Platination of telomeric sequences and nuclease hypersensitive elements of human c-myc and PDGF-A promoters and their ability to form G-quadruplexes

摘要

Naturally occurring G-rich DNA sequences that are able to form G-quadruplex structures appear as potential targets for anti-cancer chemotherapy, and therefore play an important role in cellular processes, such as cell aging, death and carcinogenesis. The telomeric regions of DNA and nuclease hypersensitive elements of human c-myc and PDGF-A promoters represent a very appealing target for cisplatin and may interfere with normal DNA function. Platinum complexes bind covalently to nucleobases, and especially to the N7 atom of guanines, and the four guanines of a G-quartet have their N7 atoms involved in hydrogen bonding. Therefore, within a G-quadruplex structure, only the guanines out of the stack of G-quartets should react with electrophilic species such as platinum (II) complexes. Platinum complexes have significant influence on the formation of G-quadruplexes. Results obtained by CD spectroscopy and temperature gradient-gel electrophoresis clearly demonstrate that DNA platination significantly affects G-quadruplex folding for telomeric sequences; the abundance of un/misfolded DNAs compared to the G-quadruplex is proportional to the platinum concentration.