MSH6, MSH2, and MSH3 function in the mismatch repair (MMR) system which plays an important role in substantially lowering mutation rates and blocking recombination between nonidentical sequences (1,5, 6). Msh6p interacts with Msh2p to repair GT mismatches and insertion/deletion mismatches (1,2), but the binding affinity for the latter decreases as the size of the extrahelical loop increases (7). Msh2p-Msh6p interacts asymmetrically with the DNA through base-specific stacking and hydrogen-bonding interactions as well as backbone contacts (8). The Msh2p-Msh6p complex also functions in the resolution of recombination intermediates, and binds to Holliday junctions with an affinity at least as high as it has for mispaired bases (9). The Msh6p subunit of the Msh2p-Msh6p complex appears to use its ATP binding or hydrolysis activity to coordinate mismatch binding with additional mismatch repair components such as the Mlh1p-Pms1p complex, leading to the formation of a ternary complex (10, 7). Msh6p and Msh3p also function in removing specific types of frameshift intermediates (11). Mutations in MSH6 or MSH3 cause partial defects in MMR, with inactivation of MSH6 resulting in high rates of base-substitution mutations and low rates of frameshift mutations (12).

Msh6p is one of 6 E. coli MutS homologs in S. cerevisiae (13). Mutations in the human MSH6 protein have been identified in an endometrial carcinoma cell line (14).

Last updated: 2002-10-28