Crystal Structure of a Cisplatin-(1,3-GTG) Cross-Link within DNA Polymerase η

摘要

Cisplatin (cis-diamminedichloroplatmum(II)) is one of the most widely used anticancer agents against ovarian, cervical, head and neck, and non-small-cell lung cancer. It is one of the few therapeutics able to cure cancer. However, this property is limited to testicular cancer, where overall cure rates of 90 % are reached. Cisplatin exerts its anticancer function by forming stable DNA adducts (Figure 1). The major adducts are 1,2-intrastrand cross-links (Pt-GG (1), 47-50%; Pt-AG, 23-28%) and 1,3-intrastrand cross-links (Pt-GNG, 8-10 %) between two guanines separated by another base.It was recently shown that the 1,2-cross-link 1 is tolerated by cells. Two specialized polymerases (Pol η and Pol ζ) act in concert to enable cells to bypass lesion 1 during replication. The complex process is initiated by Pol η, which inserts a correct dC opposite the lesion. Pol ζ subsequently extends this structure to achieve full bypass. This process counteracts the therapeutic effect of cisplatin and contributes to tumor resistance. Currently it is believed that the 1,3-cross-links are stronger replication blocks and hence more cytotoxic.