MutSβ exceeds MutSα in dinucleotide loop repair

BACKROUND: The target substrates of DNA mismatch recognising factors MutS alpha (MSH2 + MSH6) and MutS beta (MSH2 + MSH3) 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 MutS alpha and MutS beta 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 MutS alpha alone seems to be responsible for GT and IDL1 repair, MutS alpha and MutS beta indeed have functional redundancy in IDL2 repair and in contrast with earlier studies, MutS beta seems to exceed MutS alpha. CONCLUSION: The finding is clinically relevant because the strong role of MutS beta in IDL2 repair indicates MSH3 deficiency in tumours with low dinucleotide and no mononucleotide repeat instability. British Journal of Cancer (2010) 102, 1068-1073. doi:10.1038/sj.bjc.6605531 www.bjcancer.com Published online 16 February 2010 (C) 2010 Cancer Research UK