study reviewed the area of metal complexes and DNA interac-
if the Se compounds extract bound metal ions from DNA tions (5, 61–63).
to produce complexes free in solution or if DNA-metal-Se
coordination complexes form. In addition, questions still
remain concerning whether the Se-metal complexes are DNA-metal complex interactions
unreactive toward H2O2 (due to a shift in the redox poten-
tial of the complexed metal ion), if ROS are formed and Delivery of chemotherapeutic agents as structured nano-
scavenged by the Se compound, or if ROS are produced but particles has the potential to employ the cytotoxic effects
lead to more generalized DNA damage (e.g., single-strand of bound metal ions and metal complexes in a targeted
breaks) rather than the site-specific marker 8-OH-dG. fashion. A heterobimetallic complex containing Cu(II)
402 D.L. Morris: DNA-bound metal ions: recent developments

and Sn(IV) coordinated with pyrazole and phenyl glycine has demonstrated that at low concentrations ( < 3.0 mm),
chloride ligands was shown to interact with calf thymus Mg2+ ions enhance quinolone binding to DNA by binding
DNA (CT-DNA) through an electrostatic interaction and to phosphate groups on the DNA and creating a bridge
induce condensation to a particulate nanostructure. The for the interaction of the quinolone with the phosphate
complex also exhibited oxidative cleavage activity toward groups (71, 72). Cu2+ also increases the binding interac-
plasmid DNA. Besides forming a condensed nanoparticu- tion with several quinolones and DNA by interacting with
late form of DNA, which allows transportation across cell the drug molecule and DNA bases. However, for the case
barriers and resistance to enzymatic degradation, a key of the quinolone sparfloxacin (SPFX), which also has an
and novel feature of this complex is reported to be its amino group with which it can bind directly to a DNA
dual-binding mode to DNA that arises from Cu(II) binding base, the presence of Cu2+ decreased the binding affin-
to the N7 of the G base and Sn(IV) interacting with the ity because of a possible competitive binding interaction
phosphate backbone (64). between Cu2+, DNA bases, and SPFX (71). An interesting
Complexes of Cu(II), Co(II), and Ni(II) of the form comparison of metal ions and their abilities to enhance
[M(H2O)3(SO4)(4-CNpy)2] .H2O (where 4-CNpy is 4-cyano- quinolone-DNA binding is Cr(III) and Cr(VI). Cr(III) does
pyradine) were found to exhibit the same solid and solu- not bind to SPFX as strongly as Cr(VI); however, increas-
tion phase structures. Their solution phase structure was ing amounts of Cr(III) increase the SPFX-DNA binding
reported as [M(H2O)4(4-CNpy)2]2+, which exhibited strong constant. This is explained by the ability of Cr(III) to
binding with CT-DNA. The binding stoichiometry was bind mainly to DNA bases at low concentrations and
dependent on the identity of the metal ion, and a notewor- bind to phosphate groups at higher concentrations, thus
thy feature of this study was that it employed isothermal increasing the SPFX-DNA binding constant. While Cr(VI)
titration calorimetry (ITC) to study the thermodynamics coordinates with SPFX, it does not have a high affinity
of the binding interaction (65). ITC has been employed for DNA, and the presence of Cr(VI) had no effect on
to observe the thermodynamics of DNA binding with the binding constant between SPFX and DNA (48). The
metal complexes (66–68), and its applicability to binding binding interaction between SPFX and DNA decreases in
of metals and metal complexes with DNA is expected to the presence of Cd2+, which is reported to bind mainly to
increase (65). It is being employed in studying alternative DNA bases, indicating that Cd2+ competes with SPFX for
base pairing mediated by metal ions, which is addressed DNA binding sites (72).
in a later section.

Quinolone-based antibacterial agents

Alternative DNA base pairing using
metal ion coordination
The mechanism by which quinolone-based antibacte-
rial agents function is not fully understood; however, it Base pairing through hydrogen bonding is essential to
is believed that they function as bacterial topoisomerase the correct form and function of DNA, and any disrup-
inhibitors by forming complexes with DNA and the bac- tions in this relatively strong intermolecular force can
terial enzymes topoisomerase II (DNA gyrase) or topoi- lead to destabilization of the DNA double helix. However,
somerase IV. This binding interaction ultimately leads researchers are starting to ask the question ‘What if hydro-
to DNA cleavage and bacterial cell death. Quinolone gen bonding was replaced with another attractive force
antibacterial agents have been reviewed (69), and recent for DNA base pairing?’ Not only would the DNA conforma-
work supports the role of DNA-bound metal ions in the tion be different but also other properties would change,
quinolone-DNA interaction. Quinolones are capable of including the conditions (temperature, ionic strength,
binding to the phosphate groups of DNA through the and pH) at which DNA melts (i.e., the strands in double-
carboxyl and carbonyl moieties, and it has been demon- stranded DNA separate to form single-stranded DNA). The
strated that the presence of DNA-bound metal ions can double-helical structure of DNA could have other applica-
enhance or inhibit this binding in a manner dependent tions if these physical properties could be ‘tuned’ through
on both the identity of the metal ion and its concentra- the pattern and strength of base pairing. Metal ion-medi-
tion. Mg2+ ions are reported to play a major role (cofactor) ated base pairing (metallo-base pairing) is being studied
in the DNA cleavage-rejoining activity of topoisomer- as an alternative to hydrogen-bonded base pairing. In
ases (70), and the presence of Mg2+ was noted to have addition to forming base pairs between naturally occur-
an effect on quinolone binding to DNA. Recent work ring bases, metallo-base pairing using synthetic ligands
 D.L. Morris: DNA-bound metal ions: recent developments 403

that behave like nucleobases allows base pairing that is Besides DNA duplexes, other structures, including hairpin
orthogonal to naturally occurring base pairs, opening loops and triple-stranded DNA, can be formed and manip-
opportunities to expand genetic information and infor- ulated by metal-mediated base pairing. Kuklenyik and
mation storage capabilities. Metal-mediated base pairing Marzilli demonstrated that forming Hg(II)-mediated base
involving naturally occurring bases and synthetic nucle- pairs in oligonucleotide sequences containing different
obases is a rapidly expanding area for which several numbers of mismatched T residues influenced conforma-
reviews exist (73–76). tional changes between hairpin and duplex forms (84).
Mismatched base pairs from naturally occurring Taking advantage of the absence or presence of metal ions
nucleobases have been achieved using Hg(II) and Ag(I) to induce conformational changes between hairpin loops
ions. As early as 1963, a 2:1 T-Hg complex (T-Hg2+-T) was and duplexes in these structures has several applications
theorized to exist in duplex oligonucleotides (8), and as DNA-based metal ion sensors, devices, and machines.
binding of Hg(II) and CH3Hg(II) to N3 of T was shown The T-Hg2+-T base pair mentioned above was employed
to be thermodynamically favored over binding to N1 as an integral part of a fluorescence-based Hg(II) sensor
of G (77). The stabilizing effect of this interaction was in which base pairing results in a hairpin structure that
demonstrated using UV melting, and the specificity of increases fluorescence resonance energy transfer (FRET)
Hg(II) for the T-T mispairs was confirmed along with for- between donor-acceptor groups attached to the ends of
mation of a double-helical duplex structure consisting an oligonucleotide (85). Base pairing from the addition
of only T-Hg2+-T pairs. NMR studies demonstrated that of Ag(I) was demonstrated for a 1,2,4-triazole nucleoside
Hg(II) displaces the imino proton on N3 of T to form incorporated into an oligonucleotide sequence. The oligo-
the T-Hg2+-T pairs (78, 79). Recent work involves char- nucleotide existed in a hairpin structure when Ag(I) was
acterizing further the T-Hg2+-T interaction using ITC to absent, and addition of Ag(I) resulted in the formation of
obtain thermodynamic data. It is reported that double a regular double-helix conformation. This conformational
T-T mismatches can be paired with two stoichiomet- change also holds promise as an Ag(I) sensor, as the con-
ric quantities of Hg(II), and the binding affinity of the formational change from hairpin to double helix results in
second Hg(II) ion is more favorable than the first, result- fluorescence quenching through FRET (86). Other exam-
ing in positively cooperative binding. It is suggested that ples of conformational changes based on metal-mediated
this may be favorable for aligning multiple Hg(II) ions base pairing include imidazole nucleotides that are paired
in duplex DNA for use in nanotecholoogy applications upon adding Ag(I) ions and T-C-rich oligonucleotides that
(80). Stable duplexes containing C-C pairs were reported bind Hg(II) and Ag(I), promoting a conformational change
in the presence of Ag(I), and it was concluded that Ag(I) from a random coil to a hairpin (87). Very recently, a set of
binds selectively to the C-C mismatch. A DNA-based nucleosides was developed on the basis of 1,2,3-triazole
Ag(I) sensor was developed on the basis of this behavior with 1,2,4-triazole, pyrazole, and pyridine complements,
(81). The thermodynamic properties of this very specific producing bidentate nucleosides that form base pairs in
C-Ag+-C pair were investigated using UV melting and the presence of Ag(I). This set of synthetic nucleosides
other techniques including ITC. Only a duplex contain- was aimed at understanding further the various effects
ing the C-C mismatch was stabilized in the presence that stabilize duplexes formed from metal-mediated base
of Ag(I), and 1:1 binding between Ag+ and the C-C pair pairing (88).
was reported with a binding constant of 106 m-1 (76, 82). Metal-mediated pairing of natural bases has also
A noteworthy example of artificial base pairing that resulted in DNA-based logic gates. Applications include
results in an exceptionally stable duplex was achieved CdSe/ZnS quantum dots with nucleic acid functional
by pairing salicylic aldehyde nucleobase derivatives groups that use Ag(I) and Hg(II) ions as inputs (89), and
incorporated into an oligonucleotide with the metal ions PCR amplification that proceeds only when Hg(II) and Ag
Cu(II) and Mn(II). In addition to base pairing, the duplex are available to form T-Hg2+-T and C-Ag+-C base pairs (90).
was further stabilized by adding ethelynediamine as an A unique development in DNA-based logic gates involves
additional cross-linking agent (83). using gold nanoparticles (AuNPs) that have been modified
with either T- or C-rich oligonucleotide strands. Addition
of Ag(I) and Hg(II) (inputs) results in a conformational
Base pairing and conformational changes transition (due to the formation of C-Ag+-C and T-Hg2+-
T base pairs) that leads to aggregation of the modified
The incorporation of a single metal-base pair into a DNA AuNPs and a distinct color change in the visible region
duplex shows a marked increase in duplex stability. of the electromagnetic spectrum. The aggregation can be
404 D.L. Morris: DNA-bound metal ions: recent developments

reversed by addition of EDTA and NH4OH to capture Hg(II) including cancers, diabetes, hypertension, and the
and Ag(I), respectively. YES, AND, INHIBI, and XOR colori- aging process.
metric logic gates were constructed on the basis of these –– Fe(II) reacts with H2O2 to produce .OH (Fenton reac-
AuNPs, which do not require targeted design or altera- tion). Cu(I), Cu(II), and Cr(III) exhibit Fenton-like
tion of the DNA sequence. The output is colorimetric and behavior in the presence of H2O2. These reactions pro-
visible to the naked eye, and the modified AuNPs aggre- duce oxidative DNA damage in the form of single- and
gate in a selective manner on the basis of the addition of double-strand breaks and modified bases.
Ag(I) and Hg(II) (91). Metal-based DNA base pairing also –– 8-OH-dG is an accepted, site-specific oxidative DNA
has promise in molecular machines and artificial genetic damage marker that must be produced by ROS gen-
circuits (92), and Liu and Sadler recently performed a erated from metal ions bound at or near the G base.
computational study that supports the possibility of pro- 8-OH-dG levels are correlated closely with double-
ducing DNA nanowires by using Cu(I) ions to form multi- strand breaks, suggesting a similar mechanism for
ple, adjacent base pairs (three adjacent G-Cu+-C base pairs both types of damage.
and two adjacent A-Cu+-T base pairs) (62). –– Several sulfur and selenium compounds function as
antioxidants in metal-mediated oxidative DNA dam-
age studies by a mechanism that involves metal ion

Expert opinion and outlook ––

binding.
DNA-metal interactions are important in promoting
the efficacy of anticancer, antiviral, and antibacterial
Interactions of metal ions with DNA are an extensive
drugs.
research area. Multiple sites for metal ion binding exist
–– Metal-mediated base pairing provides an alternative
(phosphate backbone, deoxyribose sugar, and individ-
to naturally occurring hydrogen bonding. It results in
ual bases), and even the most fundamental interactions
mismatched base pairs and induces conformational
depend on the identity of the metal ion. Redox-active
changes in DNA that can be used for metal ion sens-
metal ions are of particular interest because, besides their
ing, DNA-based machines, and logic gates where
innate ability to bind to DNA, they can also mediate oxida-
metal ions serve as the inputs.
tive DNA damage through reactions with endogenous oxi-
dizing agents. Metal-mediated oxidative DNA damage is
implicated in various diseases and conditions, and under-
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Daniel L. Morris, Jr. received a BS degree in chemistry from East

Tennessee State University in 1989. He received a MS degree in
chemistry (1992) and a PhD in analytical chemistry (1995) from The
Ohio State University. He joined the faculty of Rose-Hulman Institute
of Technology in 1996 and currently serves as a full professor in
the Department of Chemistry and Biochemistry. His professional
activities include the position of Innovation Fellow at Rose-Hulman
Ventures/NPD Labs (1999–2002) and Visiting Scientist at Protea
Bioscience (2003–2004). His research interests include chemical
analysis using microfluidic device platforms and metal-mediated
oxidative DNA damage.