Structural and energetic characterization of the major DNA adduct formed from the food mutagen ochratoxin A in the NarI hotspot sequence: influence of adduct ionization on the conformational preferences and implications for the NER propensity

Simple item page
dc.contributor.authorSharma, Purshotam
dc.contributor.authorManderville, Richard A.
dc.contributor.authorWetmore, Stacey D.
dc.date.accessioned2016-08-17T17:49:53Z
dc.date.available2016-08-17T17:49:53Z
dc.date.issued2014
dc.descriptionSherpa Romeo green journal, open accessen_US
dc.description.abstractThe nephrotoxic food mutagen ochratoxin A (OTA) produces DNA adducts in rat kidneys, the major lesion being the C8-linked-2 -deoxyguanosine adduct (OTB-dG). Although research on other adducts stresses the importance of understanding the structure of the associated adducted DNA, site-specific incorporation of OTB-dG into DNA has yet to be attempted. The present work uses a robust computational approach to determine the conformational preferences of OTB-dG in three ionization states at three guanine positions in the NarI recognition sequence opposite cytosine. Representative adducted DNA helices were derived from over 2160 ns of simulation and ranked via free energies. For the first time, a close energetic separation between three distinct conformations is highlighted, which indicates OTA-adducted DNA likely adopts a mixture of conformations regardless of the sequence context. Nevertheless, the preferred conformation depends on the flanking bases and ionization state due to deviations in discrete local interactions at the lesion site. The structural characteristics of the lesion thus discerned have profound implications regarding its repair propensity andmutagenic outcomes, and support recent experiments suggesting the induction of double-strand breaks and deletion mutations upon OTA exposure. This combined structural and energetic characterization of the OTB-dG lesion in DNA will encourage future biochemical experiments on this potentially genotoxic lesion.en_US
dc.description.peer-reviewYesen_US
dc.identifier.citationPurshotam, S., Manderville, R. A., & Wetmore, S. D. (2014). Structural and energetic characterization of the major DNA adduct formed from the food mutagen ochratoxin A in the NarI hotspot sequence: influence of adduct ionization on the conformational preferences and implications for the NER propensity. Nucleic Acids Research, 42(18), 11831-11845. doi: 10.1093/nar/gku821en_US
dc.identifier.urihttps://hdl.handle.net/10133/4586
dc.language.isoen_CAen_US
dc.publisherOxford University Pressen_US
dc.publisher.departmentDepartment of Chemistry and Biochemistryen_US
dc.publisher.facultyArts and Scienceen_US
dc.publisher.institutionUniversity of Lethbridgeen_US
dc.publisher.institutionUniversity of Guelphen_US
dc.subjectDNA adducten_US
dc.subjectNarIen_US
dc.subjectIonizationen_US
dc.subjectOTB-dGen_US
dc.titleStructural and energetic characterization of the major DNA adduct formed from the food mutagen ochratoxin A in the NarI hotspot sequence: influence of adduct ionization on the conformational preferences and implications for the NER propensityen_US
dc.typeArticleen_US
Files
Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
wetmore 11831.full.pdf
Size:
3.39 MB
Format:
Adobe Portable Document Format
Description:
Download
License bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
license.txt
Size:
3.13 KB
Format:
Item-specific license agreed upon to submission
Description:
Download
Collections
Wetmore, Stacey