Journal
NATURE
Volume 449, Issue 7161, Pages 433-U2Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nature06131
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Funding
- NIGMS NIH HHS [R01 GM066895, R01 GM056834-11A2, R01 GM056834] Funding Source: Medline
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The enzyme uracil DNA glycosylase (UNG) excises unwanted uracil bases in the genome using an extrahelical base recognition mechanism. Efficient removal of uracil is essential for prevention of C-to-T transition mutations arising from cytosine deamination, cytotoxic U center dot A pairs arising from incorporation of dUTP in DNA, and for increasing immunoglobulin gene diversity during the acquired immune response. A central event in all of these UNG-mediated processes is the singling out of rare U center dot A or U center dot G base pairs in a background of approximately 10(9) T center dot A or C center dot G base pairs in the human genome. Here we establish for the human and Escherichia coli enzymes that discrimination of thymine and uracil is initiated by thermally induced opening of T center dot A and U center dot A base pairs and not by active participation of the enzyme. Thus, base-pair dynamics has a critical role in the genome-wide search for uracil, and may be involved in initial damage recognition by other DNA repair glycosylases.
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