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Modulation of MutS ATP-dependent functional activities by DNA containing a cisplatin compound lesion (base damage and mismatch).
- Source :
-
Journal of molecular biology [J Mol Biol] 2007 May 25; Vol. 369 (1), pp. 27-40. Date of Electronic Publication: 2007 Feb 22. - Publication Year :
- 2007
-
Abstract
- DNA damage-dependent signaling by the DNA mismatch repair (MMR) system is thought to mediate cytotoxicity of the anti-tumor drug cisplatin through molecular mechanisms that could differ from those required for normal mismatch repair. The present study investigated whether ATP-dependent biochemical properties of Escherichia coli MutS protein differ when the protein interacts with a DNA oligonucleotide containing a GT mismatch versus a unique site specifically placed cisplatin compound lesion, a cisplatin 1,2-d(GpG) intrastrand cross-link with a mispaired thymine opposite the 3' platinated guanine. MutS exhibited substantial affinity for this compound lesion in hydrolytic and in non-hydrolytic conditions of ATP, contrasting with the normal nucleotide inhibition effect of mispair binding. The cisplatin compound lesion was also shown to stimulate poorly MutS ATPase activity to approach the hydrolysis rate induced by nonspecific DNA. Moreover, MutS undergoes distinct conformation changes in the presence of the compound lesion and ATP under hydrolytic conditions as shown by limited proteolysis. In the absence of MutS, the cisplatin compound lesion was shown to induce a 39 degrees rigid bending of the DNA double helix contrasting with an unbent state for DNA containing a GT mispair. Furthermore, an unbent DNA substrate containing a monofunctional adduct mimicking a cisplatin residue failed to form a persistent nucleoprotein complex with MutS in the presence of adenine nucleotide. We propose that DNA bending could play a role in MutS biochemical modulations induced by a compound lesion and that cisplatin DNA damage signaling by the MMR system could be modulated in a direct mode.
- Subjects :
- Adenine metabolism
Adenosine Triphosphate analogs & derivatives
Adenosine Triphosphate pharmacology
Adenylyl Imidodiphosphate pharmacology
Base Sequence
Cisplatin analogs & derivatives
Cisplatin chemistry
DNA Adducts metabolism
Escherichia coli drug effects
Hydrolysis drug effects
Molecular Sequence Data
MutS DNA Mismatch-Binding Protein chemistry
Nucleic Acid Heteroduplexes metabolism
Protein Binding drug effects
Protein Conformation drug effects
Substrate Specificity drug effects
Surface Plasmon Resonance
Thymine metabolism
Adenosine Triphosphate metabolism
Base Pair Mismatch drug effects
Cisplatin pharmacology
DNA metabolism
DNA Damage
Escherichia coli enzymology
MutS DNA Mismatch-Binding Protein metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0022-2836
- Volume :
- 369
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Journal of molecular biology
- Publication Type :
- Academic Journal
- Accession number :
- 17400248
- Full Text :
- https://doi.org/10.1016/j.jmb.2007.02.048