Sequence dependence of DNA radioprotection by the thiols WR-1065 and WR-151326

Sequence-dependent variations of DNA structure modulate radiation-induced s trand 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-15133 61 a larger thiol, is more evenly distributed. Molecular modelling was perf ormed on complexes of a 53 bp oligonucleotide (belonging to a natural restr iction fragment) with one molecule of WR-1065 or WR-151326. Energy minimise d structures exhibit a broadening of the minor groove of an AAATT motif upo n WR-1065 binding, and a narrowing of the groove upon WR-151326 binding. Co nsequently, the accessibility to OH. of H4' (whose abstraction leads to str and 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, where as that of WR-1065 diminishes it in some regions, in good agreement with th e observed radioprotection distribution.