Potential double-flipping mechanism by E. coli MutY

House, Paul G.; Volk, David E.; Thiviyanathan, Varatharasa; Manuel, Raymond C.; Luxon, Bruce A.; Gorenstein, David G.; Lloyd, R. Stephen

doi:10.1016/s0079-6603(01)68111-x

Cited by 14 publications

(7 citation statements)

References 45 publications

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“…MutY was chosen for initial studies, since base flipping was thought to be involved in lesion detection. It is worth noting that lysine 142 in MutY was thought to play a large mechanistic role during the repair of 8-oxodG:A lesions based on early cross-linking and NMR investigations [50,134,142]. In our experiments, interestingly, there was no apparent change in distal/proximal guanine ratios upon DNA-mediated guanine oxidation in the presence of up to 200 nM of protein.…”

Section: Dna Charge Transport In a Biological Contextmentioning

confidence: 49%

Metal complexes for DNA-mediated charge transport

Barton

Olmon

Sontz

2011

Coordination Chemistry Reviews

142

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In all organisms, oxidation threatens the integrity of the genome. DNA-mediated charge transport (CT) may play an important role in the generation and repair of this oxidative damage. In studies involving long-range CT from intercalating Ru and Rh complexes to 5′-GG-3′ sites, we have examined the efficiency of CT as a function of distance, temperature, and the electronic coupling of metal oxidants bound to the base stack. Most striking is the shallow distance dependence and the sensitivity of DNA CT to how the metal complexes are stacked in the helix. Experiments with cyclopropylamine-modified bases have revealed that charge occupation occurs at all sites along the bridge. Using Ir complexes, we have seen that the process of DNA-mediated reduction is very similar to that of DNA-mediated oxidation. Studies involving metalloproteins have, furthermore, shown that their redox activity is DNA-dependent and can be DNA-mediated. Long range DNA-mediated CT can facilitate the oxidation of DNA-bound base excision repair proteins to initiate a redox-active search for DNA lesions. DNA CT can also activate the transcription factor SoxR, triggering a cellular response to oxidative stress. Indeed, these studies show that within the cell, redox-active proteins may utilize the same chemistry as that of synthetic metal complexes in vitro, and these proteins may harness DNA-mediated CT to reduce damage to the genome and regulate cellular processes.

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Section: Dna Charge Transport In a Biological Contextmentioning

confidence: 49%

Metal complexes for DNA-mediated charge transport

Barton

Olmon

Sontz

2011

Coordination Chemistry Reviews

142

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“…Substrates for the Bacterial DNA Glycosylase MutY-Although MutS recognizes specifically a 1,2-d(GpG) cisplatin cross-link when an adenine is opposite either platinated guanine, it is possible that in vivo, these lesions are primarily substrates for MutY, a DNA glycosylase responsible for the first step of base excision repair of adenine misincorporated opposite guanine or opposite the damaged guanine, 8-oxoguanine (51). Due to its glycosylase activity, it is difficult to study the binding of MutY with DNA substrates containing a G/A mismatch.…”

Section: Compound Lesions With Adenine Opposite Either Platinated Guamentioning

confidence: 99%

Binding Discrimination of MutS to a Set of Lesions and Compound Lesions (Base Damage and Mismatch) Reveals Its Potential Role as a Cisplatin-damaged DNA Sensing Protein

Fourrier

Brooks²,

Malinge³

2003

Journal of Biological Chemistry

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The DNA mismatch repair (MMR) system plays a critical role in sensitizing both prokaryotic and eukaryotic cells to the clinically potent anticancer drug cisplatin. It is thought to mediate cytotoxicity through recognition of cisplatin DNA lesions. This drug generates a range of lesions that may also give rise to compound lesions resulting from the misincorporation of a base during translesion synthesis. Using gel mobility shift competition assays and surface plasmon resonance, we have analyzed the interaction of Escherichia coli MutS protein with site-specifically modified DNA oligonucleotides containing each of the four cisplatin cross-links or a set of compound lesions. The major 1,2-d(GpG) cisplatin intrastrand cross-link was recognized with only a 1.5-fold specificity, whereas a 47-fold specificity was found with a natural G/T containing DNA substrate. The rate of association, k on, for binding to the 1,2-d(GpG) adduct was 3.1 ؋ 10 4 M ؊1 s ؊1 and the specificity of binding was essentially dependent on k off . DNA duplexes containing a single 1,2-d(ApG), 1,3-d(GpCpG) adduct, and an interstrand cross-link of cisplatin were not preferentially recognized. Among 12 DNA substrates, each containing a different cisplatin compound lesion derived from replicative misincorporation of one base opposite either of the 1,2-intrastrand adducts, 10 were specifically recognized including those that are more likely formed in vivo based on cisplatin mutation spectra. Moreover, among these lesions, two compound lesions formed when an adenine was misincorporated opposite a 1,2-d(GpG) adduct were not substrates for the MutYdependent mismatch repair pathway. The ability of MutS to sense differentially various platinated DNA substrates suggests that cisplatin compound lesions formed during misincorporation of a base opposite either adducted base of both 1,2-intrastrand cross-links are more plausible critical lesions for MMR-mediated cisplatin cytotoxicity.cis-Diamminedichloroplatinum(II) (cisplatin) 1 is among the most widely used anticancer chemotherapeutic agents in the treatment of many human tumors, particularly testicular and ovarian tumors (1). In the reaction between DNA and cisplatin, different types of bifunctional adducts are formed that are thought to be the key toxic lesions (2-4). Although these adducts are responsible for a variety of cellular responses including replication and/or transcription inhibition, there is not yet a clear understanding of the molecular mechanisms linking the formation of adducts and cisplatin-induced apoptosis (5, 6). Cisplatin reacts preferentially with the N-7 atoms of purine residues in DNA. The major adducts (90%) are 1,2-intrastrand cross-links at d(GpG) and d(ApG) sites and the minor adducts correspond to 1,3-intrastrand cross-links at d(GpNpG) (N being a nucleotide residue) and interstrand cross-links formed at d(GpC/GpC) sites (7-10). Once formed, cisplatin lesions such as the major 1,2-intrastrand cross-links can undergo replication bypass in cells treated with cisplatin (11,12). Be...

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“…NMR studies of this missing domain reveal significant structural homologies with the known structure of , an enzyme that hydrolyzes deoxy-8-oxoguanosine 5Ј-triphosphate. As MutT uses a binding pocket to recognize the 8-oxoguanine portion of its substrate (32), the presence of an analogous pocket has been postulated for the C-terminal domain of MutY (29,30). If such a cleft were to exist, then the recognition of an 8-oxoguanine by MutY would likely require the flipping of the non-scissile 8-ox-…”

mentioning

confidence: 98%

Flipping Duplex DNA Inside Out

Bernards

Miller

Bao

et al. 2002

Journal of Biological Chemistry

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The Escherichia coli MutY adenine glycosylase plays a critical role in repairing mismatches in DNA between adenine and the oxidatively damaged guanine base 8-oxoguanine. Crystallographic studies of the catalytic core domain of MutY show that the scissile adenine is extruded from the DNA helix to be bound in the active site of the enzyme (Guan, Y., Manuel, R. C., Arvai, A. S., Parikh, S. S., Mol, C. D., Miller, J. H., Lloyd, S., and Tainer, J. A. (1998) Nat. Struct. Biol. 5, 1058 -1064). However, the structural and mechanistic bases for the recognition of the 8-oxoguanine remain poorly understood. In experiments using a single-stranded 8-bromoguanine-containing synthetic oligodeoxyribonucleotide alone and in a duplex construct mismatched to an adenine, we observed UV cross-linking between MutY and the 8-bromoguanine probe. We further observed enhanced cross-linking in the single strand experiments, suggesting that neither the duplex context nor the mismatch with adenine is required for recognition of the 8-oxoguanine moiety. Stopped-flow fluorescence studies using 2-aminopurine-containing oligodeoxyribonucleotides further revealed the sequential extrusion of the 8-oxoguanine at 108 s ؊1 followed by the adenine at 16 s ؊1 . A protein isomerization step following base flipping at 1.9 s ؊1 was also observed and is postulated to provide additional stabilization of the extruded adenine thereby facilitating its capture by the active site for excision.The effect of cellular damages by reactive oxygen species in carcinogenesis and aging is well documented (1-3). Even in the absence of external oxidative stress, normal metabolic processes produce oxidative damages to DNA (4 -6) requiring repair. Oxidative damage of DNA bases alters their base pairing properties (5, 7) thereby interfering with replication and transcription (8). A predominant lesion found in DNA exposed to reactive oxygen species is 8-oxoguanine, which is especially deleterious due to its ability to form a stable Hoogsteen base pair with adenine in addition to the canonical Watson-Crick base pair with cytosine (9, 10). The facile by DNA polymerase misincorporation of an adenine across from the 8-oxoguanine (11) results in a mutagenic adenine:8-oxoguanine mismatch, a site where further replication prior to repair would lead to C 3 A or G 3 T transversions. In Escherichia coli, the MutY adenine glycosylase (MutY) 1 plays a critical role in preventing mutations stemming from oxidative damages to DNA by excising the adenine from the adenine:8-oxoguanine mismatch.Like all DNA-nucleotide-modifying enzymes, including DNA methylases, base-excision repair glycosylases, and endonucleases (12-15), MutY faces the 2-fold task of recognizing and accessing chemical moieties on DNA bases hidden within the double helix of duplex DNA. These enzymes have evolved an elegantly simple strategy for exposing their targets by rotating the phosphodiester bonds surrounding the nucleotide, causing the target base to be flipped out of the DNA helix (16 -21).Using the E. coli uracil-D...

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Potential double-flipping mechanism by E. coli MutY

Cited by 14 publications

References 45 publications

Metal complexes for DNA-mediated charge transport

Metal complexes for DNA-mediated charge transport

Binding Discrimination of MutS to a Set of Lesions and Compound Lesions (Base Damage and Mismatch) Reveals Its Potential Role as a Cisplatin-damaged DNA Sensing Protein

Flipping Duplex DNA Inside Out

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