8‐Chloro‐dGTP, a hypochlorous acid‐modified nucleotide, is hydrolyzed by hMTH1, the human MutT homolog

Fujikawa, Katsuyoshi; Yakushiji, Hiroyuki; Nakabeppu, Yusaku; Suzuki, Toshinori; Masuda, Michiaki; Ohshima, Hiroshi; Kasai, Hiroshi

doi:10.1016/s0014-5793(02)02240-8

Cited by 14 publications

(8 citation statements)

References 13 publications

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“…To gain insights into this, we obtained ternary structures of polβ in precatalytic complex with an incoming nonhydrolyzable dCMPNPP (hereafter dCTP*) to be paired with templating ClG with both Mg 2+ metal ions (Figure 3). The use of this nucleotide analog has been suggested to retain the same structure as dCTP [42,43,44]. This precatalytic ClG:dCTP*(Mg 2+ ) ternary structure was refined to 2.0 Å (Figure 3A and Table 2).…”

Section: Resultsmentioning

confidence: 99%

Promutagenicity of 8-Chloroguanine, A Major Inflammation-Induced Halogenated DNA Lesion

2019

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Chronic inflammation is closely associated with cancer development. One possible mechanism for inflammation-induced carcinogenesis is DNA damage caused by reactive halogen species, such as hypochlorous acid, which is released by myeloperoxidase to kill pathogens. Hypochlorous acid can attack genomic DNA to produce 8-chloro-2′-deoxyguanosine (ClG) as a major lesion. It has been postulated that ClG promotes mutagenic replication using its syn conformer; yet, the structural basis for ClG-induced mutagenesis is unknown. We obtained crystal structures and kinetics data for nucleotide incorporation past a templating ClG using human DNA polymerase β (polβ) as a model enzyme for high-fidelity DNA polymerases. The structures showed that ClG formed base pairs with incoming dCTP and dGTP using its anti and syn conformers, respectively. Kinetic studies showed that polβ incorporated dGTP only 15-fold less efficiently than dCTP, suggesting that replication across ClG is promutagenic. Two hydrogen bonds between syn-ClG and anti-dGTP and a water-mediated hydrogen bond appeared to facilitate mutagenic replication opposite the major halogenated guanine lesion. These results suggest that ClG in DNA promotes G to C transversion mutations by forming Hoogsteen base pairing between syn-ClG and anti-G during DNA synthesis.

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Section: Resultsmentioning

confidence: 99%

Promutagenicity of 8-Chloroguanine, A Major Inflammation-Induced Halogenated DNA Lesion

2019

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“…For example, 8CldGTP is a substrate for the human mutT homologue (hMTH1), which could prevent mis-incorporation of 8CldG by favoring the formation of 8CldGMP. 42 However, whether 8CldATP is also a substrate for hMTH1, and the relevance of this pathway in macrophages, remains to be established.…”

Section: ■ Discussionmentioning

confidence: 99%

A Role for Chlorinated Nucleosides in the Perturbation of Macrophage Function and Promotion of Inflammation

Macer-Wright

Stanley

Portman

et al. 2019

Chem. Res. Toxicol.

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During inflammation, myeloperoxidase released from activated phagocytes generates the highly reactive oxidant hypochlorous acid (HOCl). This oxidant plays an important role in the immune response but can also promote tissue damage and has been strongly linked with the development of numerous inflammatory diseases. HOCl reacts with cellular DNA forming chlorinated nucleobases, which induce strand breaks, mutations, and cross-links. Although it has been shown that chlorinated nucleosides are present within inflammatory pathologies and diseased tissue, whether or not these species are biomarkers formed as a byproduct of chronic inflammation or play a role in the disease progression has not been ascertained. In this study, we show that exposure of J774A.1 macrophage-like cells to chlorinated ribose and deoxyribose nucleosides results in the incorporation of 5-chloro-cytidine (5ClC), 8-chloro-adenosine (8ClA), and 8-chloro-guanosine (8ClG) into the cellular RNA and 5-chloro-deoxycytidine (5CldC) but not 8-chloro-deoxyguanosine (8CldG) or 8-chloro-deoxyadenosine (8CldA) into cellular DNA. Evidence was obtained for the clearance of 5ClC from the RNA, with a loss of 8ClA and 8ClG observed to a lesser extent, whereas an increase in the level of 5CldC in DNA was seen on further incubation of treated cells in the absence of chlorinated nucleosides. Importantly, exposure of the macrophages to chlorinated nucleosides, particularly 8ClG and 5ClC, resulted in the increased expression of interleukin-1β, and other pro-inflammatory cytokines and chemokines. With 5ClC, this inflammatory response was associated with the increased nuclear translocation of the NF-κB subunit, p65, rather than inflammasome activation. This alteration in gene expression appeared to be unrelated to the extent of incorporation of the chlorinated nucleosides into RNA or DNA and was not associated with any significant changes in cell viability or proliferation. Taken together, these results highlight a potential biological role for chlorinated nucleosides to promote inflammatory disease, in addition to their utility as biomarkers.

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“…The urine concentration of haloG was one tenth of that of 8-oxoguanine (oxoG) in healthy subjects, and half of that in diabetic patients, suggesting haloG as a potentially important lesion (10). Interestingly, 8-chloro-dGTP was efficiently hydrolyzed by hMTH1 (11), which hydrolyzes 8-oxo-dGTP to 8-oxo-dGMP. In addition, haloG was excreted to urine three times faster than oxoG in lipopolysaccharide-treated rats (10), suggesting the existence of an efficient DNA repair enzyme for haloG in cells.…”

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confidence: 99%

Structural Basis for Promutagenicity of 8-Halogenated Guanine

Koag

Min

Lee

2014

Journal of Biological Chemistry

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Background: 8-Halogenated guanine is a promutagenic lesion that promotes insertion of guanine opposite the lesion during DNA replication. Results: 8-Bromoguanine forms Hoogsteen base pairing with G and Watson-Crick base pairing with C in the active site of pol␤. Conclusion: 8-Bromoguanine is well accommodated in the nascent base pair binding pocket of pol␤. Significance: Our structural studies provide insights into potential G to C mutations.

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8‐Chloro‐dGTP, a hypochlorous acid‐modified nucleotide, is hydrolyzed by hMTH1, the human MutT homolog

Cited by 14 publications

References 13 publications

Promutagenicity of 8-Chloroguanine, A Major Inflammation-Induced Halogenated DNA Lesion

Promutagenicity of 8-Chloroguanine, A Major Inflammation-Induced Halogenated DNA Lesion

A Role for Chlorinated Nucleosides in the Perturbation of Macrophage Function and Promotion of Inflammation

Structural Basis for Promutagenicity of 8-Halogenated Guanine

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