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Nucleic Acids Research Advance Access originally published online on April 1, 2009
Nucleic Acids Research 2009 37(11):3493-3500; doi:10.1093/nar/gkp161
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Nucleic Acids Research, 2009, Vol. 37, No. 11 3493-3500
© 2009 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Nucleic Acids Enzymes

Nontarget DNA binding shapes the dynamic landscape for enzymatic recognition of DNA damage

Joshua I. Friedman1, Ananya Majumdar2 and James T. Stivers1,*

1Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, 725 North Wolfe Street Baltimore, MD 21205 and 2Johns Hopkins Biomolecular NMR Center, 3400 North Charles Street, Baltimore, MD 21218, USA

*To whom correspondence should be addressed. Tel: +1 410 502 2758; Fax: +1 410 955 3023; Email: jstivers{at}jhmi.edu

Received January 20, 2009. Revised February 20, 2009. Accepted February 22, 2009.

The DNA repair enzyme human uracil DNA glycosylase (UNG) scans short stretches of genomic DNA and captures rare uracil bases as they transiently emerge from the DNA duplex via spontaneous base pair breathing motions. The process of DNA scanning requires that the enzyme transiently loosen its grip on DNA to allow stochastic movement along the DNA contour, while engaging extrahelical bases requires motions on a more rapid timescale. Here, we use NMR dynamic measurements to show that free UNG has no intrinsic dynamic properties in the millisecond to microsecond and subnanosecond time regimes, and that the act of binding to nontarget DNA reshapes the dynamic landscape to allow productive millisecond motions for scanning and damage recognition. These results suggest that DNA structure and the spontaneous dynamics of base pairs may drive the evolution of a protein sequence that is tuned to respond to this dynamic regime.


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