Inhibitors of DNA Glycosylases as Prospective Drugs

Mechetin, Grigory V.; Endutkin, Anton V.; Diatlova, Evgeniia A.; Zharkov, Dmitry O.

doi:10.3390/ijms21093118

Cited by 23 publications

(13 citation statements)

References 253 publications

(287 reference statements)

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“…In addition, UNG is among the most important factors limiting the efficiency of antifolates and fludarabine. Reduction in UNG activity sensitizes many cancer types to chemotherapy treatment [ 38 ]. UNG is also a promising target for drug intervention in protozoan infections, since UNG inhibitors in combination with genotoxic stress effectively suppress the growth of Plasmodium falciparum , Trypanosoma brucei , and Trypanosoma cruzi [ 38 ].…”

Section: Ung Inhibitors and Their Potential Biotechnological Applicationsmentioning

confidence: 99%

Viruses with U-DNA: New Avenues for Biotechnology

Nagy

Skurnik

Vértessy

2021

Viruses

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Deoxyuridine in DNA has recently been in the focus of research due to its intriguing roles in several physiological and pathophysiological situations. Although not an orthodox DNA base, uracil may appear in DNA via either cytosine deamination or thymine-replacing incorporations. Since these alterations may induce mutation or may perturb DNA–protein interactions, free living organisms from bacteria to human contain several pathways to counteract uracilation. These efficient and highly specific repair routes uracil-directed excision repair initiated by representative of uracil-DNA glycosylase families. Interestingly, some bacteriophages exist with thymine-lacking uracil-DNA genome. A detailed understanding of the strategy by which such phages can replicate in bacteria where an efficient repair pathway functions for uracil-excision from DNA is expected to reveal novel inhibitors that can also be used for biotechnological applications. Here, we also review the several potential biotechnological applications already implemented based on inhibitors of uracil-excision repair, such as Crispr-base-editing and detection of nascent uracil distribution pattern in complex genomes.

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Section: Ung Inhibitors and Their Potential Biotechnological Applicationsmentioning

confidence: 99%

Viruses with U-DNA: New Avenues for Biotechnology

Nagy

Skurnik

Vértessy

2021

Viruses

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“…Nevertheless, bearing in mind that knockout mice for Ape1 are embryonic lethal, the treatment with APE1 inhibitors might cause unforeseen on-target toxicities in normal tissues ( 14 ). On the contrary, the deficiency of individual DNA glycosylases, which initiate BER, is relatively well-tolerated, and therefore these enzymes may be more promising candidates for drug development ( 14 , 16 , 18 , 19 ). In particular, it has been described that the knockdown of OGG1 conferred sensitivity to PARP1 inhibition ( 20 , 21 ).…”

Section: Introductionmentioning

confidence: 99%

OGG1 Inhibition Triggers Synthetic Lethality and Enhances The Effect of PARP Inhibitor Olaparib in BRCA1-Deficient TNBC Cells

et al. 2022

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BackgroundPARP1 plays a critical role in the base excision repair (BER) pathway, and PARP1 inhibition leads to specific cell death, through a synthetic lethal interaction, in the context of BRCA1/2 deficiency. To date, up to five different PARP inhibitors (PARPi), have been approved, nevertheless, the acquisition of resistance to PARPi is common and there is increasing interest in enhancing responses and expand their use to other tumour types.MethodsWe hypothesized that other BER members could be additional synthetic lethal partners with mutated BRCA genes. To test this, we decided to evaluate the glycosylase OGG1 as a potential candidate, by treating BRCA1 proficient and deficient breast cancer cells with PARPi olaparib and the OGG1 inhibitor TH5478.ResultsKnocking out BRCA1 in triple-negative breast cancer cell lines causes hypersensitivity to the OGG1 inhibitor TH5487. Besides, TH5487 enhances the sensitivity to the PARP inhibitor olaparib, especially in the context of BRCA1 deficiency, reflecting an additive interaction.DiscussionThese results provide the first evidence that OGG1 inhibition is a promising new synthetic lethality strategy in BRCA1-deficient cells, and could lead to a new framework for the treatment of hereditary breast and ovarian cancer.

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“…We next analyzed hyTDG cleavage using a real-time fluorescence assay ( 32 , 33 ) with 5′-6FAM oligos duplexed with a complementary strand containing a 3′-black hole fluorescence quencher 1 (BHQ1) quencher ( Fig. S8 ).…”

Section: Resultsmentioning

confidence: 99%

Measurement of deaminated cytosine adducts in DNA using a novel hybrid thymine DNA glycosylase

Hsu

Sowers

Baljinnyam

et al. 2022

Journal of Biological Chemistry

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Inhibitors of DNA Glycosylases as Prospective Drugs

Cited by 23 publications

References 253 publications

Viruses with U-DNA: New Avenues for Biotechnology

Viruses with U-DNA: New Avenues for Biotechnology

OGG1 Inhibition Triggers Synthetic Lethality and Enhances The Effect of PARP Inhibitor Olaparib in BRCA1-Deficient TNBC Cells

Measurement of deaminated cytosine adducts in DNA using a novel hybrid thymine DNA glycosylase

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