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Published online on October 2, 2006, 10.1073/pnas.0603644103
PNAS | October 10, 2006 | vol. 103 | no. 41 | 15020-15025


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PHYSICAL SCIENCES / BIOLOGICAL SCIENCES / CHEMISTRY / BIOCHEMISTRY
A nucleobase lesion remodels the interaction of its normal neighbor in a DNA glycosylase complex

Anirban Banerjee*,{dagger}, and Gregory L. Verdine*,{ddagger},§

Departments of *Chemistry and Chemical Biology and {ddagger}Molecular and Cellular Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138

Edited by Jacqueline K. Barton, California Institute of Technology, Pasadena, CA, and approved August 10, 2006 (received for review May 3, 2006)

How DNA glycosylases search through millions of base pairs and discriminate between rare sites of damage and otherwise undamaged bases is poorly understood. Even less understood are the details of the structural states arising from DNA glycosylases interacting with undamaged DNA. Recognizing the mutagenic lesion 7,8-dihydro-8-oxoguanine (8-oxoguanine, oxoG) represents an especially formidable challenge, because this oxidized nucleobase differs by only two atoms from its normal counterpart, guanine (G), and buried in the structure of naked B-form DNA, oxoG and G are practically indistinguishable from each other. We have used disulfide cross-linking technology to capture a human oxoG repair protein, 8-oxoguanine DNA glycosylase I (hOGG1) sampling an undamaged G:C base pair located adjacent to an oxoG:C base pair in DNA. The x-ray structure of the trapped complex reveals that the presence of the 8-oxoG drastically changes the local conformation of the extruded G. The extruded but intrahelical state of the G in this structure offers a view of an early intermediate in the base-extrusion pathway.

8-oxoguanine | base-excision repair | disulfide trapping | base-extrusion pathway

Author contributions: A.B. and G.L.V. designed research; A.B. performed research; A.B. contributed new reagents/analytic tools; A.B. and G.L.V. analyzed data; and A.B. and G.L.V. wrote the paper.

{dagger}Present address: The Rockefeller University, New York, NY 10021.

This paper was submitted directly (Track II) to the PNAS office.

Data deposition: The atomic coordinates have been deposited in the Protein Data Bank, www.pdb.org (PDB ID code 2I5W).

§To whom correspondence should be addressed. E-mail: gregory_verdine{at}harvard.edu

© 2006 by The National Academy of Sciences of the USA


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C. T. Radom, A. Banerjee, and G. L. Verdine
Structural Characterization of Human 8-Oxoguanine DNA Glycosylase Variants Bearing Active Site Mutations
J. Biol. Chem., March 23, 2007; 282(12): 9182 - 9194.
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