期刊
NUCLEIC ACIDS RESEARCH
卷 38, 期 1, 页码 97-116出版社
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkp1036
关键词
DNA bulges; sequence context; differential scanning calorimetry; heat-capacity; cooperativity; conformational transitions; thermal stability; thermodynamic stability; hot-spot sequence
资金
- National Institutes of Health [GM23509, GM34469, CA47995]
- Rutgers - The State University of New Jersey, Department of Chemistry and Chemical Biology
- NATIONAL CANCER INSTITUTE [P01CA047995] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM023509, R01GM034469] Funding Source: NIH RePORTER
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 G(Bulge)); the thermodynamic origins of delta delta G(Bulge) (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 G(Bulge) 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 G(Bulge) 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.
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