Nucleotide Excision Repair Proteins May Be Involved in the Fixation of Glyoxal-Induced Mutagenesis inEscherichia coli

Murata‐Kamiya, Naoko; Kamiya, Hiroyuki; Kaji, Hiroshi; Kasai, Hiroshi

doi:10.1006/bbrc.1998.8973

Cited by 17 publications

(5 citation statements)

References 36 publications

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“…There were also G:C → A:T transitions and A:T → T:A transversions with glyoxal, and TGGC frameshift mutations for methylglyoxal. These studies indicate that nucleotide glycation and its effects are suppressed by NER [29,30]. Introduction of the specific nucleotide AGE CEdG into DNA was also associated with increased mutation frequency and increased DNA strand breaks in E. coli [31].…”

Section: Dna Glycation Mutagenesis and Ner (Nucleotide Excision Repair)mentioning

confidence: 81%

Protecting the genome: defence against nucleotide glycation and emerging role of glyoxalase I overexpression in multidrug resistance in cancer chemotherapy

Thornalley

2003

Biochemical Society Transactions

117

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Glycation of nucleotides in DNA forms AGEs (advanced glycation end-products). Nucleotide AGEs are: the imidazopurinone derivative dG-G [3-(2'-deoxyribosyl)-6,7-dihydro-6,7-dihydroxyimidazo[2,3-b]purin-9(8)one], CMdG ( N (2)-carboxymethyldeoxyguanosine) and gdC (5-glycolyldeoxycytidine) derived from glyoxal, dG-MG [6,7-dihydro-6,7-dihydroxy-6-methylimidazo-[2,3-b]purine-9(8)one], dG-MG(2) [ N (2),7-bis-(1-hydroxy-2-oxopropyl)deoxyguanosine] and CEdG [ N (2)-(1-carboxyethyl)deoxyguanosine] derived from methylglyoxal, and dG-3DG [ N (2)-(1-oxo-2,4,5,6-tetrahydroxyhexyl)deoxyguanosine] derived from 3-deoxyglucosone and others. Glyoxal and methylglyoxal induce multi-base deletions, and base-pair substitutions - mostly occurring at G:C sites with G:C-->C:G and G:C-->T:A transversions. Suppression of nucleotide glycation by glyoxalase I and aldehyde reductases and dehydrogenases, and base excision repair, protects and recovers DNA from damaging glycation. The effects of DNA glycation may be most marked in diabetes and uraemia. Mutations arising from DNA glycation may explain the link of non-dietary carbohydrate intake to incidence of colorectal cancer. Overexpression of glyoxalase I was found in drug-resistant tumour cells and may be an example of an undesirable effect of the enzymatic protection against DNA glycation. Experimental overexpression of glyoxalase I conferred resistance to drug-induced apoptosis. Glyoxalase I-mediated drug resistance was found in human leukaemia and lung carcinoma cells. Methylglyoxal-mediated glycation of DNA may contribute to the cytotoxicity of some antitumour agents as a consequence of depletion of NAD(+) by poly(ADP-ribose) polymerase, marked increases in triosephosphate concentration and increased formation of methylglyoxal. S - p -Bromobenzylglutathione cyclopentyl diester is a cell-permeable glyoxalase I inhibitor. It countered drug resistance and was a potent antitumour agent against lung and prostate carcinoma. Glyoxalase I overexpression was also found in invasive ovarian cancer and breast cancer.

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Section: Dna Glycation Mutagenesis and Ner (Nucleotide Excision Repair)mentioning

confidence: 81%

Protecting the genome: defence against nucleotide glycation and emerging role of glyoxalase I overexpression in multidrug resistance in cancer chemotherapy

Thornalley

2003

Biochemical Society Transactions

117

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“…There were also G:C → A:T transitions and A:T → T:A transversions with glyoxal and TGGC frameshift mutations for methylglyoxal. These studies indicate that nucleotide glycation and its effects are suppressed by NER /56,57/. Introduction of the specific nucleotide AGE CEdG into DNA was also associated with increased mutation frequency and increased DNA strand breaks in E. coli /58/.…”

Section: Modification Of Nucleotides By Glyoxal and Methylglyoxalmentioning

confidence: 82%

Protein and Nucleotide Damage by Glyoxal and Methylglyoxal in Physiological Systems - Role in Ageing and Disease

Thornalley¹

2008

Drug Metabolism and Drug Interactions

418

347

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Glycation of proteins, nucleotides and basic phospholipids by glyoxal and methylglyoxalphysiological substrates of glyoxalase 1 -is potentially damaging to the proteome, genome and lipidome. Glyoxalase 1 suppresses glycation by these α-oxoaldehyde metabolites and thereby represents part of the enzymatic defence against glycation. Albert Szent-Gyorgyi pioneered and struggled to understand the physiological function of methylglyoxal and the glyoxalase system. We now appreciate glyoxalase 1 protects against dicarbonyl modifications of the proteome, genome and lipome. Latest research suggests there are functional modifications of this processimplying a role in cell signalling, ageing and disease.Letter from Albert Szent-Gyorgyi "I thank you for your kind lines from May 17 th , and the reprints that reached me only now. It was very long ago that I was interested in keto-aldehydes and worked on them. Since then I forgot most of what I knew. So, to my regret I am unable to advise you. Yours truly, Albert Szent-Gyorgyi, MD, PhD, NL." From a letter to the author dated 7 th June 1984.Above are the words of Albert Szent-Gyorgyi in a letter replying to my request for advice on how to pursue a research career on studies of methylglyoxal and the glyoxalase system. The letter was sent from the National Foundation for Cancer Research, Woods Hole, Massachusetts, USA. It has been framed, along side newspaper obituary tributes to SzentGyorgyi when he died in October 1986, hanging in my office for over the last 20 years whilst I grappled with similar problems that once interested him. Our common interest was, for Szent-Gyorgyi, and still is for me the physiological significance of the glyoxalase system and its physiological substrates -primarily the reactive dicarbonyl compounds and physiological metabolites, glyoxal and methylglyoxal /1,2/ -Figure 1. Methylglyoxal and glyoxal -physiological substrates of the glyoxalase systemThe presence and significance of reactive acyclic α-oxoaldehydes, methylglyoxal and glyoxal, in physiological systems was the subject of research before, during and after the research career of Szent-Gyorgyi. Neuberg had discovered the glyoxalase system and metabolism of methylglyoxal in 1913 /3/. Szent-Gyorgyi advanced his hypothesis of the "retine and promine" theory of control of cell proliferation /1/, and recent research views Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts glyoxalase 1 (Glo1) as part of the enzymatic defence against glycation /2/. Methylglyoxal has been considered to be an environmental and/or bacterial toxin and metabolite /4,5/. We now know methylglyoxal is formed spontaneously from triosephosphates in all organisms with anaerobic glycolysis /6/ and from other non-enzymatic and enzymatic pathways of differing significance -depending on the organism /7/. Glyoxal is formed by lipid peroxidation and the degradation of monosaccharides, saccharide derivatives and glycated proteins /8,9/. A continuing problem in the area of research is reliable estimation ...

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“…Thus, methylglyoxal appears to be a more important toxic aldehyde compound when we consider crosslinking ability, which may be involved in the biological processes described above. We previously reported that both glyoxal and methylglyoxal induce mutations mainly at G:C base pairs in E.coli (12,29,30) and in mammalian cells (13,31). However, the mutations induced by the two compounds show some differences.…”

Section: Discussionmentioning

confidence: 98%

Methylglyoxal, an endogenous aldehyde, crosslinks DNA polymerase and the substrate DNA

Murata‐Kamiya¹

2001

Nucleic Acids Research

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Methylglyoxal, a known endogenous and environmental mutagen, is a reactive alpha-ketoaldehyde that can modify both DNA and proteins. To investigate the possibility that methylglyoxal induces a crosslink between DNA and DNA polymerase, we treated a 'primed template' DNA and the exonuclease-deficient Klenow fragment (KF(exo-)) of DNA polymerase I with methylglyoxal in vitro. When the reaction mixtures were analyzed by SDS-PAGE, we found that methylglyoxal induced a DNA-KF(exo-) crosslink. The specific binding complex of KF(exo-) and 'primed template' DNA was necessary for formation of the DNA-KF(exo-) crosslink. Methylglyoxal reacted with guanine residues in the single-stranded portion of the template DNA. When 2'-deoxyguanosine was incubated with Nalpha-acetyllysine or N-acetylcysteine in the presence of methylglyoxal, a crosslinked product was formed. No other amino acid derivatives tested could generate a crosslinked product. These results suggest that methylglyoxal crosslinks a guanine residue of the substrate DNA and lysine and cysteine residues near the binding site of the DNA polymerase during DNA synthesis and that DNA replication is severely inhibited by the methylglyoxal-induced DNA-DNA polymerase crosslink.

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Nucleotide Excision Repair Proteins May Be Involved in the Fixation of Glyoxal-Induced Mutagenesis inEscherichia coli

Cited by 17 publications

References 36 publications

Protecting the genome: defence against nucleotide glycation and emerging role of glyoxalase I overexpression in multidrug resistance in cancer chemotherapy

Protecting the genome: defence against nucleotide glycation and emerging role of glyoxalase I overexpression in multidrug resistance in cancer chemotherapy

Protein and Nucleotide Damage by Glyoxal and Methylglyoxal in Physiological Systems - Role in Ageing and Disease

Methylglyoxal, an endogenous aldehyde, crosslinks DNA polymerase and the substrate DNA

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