We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
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.
- Authors
Brabec, Viktor; Malina, Jaroslav; Margiotta, Nicola; Natile, Giovanni; Kasparkova, Jana
- Abstract
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 PtII complex containing a bulky carrier ligand, namely [PtCl2( 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 [PtCl2( cis-1,4-dach)]. The major products of the bypass of this double-base lesion produced by [PtCl2( 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
Chemistry - A European Journal, 2012, Vol 18, Issue 48, p15439
- ISSN
0947-6539
- Publication type
Article
- DOI
10.1002/chem.201202117