The ada operon of Mycobacterium tuberculosis encodes two DNA methyltransferases for inducible repair of DNA alkylation damage

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• 作者：Mingyi Yang^a ; ^b ; ^c ; Randi M. Aamodt^a ; ^c ; Bjø ; rn Dalhus^a ; ^b ; ^c ; Seetha Balasingham^a ; ^c ; Ina Helle^b ; ^c ; Pernille Andersen^b ; ^c ; Tone Tø ; njum^a ; ^c ; Ingrun Alseth^a ; ^c ; Torbjø ; rn Rognes^a ; ^c ; ^d ; Magnar Bjø ; rå ; s^a ; ^b ; ^c ; ^{magnar.bjoras@rr-research.no"" rel=""nofollow} ; ^{magnar.bjoras@medisin.uio.no"" rel=""nofollow}
• 关键词：M. tuberculosis ; DNA damage ; Alkylation ; Ada ; AlkA ; Methyltransferase ; DNA glycosylase
• 刊名：DNA Repair
• 出版年：2011
• 出版时间：10 June 2011
• 年：2011
• 卷：10
• 期：6
• 页码：595-602
• 全文大小：608 K

文摘

The ada operon of Mycobacterium tuberculosis, which encodes a composite protein of AdaA and AlkA and a separate AdaB/Ogt protein, was characterized. M. tuberculosis treated with N-methyl-N 32;-nitro-N-nitrosoguanidine induced transcription of the adaA-alkA and adaB genes, suggesting that M. tuberculosis mount an inducible response to methylating agents. Survival assays of the methyltransferase defective Escherichia coli mutant KT233 (ada ogt), showed that expression of the adaB gene rescued the alkylation sensitivity. Further, adaB but not adaA-alkA complemented the hypermutator phenotype of KT233. Purified AdaA-AlkA and AdaB possessed methyltransferase activity. These data suggested that AdaB counteract the cytotoxic and mutagenic effect of O⁶-methylguanine, while AdaA-AlkA most likely transfers methyl groups from innocuous methylphosphotriesters. AdaA-AlkA did not possess alkylbase DNA glycosylase activity nor rescue the alkylation sensitivity of the E. coli mutant BK2118 (tag alkA). We propose that AdaA-AlkA is a positive regulator of the adaptive response in M. tuberculosis. It thus appears that the ada operon of M. tuberculosis suppresses the mutagenic effect of alkylation but not the cytotoxic effect of lesions such as 3-methylpurines. Collectively, these data indicate that M. tuberculosis hypermutator strains with defective adaptive response genes might sustain robustness to cytotoxic alkylation DNA damage and confer a selective advantage contributing to host adaptation.