GG sequence of DNA and the human telomeric sequence react with cis-diammine-diaquaplatinum at comparable rates.
G-quadruplex structures of telomeric sequences are of growing interest because they inhibit telomerase, an enzyme involved in the maintenance of telomere length of cancer cells. As we have shown previously, the antiparallel structure of G-quadruplexes can be cross-linked in vitro by the anti-tumour drug cisplatin. The question arises whether platination of quadruplex structures of human telomeric sequences by cisplatin could be relevant from a biological point of view. Therefore, we have compared the kinetics of reactions of the diaqua form of cisplatin, cis-[Pt(NH(3))(2)(H(2)O)(2)](2+), with the human telomeric quadruplex structure, a duplex DNA and a single-stranded DNA containing one specific platination GG site. The ratio between the platination rate constants was obtained using two intramolecular competition experiments: either a construct with a junction between duplex DNA containing a unique GG platination site and the quadruplex structure of the human telomeric sequence AG(3)(T(2)AG(3))(3), or a construct with a junction between duplex DNA and a single strand containing each a unique GG platination site. Those competition experiments allowed us to conclude that the platination of the quadruplex is favoured over that of the GG duplex by a factor of about two whereas the GG duplex is platinated three times faster than the GG single strand.
Ourliac Garnier
Isabelle
I
Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR8601, Université René Descartes, 45 rue des Saints-Pères, 75270 Paris Cedex 06, France.
Bombard
Sophie
S
D000970:Antineoplastic Agents / Q000737:chemistry; D002945:Cisplatin / Q000737:chemistry*; D003432:Cross-Linking Reagents / Q000737:chemistry; D004247:DNA / Q000737:chemistry; D018736:DNA Adducts / Q000737:chemistry*; D004277:DNA, Single-Stranded / Q000737:chemistry; D004591:Electrophoresis, Polyacrylamide Gel; D054856:G-Quadruplexes; D006147:Guanine / Q000737:chemistry*; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009841:Oligonucleotides / Q000737:chemistry; D017671:Platinum Compounds / Q000737:chemistry; D016615:Telomere / Q000737:chemistry*
D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D018736:DNA Adducts; D004277:DNA, Single-Stranded; D009841:Oligonucleotides; D017671:Platinum Compounds; C057270:cisplatin-DNA adduct; D006147:Guanine; D004247:DNA; D002945:Cisplatin