An unprecedented nucleic acid capture mechanism for excision of DNA damage

Emily H. Rubinson, A. S.Prakasha Gowda, Thomas E. Spratt, Barry Gold, Brandt F. Eichman

Research output: Contribution to journalArticle

53 Scopus citations

Abstract

DNA glycosylases that remove alkylated and deaminated purine nucleobases are essential DNA repair enzymes that protect the genome, and at the same time confound cancer alkylation therapy, by excising cytotoxic N3-methyladenine bases formed by DNA-targeting anticancer compounds. The basis for glycosylase specificity towards N3- and N7-alkylpurines is believed to result from intrinsic instability of the modified bases and not from direct enzyme functional group chemistry. Here we present crystal structures of the recently discovered Bacillus cereus AlkD glycosylase in complex with DNAs containing alkylated, mismatched and abasic nucleotides. Unlike other glycosylases, AlkD captures the extrahelical lesion in a solvent-exposed orientation, providing an illustration for how hydrolysis of N3- and N7-alkylated bases may be facilitated by increased lifetime out of the DNA helix. The structures and supporting biochemical analysis of base flipping and catalysis reveal how the HEAT repeats of AlkD distort the DNA backbone to detect non-WatsonCrick base pairs without duplex intercalation.

Original languageEnglish (US)
Pages (from-to)406-413
Number of pages8
JournalNature
Volume468
Issue number7322
DOIs
StatePublished - Nov 18 2010

All Science Journal Classification (ASJC) codes

  • General

Fingerprint Dive into the research topics of 'An unprecedented nucleic acid capture mechanism for excision of DNA damage'. Together they form a unique fingerprint.

  • Cite this

    Rubinson, E. H., Gowda, A. S. P., Spratt, T. E., Gold, B., & Eichman, B. F. (2010). An unprecedented nucleic acid capture mechanism for excision of DNA damage. Nature, 468(7322), 406-413. https://doi.org/10.1038/nature09428