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Whether DNA glycosylases eliminate other types of damage formed by structurally diverse antibiotics is unknown. Here, we identify four DNA glycosylases\u2014TxnU2, TxnU4, LldU1\u00a0and LldU5\u2014important for biosynthesis of the aromatic polyketide antibiotics trioxacarcin A (TXNA) and LL-D49194 (LLD), and show that the enzymes provide self-resistance to the producing strains by excising the intercalated guanine adducts of TXNA and LLD. These enzymes are highly specific for TXNA\/LLD-DNA lesions and have no activity toward other, less stable alkylguanines as previously described for YtkR2\/AlkD and AlkZ\/YcaQ. Similarly, TXNA-DNA adducts are not excised by other alkylpurine DNA glycosylases. TxnU4 and LldU1 possess unique active site motifs that provide an explanation for their tight substrate specificity. Moreover, we show that abasic (AP) sites generated from TxnU4 excision of intercalated TXNA-DNA adducts are incised by AP endonuclease less efficiently than those formed by 7mG excision. This work characterizes a distinct class of DNA glycosylase acting on intercalated DNA adducts and furthers our understanding of specific DNA repair self-resistance activities within antibiotic producers of structurally diverse, highly functionalized DNA damaging agents.<\/jats:p>","DOI":"10.1093\/nar\/gkac085","type":"journal-article","created":{"date-parts":[[2022,1,27]],"date-time":"2022-01-27T07:13:33Z","timestamp":1643267613000},"page":"2417-2430","source":"Crossref","is-referenced-by-count":18,"title":["Base excision repair system targeting DNA adducts of trioxacarcin\/LL-D49194 antibiotics for self-resistance"],"prefix":"10.1093","volume":"50","author":[{"given":"Xiaorong","family":"Chen","sequence":"first","affiliation":[{"name":"School of Chemistry and Materials Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, 1 Sub-lane Xiangshan, Hangzhou 310024, China"},{"name":"State Key Laboratory of Bioorganic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2701-3405","authenticated-orcid":false,"given":"Noah P","family":"Bradley","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Vanderbilt University, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Lu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioorganic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine L","family":"Wahl","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Vanderbilt University, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioorganic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Yuan","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioorganic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xian-Feng","family":"Hou","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioorganic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0965-2297","authenticated-orcid":false,"given":"Brandt\u00a0F","family":"Eichman","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Vanderbilt University, Nashville, TN 37232, USA"},{"name":"Department of Biochemistry, Vanderbilt University, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3149-4683","authenticated-orcid":false,"given":"Gong-Li","family":"Tang","sequence":"additional","affiliation":[{"name":"School of Chemistry and Materials Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, 1 Sub-lane Xiangshan, Hangzhou 310024, China"},{"name":"State Key Laboratory of Bioorganic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,2,22]]},"reference":[{"key":"2022032100052967700_B1","doi-asserted-by":"crossref","first-page":"1747","DOI":"10.1021\/tx900242k","article-title":"An overview of chemical processes that damage cellular DNA: spontaneous hydrolysis, alkylation, and reactions with radicals","volume":"22","author":"Gates","year":"2009","journal-title":"Chem. 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