The unstructured linker of Mlh1 contains a motif required for endonuclease function which is mutated in cancers
Menée in vitro, cette étude identifie, dans une longue séquence nucléotidique correspondant à la liaison entre les domaines N-terminal et C-terminal (linker) de la protéine de réparation des mésappariements de l'ADN Mlh1, un motif conservé qui est nécessaire à la fonction d'endonucléase et qui se retrouve muté dans certains cancers
DNA mismatch repair (MMR) prevents mutations caused by DNA-replication errors and suppresses multiple types of cancers. During MMR, the Mlh1-Pms1 complex is recruited to mispair-containing DNA and nicks the newly replicated DNA strand, targeting it for degradation and resynthesis. Here, we identified an amino acid sequence within the unstructured linker of Mlh1 required for endonuclease activity. This sequence functioned when moved within the Mlh1 linker or when moved to the Pms1 linker. These results reveal a functional role for the intrinsically disordered region, which is conserved from yeast to humans and is mutated in cancer, suggesting that it organizes the catalytically active complex even though the required sequence can be distant from the active site.
Proceedings of the National Academy of Sciences , article en libre accès, 2022