Conformation of DNA modified by monofunctional Ru(II) arene complexes: recognition by DNA binding proteins and repair. Relationship to cytotoxicity.
We analyzed DNA duplexes modified at central guanine residues by monofunctional Ru(II) arene complexes [(eta(6)-arene)Ru(II)(en)(Cl)](+) (arene = tetrahydroanthracene or p-cymene, Ru-THA or Ru-CYM, respectively). These two complexes were chosen as representatives of two different classes of Ru(II) arene compounds for which initial studies revealed different binding modes: one that may involve DNA intercalation (tricyclic-ring Ru-THA) and the other (mono-ring Ru-CYM) that may not. Ru-THA is approximately 20 times more toxic to cancer cells than Ru-CYM. The adducts of Ru-THA and Ru-CYM have contrasting effects on the conformation, thermodynamic stability, and polymerization of DNA in vitro. In addition, the adducts of Ru-CYM are removed from DNA more efficiently than those of Ru-THA. Interestingly, the mammalian nucleotide excision repair system has low efficiency for excision of ruthenium adducts compared to cisplatin intrastrand crosslinks.
Novakova
Olga
O
Institute of Biophysics, Academy of Sciences of the Czech Republic, Kralovopolska 135, CZ-61265 Brno, Czech Republic.
Kasparkova
Jana
J
Bursova
Vendula
V
Hofr
Ctirad
C
Vojtiskova
Marie
M
Chen
Haimei
H
Sadler
Peter J
PJ
Brabec
Viktor
V
D001483:Base Sequence; D002151:Calorimetry; D004247:DNA / Q000737:chemistry* / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects; D012321:DNA-Directed RNA Polymerases / Q000737:chemistry / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation / Q000187:drug effects; D009942:Organometallic Compounds / Q000737:chemistry* / Q000494:pharmacology; D012428:Ruthenium / Q000737:chemistry*; D013329:Structure-Activity Relationship
D009942:Organometallic Compounds; D012428:Ruthenium; D004247:DNA; D012321:DNA-Directed RNA Polymerases