Sequence dependence of DNA radioprotection by the thiols WR-1065 and WR-151326 |
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Authors: | D. Sy C. Durand S. Hugot C. Savoye C. Swenberg M. Charlier M. Spotheim-Maurizot |
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Affiliation: | (1) Centre de Biophysique Moléculaire, CNRS, rue Charles-Sadron, F-45071 Orléans Cedex 2, France, FR;(2) Faculté des Sciences, B.P. 6759, Université d' Orléans, F-45067 Orléans Cedex 2, France, FR;(3) Applied Cellular Radiation Biology Department, Armed Forces Radiobiology Research Institute, Bethesda, MD 20889, USA, US |
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Abstract: | Sequence-dependent variations of DNA structure modulate radiation-induced strand breakage. Thiols reduce breakage by scavenging damaging radiolytic OH . and repairing sugar radicals. As shown by sequencing gel electrophoresis, WR-1065 radioprotection is modulated by sequence, whereas that of WR-151326, a larger thiol, is more evenly distributed. Molecular modelling was performed on complexes of a 53 bp oligonucleotide (belonging to a natural restriction fragment) with one molecule of WR-1065 or WR-151326. Energy minimised structures exhibit a broadening of the minor groove of an AAATT motif upon WR-1065 binding, and a narrowing of the groove upon WR-151326 binding. Consequently, the accessibility to OH˙ of H4′ (whose abstraction leads to strand breakage) increases near WR-1065, whereas it decreases near WR-151326. This modifies locally the otherwise homogeneous radioprotection. The effect of WR-151326 strengthens the protection at all tested binding sites, whereas that of WR-1065 diminishes it in some regions, in good agreement with the observed radioprotection distribution. Received: 24 April 1998 / Accepted: 4 August 1998 / Published online: 11 November 1998 |
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Keywords: | : DNA sequence DNA structure Molecular modelling Radioprotection WR thiols |
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