Targeting human Rad51 by specific DNA aptamers induces inhibition of homologous recombination.
Human Rad51 (HsRad51), a key element of the homologous recombination repair pathway, is related to the resistance of cancer cells to chemo- and radio-therapies. This protein is thus a good target for the development of anti-cancer treatments. We have searched for new inhibitors directed against HsRad51 using the Systematic Evolution of Ligands by EXponential enrichment (SELEX) approach. We have selected three aptamers displaying strong effects on strand exchange activity. Analysis by circular dichroism shows that they are highly structured DNA molecules. Our results also show that they affect the first step of the strand exchange reaction by promoting the dissociation of DNA from the ATP/HsRad51/DNA complex. Moreover, these inhibitors bind only weakly to RecA, a prokaryotic ortholog of HsRad51. Both the specificity and the efficiency of their inhibition of recombinase activity offer an analytical tool based on molecular recognition and the prospect of developing new therapeutic agents.
Martinez
Susan F
SF
UMR 6204, Centre National de la Recherche Scientifique & Université de Nantes, 44322 Nantes cedex 3, France.
Renodon-Cornière
Axelle
A
Nomme
Julian
J
Eveillard
Damien
D
Fleury
Fabrice
F
Takahashi
Masayuki
M
Weigel
Pierre
P
D000255:Adenosine Triphosphate / Q000378:metabolism; D052157:Aptamers, Nucleotide / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001667:Binding, Competitive; D002942:Circular Dichroism; D004247:DNA / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D009690:Nucleic Acid Conformation; D009841:Oligonucleotides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D025341:Principal Component Analysis; D011485:Protein Binding; D051135:Rad51 Recombinase / Q000235:genetics / Q000378:metabolism*; D011938:Rec A Recombinases / Q000235:genetics / Q000378:metabolism; D011995:Recombination, Genetic; D052156:SELEX Aptamer Technique; D013053:Spectrophotometry
D052157:Aptamers, Nucleotide; D009841:Oligonucleotides; D000255:Adenosine Triphosphate; D004247:DNA; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; D011938:Rec A Recombinases