MutSα maintains the mismatch repair capability by inhibiting PCNA unloading

To pass on genetic information from one generation to the next, the DNA in a cell must be precisely copied. DNA is made of two strands and genetic information is encoded by sequences of molecules called bases in the strands. The bases from one strand form pairs with complementary bases on the other strand. However, errors in the copying process result in unmatched pairs of bases. Such errors are corrected by a repair system called mismatch repair. When DNA is copied, the two strands are separated and used as templates to make new complementary strands. This means that errors only arise on the new strands. Mismatch repair must therefore target the new strands to maintain the original information encoded by the template DNA. The repair needs to happen before the copying process is complete because the template strands and the new strands become indistinguishable afterwards. However, it is not clear how the two processes communicate with each other. Previous studies have identified a ring-shaped molecule called the replication clamp – which is essential for the copying process – as a prime candidate for the molecule responsible for this communication. This molecule binds to the DNA to promote the copying process, and afterwards it is removed from the DNA by other molecules. Furthermore, a group of proteins called the MutSα complex, which recognizes unmatched bases in DNA molecules, physically interacts with the replication clamp. Kawasoe et al. used eggs from African clawed frogs to study how the replication clamp connects the copying process and mismatch repair in more detail. The experiments show that when the replication clamp is bound to the DNA, it is able to direct mismatch repair to a specific DNA strand. When MutSα recognizes unmatched bases, it prevents the replication clamp from being removed from the DNA. By doing so, MutSα prevents the information about the new DNA strand from being lost until mismatch repair has taken place. These findings reveal new interactions between DNA copying and the correction of errors by mismatch repair. The next steps will be to understand how MutSα is able to keep the replication clamp on the DNA and to clarify its role in protecting DNA from gaining mutations.