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Partition of mismatch recognition between MutSα and MutSβ

DNA mismatch repair plays an important role in genome maintenance. MutS α (MSH2–MSH6) and MutS β (MSH2–MSH3) are two major mismatch repair proteins in mammalian cells that preferentially recognize base‐base and small (1‐2 nucleotides) insertion/deletion (ID) mispairs, respectively. Normally, cells maintain a MutSα:MutSβ ratio at ~ 10:1. Overexpressing MSH3 alters the MutSα:MutSβ ratio, leading to a mutator phenotype. To determine the molecular basis by which mispairs are differentially recognized by MutSα and MutS β, purified proteins were tested for interactions, independently or competitively, with a G‐T or an ID heteroduplex using gel shift and stopped‐flow kineticanalyses. Although MutS α bound both the G‐T and ID substrates, the affinity of the protein to the G‐T duplex is ~ 1.5‐fold higher than that to the ID duplex. Surprisingly, MutS β could also interact with the G‐T substrate, but the binding affinity was only ~ 1/3 of the activity that the protein had for the ID substrate. These relative affinities measured in these equilibrium binding and competition experiments were confirmed by direct measurement of association and dissociation kinetic constants by stopped‐flow spectroscopy. The order of binding activities among these proteins and DNA substrates is MutS β ‐ID > MutSα‐G‐T > MutSα‐ID > MutS β ‐G‐T. Our findings therefore explain why cells maintain a high MutSα:MutSβ ratio.