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DNA Distortion Caused by Uracil-Containing Intrastrand Cross-Links

Journal article
Authors C. D. M. Churchill
Leif A Eriksson
S. D. Wetmore
Published in Journal of Physical Chemistry B
Volume 120
Issue 7
Pages 1195-1204
ISSN 1520-6106
Publication year 2016
Published at Department of Chemistry and Molecular Biology
Pages 1195-1204
Language en
Links dx.doi.org/10.1021/acs.jpcb.5b10381
Keywords bromodeoxyuridine-substituted dna, molecular-dynamics simulations, in-vitro replication, double-strand breaks, duplex dna, guanine-thymine, mammalian-cells, force-field, halogenated pyrimidines, anaplastic, astrocytoma, Chemistry
Subject categories Clinical Medicine

Abstract

Four uracil-containing intrastrand cross-links have been detected in human cells upon UV irradiation of 5-bromouracil-containing DNA, namely 5'-G[8-5]U-3', 5'-A[8-5]U-3', and 5'-A[2-5)U-3'. These lesions feature unique composition and connectivity compared with other intrastrand cross-links reported in the literature. For the first time, structural information obtained using molecular dynamics (MD) simulations reveal that all four lesions distort the DNA helix, which can involve an extrahelical location of the cross-link, changes in the helical interactions of the complementary nucleotides, or disruption of hydrogen bonding in the flanking base pairs up to two positions from the cross-linked site; however, the degree of distortion varies between the cross-links, being affected by the sequence, nucleobase-nucleobase connectivity, and the purine involved. Most importantly, the relative distortion of the damaged DNA provides the first structural explanation for the observed abundances of the four uracil-containing cross-links. Furthermore, the highly distorted conformations suggest that these lesions will likely have severe implications for DNA replication and repair processes in cells.

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