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

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.

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1
Department of Molecular Biophysics and Pharmacology, Institute of Biophysics, Academy of Sciences of the Czech Republic, v.v.i., Kralovopolska 135, 61265 Brno, Czech Republic.

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 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.

PMID:
23065963
DOI:
10.1002/chem.201202117
[Indexed for MEDLINE]
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