REQUIREMENT OF THE YEAST MSH3 AND MSH6 GENES FOR MSH2-DEPENDENT GENOMIC STABILITY

Defects in DNA mismatch repair result in instability of simple repetit ive DNA sequences and elevated levels of spontaneous mutability. The h uman G/T mismatch binding protein, GTBP/p160, has been suggested to ha ve a role in the repair of base-base and single nucleotide insertion-d eletion mismatches. Here we examine the role of the yeast GTBP homolog , MSH6, in mismatch repair. We show that both MSH6 and MSH3 genes are essential for normal genomic stability. Interestingly, although mutati ons in either MSH3 or MSH6 do not cause the extreme microsatellite ins tability and spontaneous mutability observed in the msh2 mutant, yeast cells harboring null mutations in both the MSH3 and MSH6 genes exhibi t microsatellite instability and mutability similar to that in the msh 2 mutant. Results from epistasis analyses indicate that MSH2 functions in mismatch repair in conjunction with MSH3 or MSH6 and that MSH3 and MSH6 constitute alternate pathways of MSH2-dependent mismatch repair.