Insights from a decade of biophysical studies on MutL: Roles in strand discrimination and mismatch removal

DNA mismatch repair (MMR) is a conserved pathway that safeguards genome integrity by correcting replication errors. The coordinated actions of two proteins (MutS and MutL) initiate the mismatch repair response and defects in the genes encoding for these proteins have been linked to sporadic and hereditary cancers. The basic steps to repair a mismatch include recognizing the mismatch, discriminating the newly synthesized from the parental strand, removing and re-synthesizing the erroneous strand. Although the DNA mismatch repair pathway has been extensively studied over the last four decades, the strand discrimination mechanism has remained elusive in most organisms. Work over the last decade has brought significant progress onto this step of the pathway, in turn ascribing new and critical roles to the MutL protein. In this review, we describe biochemical, biophysical and structural analyses that have clarified how MutL aids at discriminating the newly synthesized strand from its template and marking it for removal.