Naturally occurring polyphenol, morin hydrate, inhibits enzymatic activity of N-methylpurine DNA glycosylase, a DNA repair enzyme with various roles in human disease

Dixon, Monica; Woodrick, Jordan; Gupta, Suhani; Karmahapatra, Soumendra Krishna; Devito, Stephen; Vasudevan, Sona; Dakshanamurthy, Sivanesan; Adhikari, Sanjay; Yenugonda, Venkata Mahidhar; Roy, Rabindra

doi:10.1016/j.bmc.2014.12.067

Cited by 14 publications

(8 citation statements)

References 38 publications

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“…DNA binding studies were performed in a Biacore T100 system (BIAcore, Uppsala, Sweden) as published previously [94, 95]. Briefly, the affinity of DY131, GSK4716, and mitoxantrone for DNA was tested using a 50-mer oligonucleotide:…”

Section: Methodsmentioning

confidence: 99%

Antimitotic activity of DY131 and the estrogen-related receptor beta 2 (ERRβ2) splice variant in breast cancer

et al. 2016

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Breast cancer remains a leading cause of cancer-related death in women, and triple negative breast cancer (TNBC) lacks clinically actionable therapeutic targets. Death in mitosis is a tumor suppressive mechanism that occurs in cancer cells experiencing a defective M phase. The orphan estrogen-related receptor beta (ERRβ) is a key reprogramming factor in murine embryonic and induced pluripotent stem cells. In primates, ERRβ is alternatively spliced to produce several receptor isoforms. In cellular models of glioblastoma, short form (ERRβsf) and beta2 (ERRβ2) splice variants differentially regulate cell cycle progression in response to the synthetic agonist DY131, with ERRβ2 driving arrest in G2/M.The goals of the present study are to determine the cellular function(s) of ligand-activated ERRβ splice variants in breast cancer and evaluate the potential of DY131 to serve as an antimitotic agent, particularly in TNBC. DY131 inhibits growth in a diverse panel of breast cancer cell lines, causing cell death that involves the p38 stress kinase pathway and a bimodal cell cycle arrest. ERRβ2 facilitates the block in G2/M, and DY131 delays progression from prophase to anaphase. Finally, ERRβ2 localizes to centrosomes and DY131 causes mitotic spindle defects. Targeting ERRβ2 may therefore be a promising therapeutic strategy in breast cancer.

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Section: Methodsmentioning

confidence: 99%

Antimitotic activity of DY131 and the estrogen-related receptor beta 2 (ERRβ2) splice variant in breast cancer

et al. 2016

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“…Base excision repair (BER) is one of the most commonly used DNA repair mechanisms in cells. Poly(ADP‐ribose)polymerase 1 (PARP1), N ‐methylpurine‐DNA glycosylase (MPG), and X‐ray repair cross‐complementary 1 (XRCC1) play indispensable roles in DNA damage BER (Dixon et al, 2015; Hinz & Czaja, 2015; Valérie et al, 2002). It has been found that in mouse embryonic fibroblasts, H3K9me3 interacts with acetyltransferase Tip60 at the site of DNA double‐strand breaks, triggering downstream DNA damage responses to repair the breaks (Sun et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Histone demethylase JHDM2A regulates H3K9 dimethylation in response to arsenic‐induced DNA damage and repair in normal human liver cells

Zhang

Tang

Yang

et al. 2020

J of Applied Toxicology

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Long‐term arsenic exposure is a worldwide public health problem that causes serious harm to human health. The liver is the main target organ of arsenic toxicity; arsenic induces disruption of the DNA damage repair pathway, but its mechanisms remain unclear. In recent years, studies have found that epigenetic mechanisms play an important role in arsenic‐induced lesions. In this study, we conducted experiments in vitro using normal human liver cells (L‐02) to explore the mechanism by which the histone demethylase JHDM2A regulates H3K9 dimethylation (me2) in response to arsenic‐induced DNA damage. Our results indicated that arsenic exposure upregulated the expression of JHDM2A, downregulated global H3K9me2 modification levels, increased the H3K9me2 levels at the promoters of base excision repair (BER) genes (N‐methylpurine‐DNA glycosylase [MPG], XRCC1 and poly(ADP‐ribose)polymerase 1) and inhibited their expression levels, causing DNA damage in cells. In addition, we studied the effects of overexpression and inhibition of JHDM2A and found that JHDM2A can participate in the molecular mechanism of arsenic‐induced DNA damage via the BER pathway, which may not be involved in the BER process because H3K9me2 levels at the promoter region of the BER genes were unchanged following JHDM2A interference. These results suggest a potential mechanism by which JHDM2A can regulate the MPG and XRCC1 genes in the process of responding to DNA damage induced by arsenic exposure and can participate in the process of DNA damage repair, which provides a scientific basis for understanding the epigenetic mechanisms and treatments for endemic arsenic poisoning.

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“…Based on this observation, a series of structural analogs has been computationally designed to inhibit TagA from Leptospira interrogans, the infectious agent of leptospirosis, although no experimental evidence was provided for their activity against the enzyme or the pathogen [231]. A natural flavonol, morin, inhibits MPG [78] (Table 2).…”

Section: Alkylation Damage Repair: Dual Consequencesmentioning

confidence: 99%

Inhibitors of DNA Glycosylases as Prospective Drugs

Mechetin

Endutkin

Diatlova

et al. 2020

IJMS

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DNA glycosylases are enzymes that initiate the base excision repair pathway, a major biochemical process that protects the genomes of all living organisms from intrinsically and environmentally inflicted damage. Recently, base excision repair inhibition proved to be a viable strategy for the therapy of tumors that have lost alternative repair pathways, such as BRCA-deficient cancers sensitive to poly(ADP-ribose)polymerase inhibition. However, drugs targeting DNA glycosylases are still in development and so far have not advanced to clinical trials. In this review, we cover the attempts to validate DNA glycosylases as suitable targets for inhibition in the pharmacological treatment of cancer, neurodegenerative diseases, chronic inflammation, bacterial and viral infections. We discuss the glycosylase inhibitors described so far and survey the advances in the assays for DNA glycosylase reactions that may be used to screen pharmacological libraries for new active compounds.

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Naturally occurring polyphenol, morin hydrate, inhibits enzymatic activity of N-methylpurine DNA glycosylase, a DNA repair enzyme with various roles in human disease

Cited by 14 publications

References 38 publications

Antimitotic activity of DY131 and the estrogen-related receptor beta 2 (ERRβ2) splice variant in breast cancer

Antimitotic activity of DY131 and the estrogen-related receptor beta 2 (ERRβ2) splice variant in breast cancer

Histone demethylase JHDM2A regulates H3K9 dimethylation in response to arsenic‐induced DNA damage and repair in normal human liver cells

Inhibitors of DNA Glycosylases as Prospective Drugs

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