Vaisman A, Warren M W, Chaney S G
Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599-7260, USA.
J Biol Chem. 2001 Jun 1;276(22):18999-9005. doi: 10.1074/jbc.M007805200. Epub 2001 Mar 20.
DNA adducts formed by platinum-based anticancer drugs interfere with DNA replication. The carrier ligand of the platinum compound is likely to affect the conformation of the Pt-DNA adducts. In addition, the conformation of the adduct can also change upon binding of damaged DNA to the active site of DNA polymerase. From the crystal structures of pol beta ternary complexes it is evident that undamaged gapped and primed single-stranded (non-gapped) DNA templates exist in very different conformations when bound to pol beta. Therefore, one might expect that the constraints imposed on the damaged templates by binding to the polymerase active site should also affect the conformation of the Pt-DNA adducts and their ability to inhibit DNA replication. In support of this hypothesis we have found that the efficiency, carrier ligand specificity, site of discrimination (3'-G versus 5'-G of the Pt-GG adducts), and fidelity of translesion synthesis past Pt-DNA adducts by pol beta are strongly affected by the structure of the DNA template. Previous studies have suggested that the conformation of Pt-DNA adducts may be affected by the sequence context of the adduct. In support of this hypothesis, our data show that sequence context affects the efficiency, fidelity, and pattern of misincorporation by pol beta.
铂类抗癌药物形成的DNA加合物会干扰DNA复制。铂化合物的载体配体可能会影响Pt-DNA加合物的构象。此外，当受损DNA与DNA聚合酶的活性位点结合时，加合物的构象也会发生变化。从pol β三元复合物的晶体结构可以明显看出，未受损的有缺口和带引物的单链（无缺口）DNA模板在与pol β结合时存在非常不同的构象。因此，人们可能会预期，与聚合酶活性位点结合对受损模板施加的限制也会影响Pt-DNA加合物的构象及其抑制DNA复制的能力。为支持这一假设，我们发现pol β对Pt-DNA加合物进行跨损伤合成的效率、载体配体特异性、区分位点（Pt-GG加合物的3'-G与5'-G）和保真度受到DNA模板结构的强烈影响。先前的研究表明，Pt-DNA加合物的构象可能受加合物序列背景的影响。为支持这一假设，我们的数据表明序列背景会影响pol β的错配掺入效率、保真度和模式。
