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J Biol Chem, Vol. 274, Issue 31, 21763-21768, July 30, 1999

Repairing the Sickle Cell Mutation
I. SPECIFIC COVALENT BINDING OF A PHOTOREACTIVE THIRD STRAND TO THE MUTATED BASE PAIR

From the Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544

A DNA third strand with a 3'-psoralen substituent was designed to form a triplex with the sequence downstream of the T·A mutant base pair of the human sickle cell -globin gene. Triplex-mediated psoralen modification of the mutant T residue was sought as an approach to gene repair. The 24-nucleotide purine-rich target sequence switches from one strand to the other and has four pyrimidine interruptions. Therefore, a third strand sequence favorable to two triplex motifs was used, one parallel and the other antiparallel to it. To cope with the pyrimidine interruptions, which weaken third strand binding, 5-methylcytosine and 5-propynyluracil were used in the third strand. Further, a six residue "hook" complementary to an overhang of a linear duplex target was added to the 5'-end of the third strand via a T₄ linker. In binding to the overhang by Watson-Crick pairing, the hook facilitates triplex formation. This third strand also binds specifically to the target within a supercoiled plasmid. The psoralen moiety at the 3'-end of the third strand forms photoadducts to the targeted T with high efficiency. Such monoadducts are known to preferentially trigger reversion of the mutation by DNA repair enzymes.

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