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Guieysse, AL ; Praseuth, D ; Giovannangeli, C ; Asseline, U ; Helene, C

Psoralen adducts induced by triplex-forming oligonucleotides are refractory to repair in HeLa cells

Journal of Molecular Biology 287 (2) 373-383

par Administrateur - publié le

Abstract :

The use of triple helix-forming oligonucleotides constitutes an attractive strategy to regulate gene expression by inhibition of transcription. Psoralen-oligonucleotide conjugates form, upon irradiation, covalent triplexes and thereby modify the specific target sequence. The processing of such photoproducts on the promoter of the gene coding for the interleukin-2 receptor a chain was investigated in HeLa cells and HeLa nuclear extracts. We demonstrate that psoralen cross-links are not repaired within the cell extracts nor inside cells. The mechanism of repair inhibition was elucidated in vitro : the presence of the third strand oligonucleotide inhibits the incision step of the damaged target by repair endonucleases. These results demonstrate the possibility of using this approach to induce a persistent intracellular DNA damage at a specific site and to afford prolonged transcription inhibition. (C) 2000 Academic Press.