(CAG)n-hairpin DNA binds to Msh2–Msh3 and changes properties of mismatch recognition
- 17 July 2005
- journal article
- research article
- Published by Springer Nature in Nature Structural & Molecular Biology
- Vol. 12 (8) , 663-670
- https://doi.org/10.1038/nsmb965
Abstract
Cells have evolved sophisticated DNA repair systems to correct damaged DNA. However, the human DNA mismatch repair protein Msh2–Msh3 is involved in the process of trinucleotide (CNG) DNA expansion rather than repair. Using purified protein and synthetic DNA substrates, we show that Msh2–Msh3 binds to CAG-hairpin DNA, a prime candidate for an expansion intermediate. CAG-hairpin binding inhibits the ATPase activity of Msh2–Msh3 and alters both nucleotide (ADP and ATP) affinity and binding interfaces between protein and DNA. These changes in Msh2–Msh3 function depend on the presence of A·A mispaired bases in the stem of the hairpin and on the hairpin DNA structure per se. These studies identify critical functional defects in the Msh2–Msh3–CAG hairpin complex that could misdirect the DNA repair process.Keywords
This publication has 47 references indexed in Scilit:
- Hydrolytically Deficient MutS E694A Is Defective in the MutL-dependent Activation of MutH and in the Mismatch-dependent Assembly of the MutS · MutL · Heteroduplex ComplexPublished by Elsevier ,2003
- Differential and Simultaneous Adenosine Di- and Triphosphate Binding by MutSJournal of Biological Chemistry, 2003
- The alternating ATPase domains of MutS control DNA mismatch repairThe EMBO Journal, 2003
- DNA repair and trinucleotide repeat instabilityFrontiers in Bioscience-Landmark, 2003
- Evidence for sequential action of two ATPase active sites in yeast Msh2–Msh6DNA Repair, 2002
- Composite Active Site of an ABC ATPaseMolecular Cell, 2001
- Mismatch Recognition and DNA-dependent Stimulation of the ATPase Activity of hMutSα Is Abolished by a Single Mutation in the hMSH6 SubunitPublished by Elsevier ,2000
- Contribution of DNA Sequence and CAG Size to Mutation Frequencies of Intermediate Alleles for Huntington Disease: Evidence from Single Sperm AnalysesHuman Molecular Genetics, 1997
- Exon 1 of the HD Gene with an Expanded CAG Repeat Is Sufficient to Cause a Progressive Neurological Phenotype in Transgenic MiceCell, 1996
- hMutSβ, a heterodimer of hMSH2 and hMSH3, binds to insertion/deletion loops in DNACurrent Biology, 1996