Figure 6. Model for MMR-Imposed Antirecombination.

The RecA-ssDNA filament pairs and intertwines with the homologous region of linear dsDNA and strand exchange is catalyzed within the RecA-bound three-stranded DNA complex (step 1). ATP hydrolysis in the RecA-DNA complex allows disassembly of RecA from the heteroduplex, which in turn allows the rotation of RecA-ssDNA nucleoprotein filament. This rotation is promoted by spooling out of displaced ssDNA from the heteroduplex and spooling in of linear dsDNA at the trailing end and the leading end of RecA-DNA complex respectively (steps 2, 3) (related to Movie S1). The rotation of circular RecA-ssDNA filament causes a window of RecA-DNA complex traveling from 5′ to 3′ in relation to the displaced ssDNA throughout the course of strand exchange (steps 4, 5, 6). Upon completion of strand exchange, a nicked circular dsDNA and a linear ssDNA are produced (step 7). The presence of mismatches in the heteroduplex region activates MMR-dependent antirecombination (step 8). MutS and MutL bound to mismatches in the heteroduplex and to secondary structures within the displaced ssDNA form higher-order complexes facilitated by MutS tetramerization. Due to limited freedom of the circular RecA-ssDNA filament during rotation, trapped DNA intermediates are prevented from forming new synapsis at the leading end of the RecA-DNA complex. UvrD is directed by the MutS-MutL complexes on heteroduplex to unwind from the nearest ss/ds DNA junction of heteroduplex and resolve the trapped intermediates (step 9). Stronger strand exchange inhibition is exerted when more mismatches accumulate in the heteroduplex and multiple MutS-MutL complexes are loaded. UvrD is still directed to unwind from the same ss/ds DNA junction by mismatch-activated MutS-MutL complexes (step 10). DNA substrates are re-formed from the MutS-MutL-directed unwinding by UvrD helicase (step 11).