Recent advances in the structural mechanisms of DNA glycosylases

• Published in: Biochimica et biophysica acta Vol. 1834; no. 1; pp. 247 - 271
• Main Authors: Brooks, Sonja C., Adhikary, Suraj, Rubinson, Emily H., Eichman, Brandt F.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.01.2013
• Subjects: Active DNA demethylation; alkylation; Animals; Base excision repair; deamination; DNA; DNA - chemistry; DNA - genetics; DNA - metabolism; DNA alkylation; DNA Damage; DNA glycosylase; DNA Glycosylases - chemistry; DNA Glycosylases - genetics; DNA Glycosylases - metabolism; DNA oxidation; enzymology; genome; glycosylases; Humans; oxidation; Protein Structure, Tertiary; Protein–DNA interactions; Structure-Activity Relationship; surveys; Active DNA demethylation; DNA glycosylase; DNA alkylation; Base excision repair; DNA oxidation; Protein–DNA interactions
• ISSN: 1570-9639; 0006-3002; 1878-1454; 1878-2434
• DOI: 10.1016/j.bbapap.2012.10.005

DNA glycosylases safeguard the genome by locating and excising a diverse array of aberrant nucleobases created from oxidation, alkylation, and deamination of DNA. Since the discovery 28years ago that these enzymes employ a base flipping mechanism to trap their substrates, six different protein architectures have been identified to perform the same basic task. Work over the past several years has unraveled details for how the various DNA glycosylases survey DNA, detect damage within the duplex, select for the correct modification, and catalyze base excision. Here, we provide a broad overview of these latest advances in glycosylase mechanisms gleaned from structural enzymology, highlighting features common to all glycosylases as well as key differences that define their particular substrate specificities. ► Recent structural and mechanistic studies of DNA glycosylases are reviewed. ► DNA glycosylases excise oxidized, alkylated, or deaminated nucleobases. ► Five structural folds use base flipping to recognize and remove damage. ► A sixth architecture traps destabilized base pairs without a base binding pocket.