title: Interaction studies of muts and mutl with DNA containing the major cisplatin lesion and its mismatched counterpart under equilibrium and nonequilibrium conditions.
abstract: The DNA mismatch repair (MMR) system participates in cis-diamminedichloroplatinum (II) (cisplatin) cytotoxicity through signaling of cisplatin DNA lesions by yet unknown molecular mechanisms. It is thus of great interest to determine whether specialized function of MMR proteins could be associated with cisplatin DNA damage. The major cisplatin 1,2-d(GpG) intrastrand crosslink and compound lesions arising from misincorporation of a mispaired base opposite either platinated guanine of the 1,2-d(GpG) adduct are thought to be critical lesions for MMR signaling. Previously, we have shown that cisplatin compound lesion with a mispaired thymine opposite the 3' platinated guanine triggers new Escherichia coli MutS ATP-dependent biochemical activities distinguishable from those encountered with DNA mismatch consistent with a role of this lesion in MMR-dependent signaling mechanism. In this report, we show that the major cisplatin 1,2-d(GpG) intrastrand crosslink does not confer novel MutS postrecognition biochemical activity as studied by surface plasmon resonance spectroscopy. A fast rate of MutS ATP-dependent dissociation prevents MutL recruitment to the major cisplatin lesion in contrast to cisplatin compound lesion which authorized MutS-dependent recruitment of MutL with a dynamic of ternary complex formation distinguishable from that encountered with DNA mismatch substrate. We conclude that the mode of cisplatin DNA damage recognition by MutS and the nature of MMR post-recognition events are lesion-dependent and suggest that MMR signaling through the major cisplatin lesion is unlikely to occur.
authors.affiliation: Centre de Biophysique Moléculaire, CNRS UPR 4301, affiliated to the University of Orléans and INSERM, rue Charles Sadron, 45071 Orléans Cedex 02, France.
authors.forename: Yuliya
authors.initials: Y
authors.lastname: Sedletska
authors.forename: Françoise
authors.initials: F
authors.lastname: Culard
authors.forename: Patrick
authors.initials: P
authors.lastname: Midoux
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Malinge
mesh_terms: D000251:Adenosine Triphosphatases; D002945:Cisplatin / Q000737:chemistry; D004247:DNA / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000737:chemistry; D004926:Escherichia coli / Q000235:genetics; D013941:Thymine
chemical_list: D004268:DNA-Binding Proteins; D004247:DNA; D000251:Adenosine Triphosphatases; D002945:Cisplatin; D013941:Thymine