Targeting BER enzymes in cancer therapy

Visnes, Torkild; Grube, Maurice; Hanna, Bishoy; Benítez‐Buelga, Carlos; Cázares‐Körner, Armando; Helleday, Thomas

doi:10.1016/j.dnarep.2018.08.015

Cited by 50 publications

(48 citation statements)

References 159 publications

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“…The redundancy of DNA glycosylase substrate specificity and the observation that single KO mouse of hNeil1 and hOgg1 are viable and fertile have long hampered the search for inhibitors of these enzymes. Yet this situation is ideal in the case of a synthetic lethality interaction between the pathologic context and DNA glycosylase [58,59]. Over the last few years, the search for inhibitors of DNA glycosylases hNeil1 (hNeil2) and hOgg1 has become a very active field [18][19][20][21]56,60,61].…”

Section: Discussionmentioning

confidence: 99%

Thiopurine Derivative-Induced Fpg/Nei DNA Glycosylase Inhibition: Structural, Dynamic and Functional Insights

Rieux

Goffinont

Coste

et al. 2020

IJMS

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DNA glycosylases are emerging as relevant pharmacological targets in inflammation, cancer and neurodegenerative diseases. Consequently, the search for inhibitors of these enzymes has become a very active research field. As a continuation of previous work that showed that 2-thioxanthine (2TX) is an irreversible inhibitor of zinc finger (ZnF)-containing Fpg/Nei DNA glycosylases, we designed and synthesized a mini-library of 2TX-derivatives (TXn) and evaluated their ability to inhibit Fpg/Nei enzymes. Among forty compounds, four TXn were better inhibitors than 2TX for Fpg. Unexpectedly, but very interestingly, two dithiolated derivatives more selectively and efficiently inhibit the zincless finger (ZnLF)-containing enzymes (human and mimivirus Neil1 DNA glycosylases hNeil1 and MvNei1, respectively). By combining chemistry, biochemistry, mass spectrometry, blind and flexible docking and X-ray structure analysis, we localized new TXn binding sites on Fpg/Nei enzymes. This endeavor allowed us to decipher at the atomic level the mode of action for the best TXn inhibitors on the ZnF-containing enzymes. We discovered an original inhibition mechanism for the ZnLF-containing Fpg/Nei DNA glycosylases by disulfide cyclic trimeric forms of dithiopurines. This work paves the way for the design and synthesis of a new structural class of inhibitors for selective pharmacological targeting of hNeil1 in cancer and neurodegenerative diseases.

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Section: Discussionmentioning

confidence: 99%

Thiopurine Derivative-Induced Fpg/Nei DNA Glycosylase Inhibition: Structural, Dynamic and Functional Insights

Rieux

Goffinont

Coste

et al. 2020

IJMS

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“…Therefore, studying the effect of oxidation on the function of OGG1 is important for understanding molecular mechanisms of cancer and defining the correlation between oxidative stress and cancer. Lastly, OGG1 inhibition could provide therapeutic benefits by inhibiting the proliferation of cancers with high oxidative stress and sensitizing tumor cells to apoptosis with chemotherapy and radiotherapy (57,58). Thus, OGG1 is a promising target for cancer diagnosis and treatment.…”

Section: Ogg1 Cysteine Mutations In Cancermentioning

confidence: 99%

The role of cysteines in the structure and function of OGG1

Wang

Maayah

Sweasy

et al. 2021

Journal of Biological Chemistry

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8-oxoguanine glycosylase (OGG1) is a base excision repair enzyme responsible for the recognition and removal of 8-oxoguanine, a commonly occurring oxidized DNA modification. OGG1 prevents the accumulation of mutations and regulates the transcription of various oxidative stress-response genes. In addition to targeting DNA, oxidative stress can affect proteins like OGG1 itself, specifically at cysteine residues. Previous work has shown that the function of OGG1 is sensitive to oxidants, with the cysteine residues of OGG1 being the most likely site of oxidation. Due to the integral role of OGG1 in maintaining cellular homeostasis under oxidative stress, it is important to understand the effect of oxidants on OGG1 and the role of cysteines in its structure and function. In this study, we investigate the role of the cysteine residues in the function of OGG1 by mutating and characterizing each cysteine residue. Our results indicate that the cysteines in OGG1 fall into four functional categories: those that are necessary for (1) glycosylase activity (C146 and C255), (2) lyase activity (C140S, C163, C241 and C253), (3) structural stability (C253), and (4) those with no known function (C28 and C75). These results suggest that under conditions of oxidative stress, cysteine can be targeted for modifications, thus altering the response of OGG1 and affecting its downstream cellular functions.

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“…Inhibitors of glycosylases can provide insight into their roles in cellular repair pathways, and can be especially useful when overlapping pathways exist, such as occurs for NTH1. In general, DNA repair inhibitors are clinically important in cancer treatment; cancer cells maintain the viability in high concentration of ROS through elevated DNA repair activity, and inhibiting DNA repair pathways can confer synthetic lethality to cancer cells . Using GPE probes of NTH1 activity, we developed an in vitro fluorescence assay and employed it to screen a small library of biologically active compounds with the aim of identifying potentially active molecular scaffolds (Figure a).…”

Section: Figurementioning

confidence: 99%

An Excimer Clamp for Measuring Damaged‐Base Excision by the DNA Repair Enzyme NTH1

et al. 2020

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Direct measurement of DNA repair enzyme activities is important both for the basic study of cellular repair pathways as well as for potential new translational applications in their associated diseases. NTH1, a major glycosylase targeting oxidized pyrimidines, prevents mutations arising from this damage, and the regulation of NTH1 activity is important in resisting oxidative stress and in suppressing tumor formation. Herein, we describe a novel molecular strategy for the direct detection of damaged DNA base excision activity by a ratiometric fluorescence change. This strategy utilizes glycosylase‐induced excimer formation of pyrenes, and modified DNA probes, incorporating two pyrene deoxynucleotides and a damaged base, enable the direct, real‐time detection of NTH1 activity in vitro and in cellular lysates. The probe design was also applied in screening for potential NTH1 inhibitors, leading to the identification of a new small‐molecule inhibitor with sub‐micromolar potency.

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Targeting BER enzymes in cancer therapy

Cited by 50 publications

References 159 publications

Thiopurine Derivative-Induced Fpg/Nei DNA Glycosylase Inhibition: Structural, Dynamic and Functional Insights

Thiopurine Derivative-Induced Fpg/Nei DNA Glycosylase Inhibition: Structural, Dynamic and Functional Insights

The role of cysteines in the structure and function of OGG1

An Excimer Clamp for Measuring Damaged‐Base Excision by the DNA Repair Enzyme NTH1

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