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Nucleic Acids Research Advance Access published online on November 27, 2009
Nucleic Acids Research, doi:10.1093/nar/gkp1036
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© The Author(s) 2009. Published by Oxford University Press.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Genome Integrity, Repair and Replication

Energetic signatures of single base bulges: thermodynamic consequences and biological implications

Conceição A. S. A. Minetti, David P. Remeta, Rian Dickstein and Kenneth J. Breslauer*

Department of Chemistry and Chemical Biology, Rutgers – The State University of New Jersey, Piscataway, NJ 08854, USA

*To whom correspondence should be addressed. Tel: +1 732 445 3956; Fax: +1 732 445 3409; Email: kjbdna{at}rci.rutgers.edu

Received September 25, 2009. Revised October 20, 2009. Accepted October 21, 2009.

DNA bulges are biologically consequential defects that can arise from template-primer misalignments during replication and pose challenges to the cellular DNA repair machinery. Calorimetric and spectroscopic characterizations of defect-containing duplexes reveal systematic patterns of sequence-context dependent bulge-induced destabilizations. These distinguishing energetic signatures are manifest in three coupled characteristics, namely: the magnitude of the bulge-induced duplex destabilization ({Delta}{Delta}GBulge); the thermodynamic origins of {Delta}{Delta}GBulge (i.e. enthalpic versus entropic); and, the cooperativity of the duplex melting transition (i.e. two-state versus non-two state). We find moderately destabilized duplexes undergo two-state dissociation and exhibit {Delta}{Delta}GBulge values consistent with localized, nearest neighbor perturbations arising from unfavorable entropic contributions. Conversely, strongly destabilized duplexes melt in a non-two-state manner and exhibit {Delta}{Delta}GBulge values consistent with perturbations exceeding nearest-neighbor expectations that are enthalpic in origin. Significantly, our data reveal an intriguing correlation in which the energetic impact of a single bulge base centered in one strand portends the impact of the corresponding complementary bulge base embedded in the opposite strand. We discuss potential correlations between these bulge-specific differential energetic profiles and their overall biological implications in terms of DNA recognition, repair and replication.

The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.


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