MutSΒ exceeds MutSα in dinucleotide loop repair

Abstract

Backround: The target substrates of DNA mismatch recognising factors MutSα (MSH2MSH6) and MutSΒ (MSH2MSH3) have already been widely researched. However, the extent of their functional redundancy and clinical substance remains unclear. Mismatch repair (MMR)-deficient tumours are strongly associated with microsatellite instability (MSI) and the degree and type of MSI seem to be dependent on the MMR gene affected, and is linked to its substrate specificities. Deficiency in MSH2 and MSH6 is associated with both mononucleotide and dinucleotide repeat instability. Although no pathogenic MSH3 mutations have been reported, its deficiency is also suggested to cause low dinucleotide repeat instability. Methods: To assess the substrate specificities and functionality of MutSα and MutSΒ we performed an in vitro MMR assay using three substrate constructs, GT mismatch, 1 and 2 nucleotide insertion/deletion loops (IDLs) in three different cell lines.Results: Our results show that though MutSα alone seems to be responsible for GT and IDL1 repair, MutSα and MutSΒ indeed have functional redundancy in IDL2 repair and in contrast with earlier studies, MutSΒ seems to exceed MutSα.Conclusion: The finding is clinically relevant because the strong role of MutSΒ in IDL2 repair indicates MSH3 deficiency in tumours with low dinucleotide and no mononucleotide repeat instability. © 2010 Cancer Research UK All rights reserved.