Triple-helix formation and cooperative binding by oligodeoxynucleotides with a 3'-3' internucleotide junction.
Triple-helix formation by oligodeoxynucleotides in a sequence-specific manner is limited to polypurine tracts of duplex DNA. To increase the number of biologically relevant targets for triple-helix formation, we have utilized oligodeoxynucleotides containing a 3'-3' internucleotide junction to allow for binding to opposite strands of duplex DNA. Molecular modeling was used to aid in the design of the xylose dinucleoside linker 1 that is rigid and minimizes the number of conformers to minimize the entropy of binding. Thermal denaturation studies show that a 3'-3'-linked oligodeoxynucleotide, bearing nine nucleotides on each side of the linker, has a higher Tm (47.6 degrees C) than that of a 21-mer binding to a single polypurine tract (45.3 degrees C). Binding domain minimization studies and sequence-specific alkylation of a target duplex demonstrate a high degree of cooperativity between the two triple-helix binding domains, thus allowing for an increase in the number of biologically relevant targets for triple-helix formation.
Froehler
B C
BC
Gilead Sciences Inc., Foster City, California 94404.
Terhorst
T
T
Shaw
J P
JP
McCurdy
S N
SN
D001482:Base Composition; D001483:Base Sequence; D001665:Binding Sites; D006358:Hot Temperature; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009690:Nucleic Acid Conformation; D009691:Nucleic Acid Denaturation; D009838:Oligodeoxyribonucleotides / Q000737:chemistry* / Q000378:metabolism; D011687:Purines / Q000378:metabolism; D014994:Xylose / Q000737:chemistry
D009838:Oligodeoxyribonucleotides; D011687:Purines; D014994:Xylose