SOLUTION STRUCTURES OF 5-FLUOROURACIL-SUBSTITUTED DNA AND RNA DECAMERDUPLEXES

The structures in solution of eight oligonucleotide duplexes each cont aining either zero, one, or two 5-fluorodeoxyuridine (FdUrd) or 5-fluo rouridine (FUrd) nucleosides were determined by the combined use of NM R spectroscopy, restrained molecular dynamics, and full relaxation mat rix refinement to determine how FdUrd and FUrd substitution affects th e structure of duplex DNA and RNA and to establish whether structural differences due to FdUrd and FUrd substitution in nucleic acids may be responsible, in part, for the biological effects of the anticancer dr ug 5-fluorouracil (FUra). The nucleic acid directed effects of FUra in clude induction of single-strand breaks in duplex DNA and altered proc essing of pre-mRNA and rRNA, Four self-complementary oligodeoxyribonuc leotide sequences were prepared and studied as duplexes in aqueous sol ution: (5' dGCCAAUUCGC)(2), (5' dCCGAAUFCGC)(2), (5' dGCGAAFUCGC)(2), and (5' dGCGAAFFCGC)(2). The corresponding oligoribonucleotide sequenc es (5' rGCGAAUUCGC)(2), (5' rGCGAAUFCGC)(2), (5' rGCGAAFUCGC)(2), and (5' rGCGAAFFCGC)(2) were also prepared and studied, The helical parame ters for the structures of these eight duplexes were analyzed to deter mine how substitution of FdUrd and FUrd affects the three-dimensional structures of duplex DNA and RNA. FdUrd substitution affects the base roll angle at the site of FdUrd substitution, causing the helical axis of FdUrd-substituted DNA duplexes to be bent compared to the nonsubst ituted duplex. A-FUrd base pairs show substantial RMS deviations from A-Urd base pairs in all three of the RNA duplexes substituted with FUr d, Bending of the helical axis due to FdUrd substitution may contribut e to the occurrence of single-strand breaks in duplex DNA while the al tered structures of A-FUrd base pairs may affect RNA-RNA and RNA-prote in recognition.