MutSbeta exceeds MutSalpha in dinucleotide loop repair.
BACKGROUND
The target substrates of DNA mismatch recognising factors MutSalpha (MSH2+MSH6) and MutSbeta (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 MutSalpha and MutSbeta 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 MutSalpha alone seems to be responsible for GT and IDL1 repair, MutSalpha and MutSbeta indeed have functional redundancy in IDL2 repair and in contrast with earlier studies, MutSbeta seems to exceed MutSalpha.


CONCLUSIONS
The finding is clinically relevant because the strong role of MutSbeta in IDL2 repair indicates MSH3 deficiency in tumours with low dinucleotide and no mononucleotide repeat instability.
Kantelinen
J
J
Department of Biological and Environmental Sciences, University of Helsinki, Viikinkaari 5, Helsinki, Finland.
Kansikas
M
M
Korhonen
M K
MK
Ollila
S
S
Heinimann
K
K
Kariola
R
R
Nyström
M
M
D000818:Animals; D002478:Cells, Cultured; D053843:DNA Mismatch Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D018900:Dinucleotide Repeats / Q000235:genetics*; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D054643:INDEL Mutation / Q000235:genetics; D051718:MutS Homolog 2 Protein / Q000235:genetics / Q000502:physiology*; D000074081:MutS Homolog 3 Protein; D020125:Mutation, Missense / Q000502:physiology; D009690:Nucleic Acid Conformation; D018411:Spodoptera; D013379:Substrate Specificity
D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C078444:MSH3 protein, human; D000074081:MutS Homolog 3 Protein; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein