New insights into how MutS separates its function in the regulation of the Pol IV access to replication sites from that in the conserved MMR pathway

MutS removes mutagenic replication errors by initiating the mismatch repair (MMR) or the regulation of specialized DNA polymerases (RSP) pathways. This factor recognizes mismatches in double-stranded DNAs, and following ADP-ATP exchange, forms a sliding clamp that recruits MutL during MMR. In the RSP pathway, mismatch-bound MutS controls interaction of the low-fidelity Pol IV with the processivity factor assembled onto primed DNA (pDNA) sites. Here, we demonstrated that MutS associates with pDNAs by binding to a novel DNA interaction surface, in which Arg 272 appeared to directly interact with the 3’-end. Mutation of this conserved Arg conferred a noticeable defect in mismatch binding and the MutS antimutagenic activity . MutS interaction with mismatched pDNAs inhibited ADP-ATP exchange and transition into a sliding clamp, and decreased MutS affinity for MutL. Hence, replication DNA structures modulate pathway choice, which is critical to ensure the maintenance of genome stability.