(CAG)n-hairpin DNA binds to Msh2-Msh3 and changes properties of mismatch recognition

Barbara A.L. Owen, Zungyoon Yang, Maoyi Lai, Maciez Gajek, John D. Badger, Jeffrey J. Hayes, Winfried Edelmann, Raju Kucherlapati, Teresa M. Wilson, Cynthia T. McMurray

Research output: Contribution to journalArticle

157 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)663-670
Number of pages8
JournalNature Structural and Molecular Biology
Volume12
Issue number8
DOIs
StatePublished - Aug 1 2005

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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    Owen, B. A. L., Yang, Z., Lai, M., Gajek, M., Badger, J. D., Hayes, J. J., Edelmann, W., Kucherlapati, R., Wilson, T. M., & McMurray, C. T. (2005). (CAG)n-hairpin DNA binds to Msh2-Msh3 and changes properties of mismatch recognition. Nature Structural and Molecular Biology, 12(8), 663-670. https://doi.org/10.1038/nsmb965