Thermodynamic and mechanistic insights into translesion DNA synthesis catalyzed by Y-family DNA polymerase across a bulky double-base lesion of an antitumor platinum drug

Chemistry. 2012 Nov 26;18(48):15439-48. doi: 10.1002/chem.201202117. Epub 2012 Oct 12.


To determine how the Y-family translesion DNA polymerase η (Polη) processes lesions remains fundamental to understanding the molecular origins of the mutagenic translesion bypass. We utilized model systems employing a DNA double-base lesion derived from 1,2-GG intrastrand cross-links of a new antitumor Pt(II) complex containing a bulky carrier ligand, namely [PtCl(2)(cis-1,4-dach)] (DACH=diaminocyclohexane). The catalytic efficiency of Polη for the insertion of correct dCTP, with respect to the other incorrect nucleotides, opposite the 1,2-GG cross-link was markedly reduced by the DACH carrier ligand. This reduced efficiency of Polη to incorporate the correct dCTP could be due to a more extensive DNA unstacking and deformation of the minor groove induced in the DNA by the cross-link of bulky [PtCl(2)(cis-1,4-dach)]. The major products of the bypass of this double-base lesion produced by [PtCl(2)(cis-1,4-dach)] by Polη resulted from misincorporation of dATP opposite the platinated G residues. The results of the present work support the thesis that this misincorporation could be due to sterical effects of the bulkier 1,4-DACH ligand hindering the formation of the Polη-DNA-incoming nucleotide complex. Calorimetric analysis suggested that thermodynamic factors may contribute to the forces that governed enhanced incorporation of the incorrect dATP by Polη as well.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Calorimetry
  • Catalysis
  • Cisplatin / pharmacology
  • DNA / biosynthesis
  • DNA / chemical synthesis*
  • DNA / chemistry
  • DNA / genetics
  • DNA Damage
  • DNA-Directed DNA Polymerase / classification
  • DNA-Directed DNA Polymerase / metabolism*
  • Humans
  • Molecular Structure
  • Organoplatinum Compounds / chemistry
  • Organoplatinum Compounds / pharmacology*
  • Thermodynamics


  • Antineoplastic Agents
  • Organoplatinum Compounds
  • DNA
  • DNA-Directed DNA Polymerase
  • Rad30 protein
  • Cisplatin