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Article ; Online: The aflatoxin B

Minko, Irina G / Kellum, Andrew H / Stone, Michael P / Lloyd, R Stephen

2023 Volume 65 Suppl 1, Page(s) 9–13

Abstract: Dietary exposure to aflatoxin ... ...

Abstract	Dietary exposure to aflatoxin B
MeSH term(s)	Animals ; Mutagens/toxicity ; Aflatoxin B1/toxicity ; DNA Adducts/genetics ; Guanine ; Mutagenesis ; Liver Neoplasms/pathology ; Imidazoles/adverse effects
Chemical Substances	Mutagens ; Aflatoxin B1 (9N2N2Y55MH) ; DNA Adducts ; Guanine (5Z93L87A1R) ; Imidazoles
Language	English
Publishing date	2023-06-26
Publishing country	United States
Document type	Journal Article
ZDB-ID	639145-x
ISSN	1098-2280 ; 0893-6692
ISSN (online)	1098-2280
ISSN	0893-6692
DOI	10.1002/em.22556
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Article ; Online: Functional analyses of single nucleotide polymorphic variants of the DNA glycosylase NEIL1 in sub-Saharan African populations.

Zuckerman, Jamie T / Minko, Irina G / Kant, Melis / Jaruga, Pawel / Stone, Michael P / Dizdaroglu, Miral / McCullough, Amanda K / Lloyd, R Stephen

DNA repair

2023 Volume 129, Page(s) 103544

Abstract: Nei-like glycosylase 1 (NEIL1) is a DNA repair enzyme that initiates the base excision repair (BER) pathway to cleanse the human genome of damage. The substrate specificity of NEIL1 includes several common base modifications formed under oxidative stress ...

Abstract	Nei-like glycosylase 1 (NEIL1) is a DNA repair enzyme that initiates the base excision repair (BER) pathway to cleanse the human genome of damage. The substrate specificity of NEIL1 includes several common base modifications formed under oxidative stress conditions, as well as the imidazole ring open adducts that are induced by alkylating agents following initial modification at N7 guanine. An example of the latter is the persistent and mutagenic 8,9-dihydro-8-(2,6-diamino-4-oxo-3,4-dihydropyrimid-5-yl-formamido)-9-hydroxyaflatoxin B
MeSH term(s)	Humans ; Carcinoma, Hepatocellular/genetics ; Liver Neoplasms/genetics ; DNA Glycosylases/metabolism ; Mutagenesis ; Nucleotides ; DNA Repair
Chemical Substances	DNA Glycosylases (EC 3.2.2.-) ; Nucleotides ; NEIL1 protein, human (EC 3.2.2.-)
Language	English
Publishing date	2023-07-20
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2071608-4
ISSN	1568-7856 ; 1568-7864
ISSN (online)	1568-7856
ISSN	1568-7864
DOI	10.1016/j.dnarep.2023.103544
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Article ; Online: Interaction of mitoxantrone with abasic sites - DNA strand cleavage and inhibition of apurinic/apyrimidinic endonuclease 1, APE1.

Minko, Irina G / Moellmer, Samantha A / Luzadder, Michael M / Tomar, Rachana / Stone, Michael P / McCullough, Amanda K / Stephen Lloyd, R

DNA repair

2023 Volume 133, Page(s) 103606

Abstract: Mitoxantrone (1,4-dihydroxy-5,8-bis[2-(2-hydroxyethylamino)ethylamino]-anthracene-9,10-dione) is a clinically-relevant synthetic anthracenedione that functions as a topoisomerase II poison by trapping DNA double-strand break intermediates. Mitoxantrone ... ...

Abstract	Mitoxantrone (1,4-dihydroxy-5,8-bis[2-(2-hydroxyethylamino)ethylamino]-anthracene-9,10-dione) is a clinically-relevant synthetic anthracenedione that functions as a topoisomerase II poison by trapping DNA double-strand break intermediates. Mitoxantrone binds to DNA via both stacking interactions with DNA bases and hydrogen bonding with the sugar-phosphate backbone. It has been shown that mitoxantrone inhibits apurinic/apyrimidinic (AP) endonuclease 1 (APE1)-catalyzed incision of DNA containing a tetrahydrofuran (THF) moiety and more recently, that mitoxantrone forms Schiff base conjugates at AP sites in DNA. In this study, mitoxantrone-mediated inhibition of APE1 at THF sites was shown to be consistent with preferential binding to, and thermal stabilization of DNA containing a THF site as compared to non-damaged DNA. Investigations into the properties of mitoxantrone at AP and 3' α,β-unsaturated aldehyde sites demonstrated that in addition to being a potent inhibitor of APE1 at these biologically-relevant substrates (∼ 0.5 μM IC
MeSH term(s)	Mitoxantrone/pharmacology ; DNA/metabolism ; DNA Repair ; Aldehydes ; Phosphates ; Endonucleases/metabolism ; DNA-(Apurinic or Apyrimidinic Site) Lyase/metabolism
Chemical Substances	Mitoxantrone (BZ114NVM5P) ; DNA (9007-49-2) ; Aldehydes ; Phosphates ; Endonucleases (EC 3.1.-) ; DNA-(Apurinic or Apyrimidinic Site) Lyase (EC 4.2.99.18)
Language	English
Publishing date	2023-11-20
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2071608-4
ISSN	1568-7856 ; 1568-7864
ISSN (online)	1568-7856
ISSN	1568-7864
DOI	10.1016/j.dnarep.2023.103606
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Article ; Online: Base excision repair of the N-(2-deoxy-d-erythro-pentofuranosyl)-urea lesion by the hNEIL1 glycosylase.

Tomar, Rachana / Minko, Irina G / Sharma, Pankaj / Kellum, Andrew H / Lei, Li / Harp, Joel M / Iverson, T M / Lloyd, R Stephen / Egli, Martin / Stone, Michael P

Nucleic acids research

2023 Volume 51, Issue 8, Page(s) 3754–3769

Abstract: The N-(2-deoxy-d-erythro-pentofuranosyl)-urea DNA lesion forms following hydrolytic fragmentation of cis-5R,6S- and trans-5R,6R-dihydroxy-5,6-dihydrothymidine (thymine glycol, Tg) or from oxidation of 7,8-dihydro-8-oxo-deoxyguanosine (8-oxodG) and ... ...

Abstract	The N-(2-deoxy-d-erythro-pentofuranosyl)-urea DNA lesion forms following hydrolytic fragmentation of cis-5R,6S- and trans-5R,6R-dihydroxy-5,6-dihydrothymidine (thymine glycol, Tg) or from oxidation of 7,8-dihydro-8-oxo-deoxyguanosine (8-oxodG) and subsequent hydrolysis. It interconverts between α and β deoxyribose anomers. Synthetic oligodeoxynucleotides containing this adduct are efficiently incised by unedited (K242) and edited (R242) forms of the hNEIL1 glycosylase. The structure of a complex between the active site unedited mutant CΔ100 P2G hNEIL1 (K242) glycosylase and double-stranded (ds) DNA containing a urea lesion reveals a pre-cleavage intermediate, in which the Gly2 N-terminal amine forms a conjugate with the deoxyribose C1' of the lesion, with the urea moiety remaining intact. This structure supports a proposed catalytic mechanism in which Glu3-mediated protonation of O4' facilitates attack at deoxyribose C1'. The deoxyribose is in the ring-opened configuration with the O4' oxygen protonated. The electron density of Lys242 suggests the 'residue 242-in conformation' associated with catalysis. This complex likely arises because the proton transfer steps involving Glu6 and Lys242 are hindered due to Glu6-mediated H-bonding with the Gly2 and the urea lesion. Consistent with crystallographic data, biochemical analyses show that the CΔ100 P2G hNEIL1 (K242) glycosylase exhibits a residual activity against urea-containing dsDNA.
MeSH term(s)	Deoxyribose/chemistry ; DNA/chemistry ; DNA Damage ; DNA Repair ; Urea ; DNA Glycosylases/metabolism ; Humans
Chemical Substances	Deoxyribose (533-67-5) ; DNA (9007-49-2) ; Urea (8W8T17847W) ; NEIL1 protein, human (EC 3.2.2.-) ; DNA Glycosylases (EC 3.2.2.-)
Language	English
Publishing date	2023-04-03
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	186809-3
ISSN	1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
ISSN (online)	1362-4962 ; 1362-4954
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gkad164
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Article ; Online: Mutagenic potential of nitrogen mustard-induced formamidopyrimidine DNA adduct: Contribution of the non-canonical α-anomer.

Minko, Irina G / Rizzo, Carmelo J / Lloyd, R Stephen

The Journal of biological chemistry

2017 Volume 292, Issue 46, Page(s) 18790–18799

Abstract: Nitrogen mustards (NMs) are DNA-alkylating compounds that represent the earliest anticancer drugs. However, clinical use of NMs is limited because of their own mutagenic properties. The mechanisms of NM-induced mutagenesis remain unclear. The major ... ...

Abstract	Nitrogen mustards (NMs) are DNA-alkylating compounds that represent the earliest anticancer drugs. However, clinical use of NMs is limited because of their own mutagenic properties. The mechanisms of NM-induced mutagenesis remain unclear. The major product of DNA alkylation by NMs is a cationic NM-N7-dG adduct that can yield the imidazole ring-fragmented lesion,
MeSH term(s)	Alkylating Agents/toxicity ; Alkylation/drug effects ; Animals ; COS Cells ; Chlorocebus aethiops ; DNA Adducts/chemistry ; DNA Adducts/genetics ; Escherichia coli/drug effects ; Escherichia coli/genetics ; Mechlorethamine/toxicity ; Mutagenesis/drug effects ; Mutagens/toxicity ; Pyrimidines/chemistry
Chemical Substances	Alkylating Agents ; DNA Adducts ; Mutagens ; Pyrimidines ; Mechlorethamine (50D9XSG0VR)
Language	English
Publishing date	2017-09-28
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M117.802520
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Article ; Online: DNA Sequence Modulates the Efficiency of NEIL1-Catalyzed Excision of the Aflatoxin B

Tomar, Rachana / Minko, Irina G / Kellum, Andrew H / Voehler, Markus W / Stone, Michael P / McCullough, Amanda K / Lloyd, R Stephen

Chemical research in toxicology

2021 Volume 34, Issue 3, Page(s) 901–911

Abstract: Dietary exposure to aflatoxins is a significant risk factor in the development of hepatocellular carcinomas. Following bioactivation by microsomal P450s, the reaction of aflatoxin ... ...

Abstract	Dietary exposure to aflatoxins is a significant risk factor in the development of hepatocellular carcinomas. Following bioactivation by microsomal P450s, the reaction of aflatoxin B
MeSH term(s)	Aflatoxin B1/chemistry ; Aflatoxin B1/metabolism ; Base Sequence ; Biocatalysis ; DNA/chemistry ; DNA/metabolism ; DNA Adducts/chemistry ; DNA Adducts/metabolism ; DNA Glycosylases/chemistry ; DNA Glycosylases/metabolism ; Guanine/chemistry ; Guanine/metabolism ; Humans ; Molecular Structure ; Pyrimidines/chemistry ; Pyrimidines/metabolism
Chemical Substances	DNA Adducts ; Pyrimidines ; 2,6-diamino-4-hydroxy-5-formamidopyrimidine (133310-38-0) ; Guanine (5Z93L87A1R) ; DNA (9007-49-2) ; Aflatoxin B1 (9N2N2Y55MH) ; DNA Glycosylases (EC 3.2.2.-) ; NEIL1 protein, human (EC 3.2.2.-)
Language	English
Publishing date	2021-02-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	639353-6
ISSN	1520-5010 ; 0893-228X
ISSN (online)	1520-5010
ISSN	0893-228X
DOI	10.1021/acs.chemrestox.0c00517
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Article ; Online: Enhanced cytarabine-induced killing in OGG1-deficient acute myeloid leukemia cells.

Owen, Nichole / Minko, Irina G / Moellmer, Samantha A / Cammann, Sydney K / Lloyd, R Stephen / McCullough, Amanda K

Proceedings of the National Academy of Sciences of the United States of America

2021 Volume 118, Issue 11

Abstract: Human clinical trials suggest that inhibition of enzymes in the DNA base excision repair (BER) pathway, such as PARP1 and APE1, can be useful in anticancer strategies when combined with certain DNA-damaging agents or tumor-specific genetic deficiencies. ... ...

Abstract	Human clinical trials suggest that inhibition of enzymes in the DNA base excision repair (BER) pathway, such as PARP1 and APE1, can be useful in anticancer strategies when combined with certain DNA-damaging agents or tumor-specific genetic deficiencies. There is also evidence suggesting that inhibition of the BER enzyme 8-oxoguanine DNA glycosylase-1 (OGG1), which initiates repair of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG) and 2,6-diamino-4-hydroxy-5-formamidopyrimidine (Fapy-dG), could be useful in treating certain cancers. Specifically, in acute myeloid leukemia (AML), both the RUNX1-RUNX1T1 fusion and the CBFB-MYH11 subtypes have lower levels of
MeSH term(s)	8-Hydroxy-2'-Deoxyguanosine/genetics ; Antimetabolites, Antineoplastic/pharmacology ; Cell Line, Tumor ; Core Binding Factor Alpha 2 Subunit/genetics ; Cytarabine/pharmacology ; DNA Glycosylases/genetics ; DNA Repair ; Humans ; Leukemia, Myeloid, Acute/enzymology ; Leukemia, Myeloid, Acute/pathology ; RNA, Messenger/genetics
Chemical Substances	Antimetabolites, Antineoplastic ; Core Binding Factor Alpha 2 Subunit ; RNA, Messenger ; RUNX1 protein, human ; Cytarabine (04079A1RDZ) ; 8-Hydroxy-2'-Deoxyguanosine (88847-89-6) ; DNA Glycosylases (EC 3.2.2.-) ; oxoguanine glycosylase 1, human (EC 3.2.2.-)
Language	English
Publishing date	2021-04-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2016833118
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Article ; Online: Error-prone replication bypass of the imidazole ring-opened formamidopyrimidine deoxyguanosine adduct.

Sha, Yan / Minko, Irina G / Malik, Chanchal K / Rizzo, Carmelo J / Lloyd, R Stephen

Environmental and molecular mutagenesis

2017 Volume 58, Issue 4, Page(s) 182–189

Abstract: ... configuration. Previous studies reported that in 5'-TGN-3' sequences, Fapy-dG predominantly induced G → T ... mutation spectra were observed that included ∼3-5% G → T transversions and ∼14-21% G → A transitions. There ... When conditions for vector preparation were modified to favor the β anomer, frequencies of both G → T and G ...

Abstract	Addition of hydroxyl radicals to the C8 position of 2'-deoxyguanosine generates an 8-hydroxyguanyl radical that can be converted into either 8-oxo-7,8-dihydro-2'-deoxyguanosine or N-(2-deoxy-d-pentofuranosyl)-N-(2,6-diamino-4-hydroxy-5-formamidopyrimidine) (Fapy-dG). The Fapy-dG adduct can adopt different conformations and in particular, can exist in an unnatural α anomeric configuration in addition to canonical β configuration. Previous studies reported that in 5'-TGN-3' sequences, Fapy-dG predominantly induced G → T transversions in both mammalian cells and Escherichia coli, suggesting that mutations could be formed either via insertion of a dA opposite the 5' dT due to primer/template misalignment or as result of direct miscoding. To address this question, single-stranded vectors containing a site-specific Fapy-dG adduct were generated to vary the identity of the 5' nucleotide. Following vector replication in primate cells (COS7), complex mutation spectra were observed that included ∼3-5% G → T transversions and ∼14-21% G → A transitions. There was no correlation apparent between the identity of the 5' nucleotide and spectra of mutations. When conditions for vector preparation were modified to favor the β anomer, frequencies of both G → T and G → A substitutions were significantly reduced. Mutation frequencies in wild-type E. coli and a mutant deficient in damage-inducible DNA polymerases were significantly lower than detected in COS7 and spectra were dominated by deletions. Thus, mutagenic bypass of Fapy-dG can proceed via mechanisms that are different from the previously proposed primer/template misalignment or direct misinsertions of dA or dT opposite to the β anomer of Fapy-dG. Environ. Mol. Mutagen. 58:182-189, 2017. © 2017 Wiley Periodicals, Inc.
MeSH term(s)	Animals ; COS Cells ; Cercopithecus aethiops ; DNA Adducts/chemistry ; DNA Replication ; Deoxyguanosine/chemistry ; Imidazoles/chemistry ; Mutagenesis
Chemical Substances	DNA Adducts ; Imidazoles ; Deoxyguanosine (G9481N71RO)
Language	English
Publishing date	2017-05
Publishing country	United States
Document type	Journal Article
ZDB-ID	639145-x
ISSN	1098-2280 ; 0893-6692
ISSN (online)	1098-2280
ISSN	0893-6692
DOI	10.1002/em.22089
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Article ; Online: Processing of N

Minko, Irina G / Christov, Plamen P / Li, Liang / Stone, Michael P / McCullough, Amanda K / Lloyd, R Stephen

DNA repair

2018 Volume 73, Page(s) 49–54

Abstract: A variety of agents cause DNA base alkylation damage, including the known hepatocarcinogen aflatoxin ... ...

Abstract	A variety of agents cause DNA base alkylation damage, including the known hepatocarcinogen aflatoxin B
MeSH term(s)	Animals ; DNA Adducts/chemistry ; DNA Adducts/metabolism ; DNA Glycosylases/metabolism ; Mice ; N-Glycosyl Hydrolases/metabolism ; Pyrimidines/chemistry ; Pyrimidines/metabolism
Chemical Substances	DNA Adducts ; Pyrimidines ; DNA Glycosylases (EC 3.2.2.-) ; N-Glycosyl Hydrolases (EC 3.2.2.-) ; NEIL1 protein, human (EC 3.2.2.-) ; NEIL3 protein, human (EC 3.2.2.-) ; pyrimidine (K8CXK5Q32L)
Language	English
Publishing date	2018-11-05
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2071608-4
ISSN	1568-7856 ; 1568-7864
ISSN (online)	1568-7856
ISSN	1568-7864
DOI	10.1016/j.dnarep.2018.11.001
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Article ; Online: Translesion synthesis past acrolein-derived DNA adducts by human mitochondrial DNA polymerase γ.

Kasiviswanathan, Rajesh / Minko, Irina G / Lloyd, R Stephen / Copeland, William C

The Journal of biological chemistry

2013 Volume 288, Issue 20, Page(s) 14247–14255

Abstract: Acrolein, a mutagenic aldehyde, is produced endogenously by lipid peroxidation and exogenously by combustion of organic materials, including tobacco products. Acrolein reacts with DNA bases forming exocyclic DNA adducts, such as γ-hydroxy-1,N(2)-propano- ... ...

Abstract	Acrolein, a mutagenic aldehyde, is produced endogenously by lipid peroxidation and exogenously by combustion of organic materials, including tobacco products. Acrolein reacts with DNA bases forming exocyclic DNA adducts, such as γ-hydroxy-1,N(2)-propano-2'-deoxyguanosine (γ-HOPdG) and γ-hydroxy-1,N(6)-propano-2'-deoxyadenosine (γ-HOPdA). The bulky γ-HOPdG adduct blocks DNA synthesis by replicative polymerases but can be bypassed by translesion synthesis polymerases in the nucleus. Although acrolein-induced adducts are likely to be formed and persist in mitochondrial DNA, animal cell mitochondria lack specialized translesion DNA synthesis polymerases to tolerate these lesions. Thus, it is important to understand how pol γ, the sole mitochondrial DNA polymerase in human cells, acts on acrolein-adducted DNA. To address this question, we investigated the ability of pol γ to bypass the minor groove γ-HOPdG and major groove γ-HOPdA adducts using single nucleotide incorporation and primer extension analyses. The efficiency of pol γ-catalyzed bypass of γ-HOPdG was low, and surprisingly, pol γ preferred to incorporate purine nucleotides opposite the adduct. Pol γ also exhibited ∼2-fold lower rates of excision of the misincorporated purine nucleotides opposite γ-HOPdG compared with the corresponding nucleotides opposite dG. Extension of primers from the termini opposite γ-HOPdG was accomplished only following error-prone purine nucleotide incorporation. However, pol γ preferentially incorporated dT opposite the γ-HOPdA adduct and efficiently extended primers from the correctly paired terminus, indicating that γ-HOPdA is probably nonmutagenic. In summary, our data suggest that acrolein-induced exocyclic DNA lesions can be bypassed by mitochondrial DNA polymerase but, in the case of the minor groove γ-HOPdG adduct, at the cost of unprecedented high mutation rates.
MeSH term(s)	Acrolein/pharmacology ; Catalytic Domain ; DNA Adducts ; DNA Damage ; DNA Polymerase gamma ; DNA Replication ; DNA-Directed DNA Polymerase/metabolism ; Deoxyguanosine/chemistry ; Humans ; Lipid Peroxidation ; Mitochondria/enzymology ; Models, Chemical ; Mutagenesis ; Oligonucleotides/chemistry ; Oxidative Stress
Chemical Substances	DNA Adducts ; Oligonucleotides ; Acrolein (7864XYD3JJ) ; DNA Polymerase gamma (EC 2.7.7.7) ; DNA-Directed DNA Polymerase (EC 2.7.7.7) ; Deoxyguanosine (G9481N71RO)
Language	English
Publishing date	2013-03-30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M113.458802
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