Nature Structural & Molecular Biology
12, 663 - 670 (2005)
Published online: 17 July 2005; | doi:10.1038/nsmb965
There is a Corrigendum (September 2005) associated with this Article.
(CAG)n-hairpin DNA binds to Msh2−Msh3 and changes properties of mismatch recognitionBarbara A L Owen1, Zungyoon Yang2, Maoyi Lai1, Maciez Gajek3, John D Badger III1, Jeffrey J Hayes2, Winfried Edelmann4, Raju Kucherlapati5, Teresa M Wilson3
& Cynthia T McMurray11
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic Rochester, Rochester, Minnesota 55905, USA. 2
Department of Biochemistry and Biophysics, University of Rochester Medical Center, Rochester, New York 14642, USA. 3
Department of Radiation Oncology, University of Maryland, Baltimore, Maryland 21201, USA. 4
Department of Cell Biology, Albert Einstein College, Bronx, New York 10461, USA. 5
Harvard Medical School-Partners Healthcare for Genetics and Genomics, Harvard Medical School, Boston, Massachusetts 02115, USA.
Correspondence should be addressed to Cynthia T McMurray mcmurray.cynthia@mayo.edu 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.
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