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Accommodation of Mispair Aligned N3T-Ethyl-N3T DNA Interstrand Cross Link

Webba da Silva, Mateus, Wilds, CJ, Noronha, AM, Colvin, OM, Miller, PS and Gamcsik, MP (2004) Accommodation of Mispair Aligned N3T-Ethyl-N3T DNA Interstrand Cross Link. Biochemistry, 43 . [Journal article]

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DOI: 10.1021/bi0486435

Abstract

The solution structure of the undecamer d(CGAAAT*TTTCG)2, where T* represents a N3Tethyl-N3T interstrand cross link, was elucidated using molecular dynamics calculations restrained by NOEand dihedral data obtained from NMR spectroscopy. The ethyl moiety is particularly well-accommodatedbetween the minor and major grooves. This is an exceptional example of the plasticity along the axisdefined by the stem and a unique finding of an interstrand cross link occupying the area associatingminor and major grooves. The mismatch-aligned tethered bases preserve good intrastrand stacking withflanking bases. Base-pair steps adjacent to the lesion site are overwound. Accommodation of the lesionalso results in an increase in mispair staggering alignment modulated by flexibility because of the tetrahedralgeometry of the exocyclic ethyl carbon atoms. This is mechanically coupled with a small measure ofconcomitant propeller twisting without an increase in intrastrand base-step distance. Both x displacementand sugar puckering are indicative of canonical B DNA throughout the stem. We have thus establishedthat the lesion defined by mismatch-aligned minor groove N3T-ethyl-N3T cross-linked thymine basesproduces very localized distortions in a DNA stem that may be difficult to recognize by repair mechanismsthat are not transcription- or replication-coupled. Thus, this synthetic DNA is a valuable structural probeto study mechanisms of repair.

Item Type:Journal article
Faculties and Schools:Faculty of Life and Health Sciences > School of Pharmacy and Pharmaceutical Science
Faculty of Life and Health Sciences
Research Institutes and Groups:Biomedical Sciences Research Institute > Genomic Medicine > Transcriptional Regulation & Epigenetics
Biomedical Sciences Research Institute > Genomic Medicine
Biomedical Sciences Research Institute
ID Code:18299
Deposited By: Dr Mateus Webba da Silva
Deposited On:03 May 2011 09:55
Last Modified:09 Dec 2015 10:56

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