期刊
EMBO JOURNAL
卷 37, 期 1, 页码 63-74出版社
WILEY
DOI: 10.15252/embj.201797833
关键词
3-methyladenine; 3-methylcytosine; base excision repair; DNA glycosylase; DNA repair
资金
- National Science Foundation [MCB-1517695, CHE-1610721]
- National Institutes of Health [R01 ES019625]
- U.S. Department of Energy [DE-AC02-06CH11357]
- Michigan Economic Development Corporation
- Michigan Technology Tri-Corridor [085P1000817]
- DOE Office of Biological and Environmental Research
- Vanderbilt Training Program in Environmental Toxicology [T32ES07028]
- National Institutes of Health training program in chemical biology [T32 GM113770]
- Direct For Biological Sciences
- Div Of Molecular and Cellular Bioscience [1517695] Funding Source: National Science Foundation
- Direct For Mathematical & Physical Scien [1610721] Funding Source: National Science Foundation
- Division Of Chemistry [1610721] Funding Source: National Science Foundation
DNA glycosylases preserve genome integrity and define the specificity of the base excision repair pathway for discreet, detrimental modifications, and thus, the mechanisms by which glycosylases locate DNA damage are of particular interest. Bacterial AlkC and AlkD are specific for cationic alkylated nucleobases and have a distinctive HEAT-like repeat (HLR) fold. AlkD uses a unique non-base-flipping mechanism that enables excision of bulky lesions more commonly associated with nucleotide excision repair. In contrast, AlkC has a much narrower specificity for small lesions, principally N3-methyladenine (3mA). Here, we describe how AlkC selects for and excises 3mA using a non-base-flipping strategy distinct from that of AlkD. A crystal structure resembling a catalytic intermediate complex shows how AlkC uses unique HLR and immunoglobulin-like domains to induce a sharp kink in the DNA, exposing the damaged nucleobase to active site residues that project into the DNA. This active site can accommodate and excise N3-methylcytosine (3mC) and N1-methyladenine (1mA), which are also repaired by AlkB-catalyzed oxidative demethylation, providing a potential alternative mechanism for repair of these lesions in bacteria.
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