Sequence context effect for hMSH2-hMSH6 mismatch-dependent activation.
Numerous DNA mismatches and lesions activate MutS homologue (MSH) ATPase activity that is essential for mismatch repair (MMR). We have found that a mismatch embedded in a nearest-neighbor sequence context containing symmetric 3'-purines (2 x 3'-purines) enhanced, whereas symmetric 3'-pyrimidines (2 x 3'-pyrimidines) reduced, hMSH2-hMSH6 ATPase activation. The 3'-purine/pyrimidine effect was most evident for G-containing mispairs. A similar trend pervaded mismatch binding (K(D)) and the melting of unbound oligonucleotides (T(m); DeltaG). However, these latter measures did not accurately predict the hierarchy of MSH ATPase activation. NMR studies of imino proton lifetime, solvent accessibility, and NOE connectivity suggest that sequence contexts that provoke improved MSH-activation displayed enhanced localized DNA flexibility: a dynamic DNA signature that may account for the wide range of lesions that activate MSH functions.
Mazurek
Anthony
A
Department of Molecular Virology, Immunology, and Medical Genetics, Ohio State University Medical Center, 400 West 12th Avenue, Columbus, OH 43210, USA.
Johnson
Christopher N
CN
Germann
Markus W
MW
Fishel
Richard
R
D000251:Adenosine Triphosphatases / Q000378:metabolism; D020137:Base Pair Mismatch; D001483:Base Sequence; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D051718:MutS Homolog 2 Protein / Q000378:metabolism*; D009690:Nucleic Acid Conformation; D011687:Purines / Q000737:chemistry; D011743:Pyrimidines / Q000737:chemistry
D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; D011687:Purines; D011743:Pyrimidines; D000251:Adenosine Triphosphatases; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein