Work

Sequence context effect for hMSH2-hMSH6 mismatch-dependent activation

Year: 2009

Type: article

Abstract: 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.

Source: Proceedings of the National Academy of Sciences

DOI: 10.1073/pnas.0808572106

Authors: Anthony Mazurek, Christopher N. Johnson, Markus W. Germann, Richard Fishel

Institutions: The Ohio State University Wexner Medical Center, The Ohio State University, Georgia State University

Language: English

Topic: DNA Repair Mechanisms

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

Open Access status: green

Funders: Georgia Cancer Coalition, National Institutes of Health, National Cancer Institute, National Institute of Allergy and Infectious Diseases

Awards: G1077829922, G1901347875, G2953411190, G3011341489, Mismatch Repair and Carcinogenesis