Mechanism of mismatch recognition revealed by human MutS beta bound to unpaired DNA loops

作者：Gupta Shikha; Gellert Martin; Yang Wei^*

来源：Nature Structural & Molecular Biology, 2012, 19(1): 72-U91.

DOI：10.1038/nsmb.2175

DNA mismatch repair corrects replication errors, thus reducing mutation rates and microsatellite instability. Genetic defects in this pathway cause Lynch syndrome and various cancers in humans. Binding of a mispaired or unpaired base by bacterial MutS and eukaryotic MutS alpha is well characterized. We report here crystal structures of human MutS beta in complex with DNA containing insertion-deletion loops (IDL) of two, three, four or six unpaired nucleotides. In contrast to eukaryotic MutS alpha and bacterial MutS, which bind the base of a mismatched nucleotide, MutS beta binds three phosphates in an IDL. DNA is severely bent at the IDL; unpaired bases are flipped out into the major groove and partially exposed to solvent. A normal downstream base pair can become unpaired; a single unpaired base can thereby be converted to an IDL of two nucleotides and recognized by MutS beta. The C-terminal dimerization domains form an integral part of the MutS structure and coordinate asymmetrical ATP hydrolysis by Msh2 and Msh3 with mismatch binding to signal for repair.

• 出版日期2012-1