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Abstract
O6-Methylguanine, the major mutagenic product of methylnitroso compounds, was previously thought to be repaired exclusively by alkyltransferases I and II. Using synthetic substrates that contain O6-methyl-guanine at defined positions, we demonstrate that the nucleotide excision repair enzyme of Escherichia coli, ABC excinuclease, also repairs DNA containing this adduct. We show that the ABC excinuclease binds specifically to the modified DNA and produces incisions at the eight phosphodiester bond 5' and at the fifth or sixth phosphodiester bond 3' to the modified guanine.
Highlights
Cells compared to uurB- cells and found that methylnitrosourea was more lethal and mutagenic in uurB- cells
It is generally assumed that thesmall DNA adducts caused by methylating agents arerepaired by methyltransferases and glycosylases and that bulky DNA adducts induced by chemicals such as psoralen, cisplatin, and acetylaminofluorene are repaired by nucleotide excision repair enzymes [1, 2]
Previous studies suggested that the ABC excinuclease encoded by the nucleotide excision repair genes uurA, uurB, and uurC did not repair methylating damage to DNA, any contribution by excision that ABC excinuclease is involved in repair of @-methylguanine in uiuo, direct evidence that the purified enzyme recognizesthis adduct and initiates itsremoval in uitro as it does for bulky DNA adducts was lacking
Summary
Cells compared to uurB- cells and found that methylnitrosourea was more lethal and mutagenic in uurB- cells. In this paper, using oligonucleotides containing 06-MeGua synthesized at a unique site, we demonstrate that theUvrA subunits binds to 06-methylguanine-containingDNA and that ABC excinuclease incises the eight phosphodiester bond 5’ andthe fifth orsixth phosphodiester bond 3’ tothe methylated Gua. The enzyme recognized and excises 06- Enzymes-The ABC excinuclease was reconstituted from individually purified subunits: UvrA, UvrB, and UvrC [2].
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