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Background  Elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) is a genetic signature observed in 60% of sporadic colorectal cancers (CRCs). Unlike microsatellite unstable CRCs where hypermethylation of the DNA mismatch repair (MMR) gene  hMLH1’s  promoter is causal, the precise cause of EMAST is not clearly defined but points towards  hMSH3  deficiency.    Aim  To examine if  hMSH3  deficiency causes EMAST, and to explore mechanisms for its deficiency.    Methods  We measured −4 bp framshifts at  D8S321  and  D20S82  loci within EGFP-containing constructs to determine EMAST formation in MMR-proficient,  hMLH1 −/−  ,  hMSH6 −/−  , and  hMSH3 −/−   CRC cells. We observed the subcellular location of hMSH3 with oxidative stress.    Results    D8S321  mutations occurred 31-and 40-fold higher and  D20S82  mutations occurred 82-and 49-fold higher in  hMLH1 −/−   and  hMSH3 −/−   cells, respectively, than in  hMSH6 −/−   or MMR-proficient cells.  hMSH3  knockdown in MMR-proficient cells caused higher  D8S321  mutation rates (18.14 and 11.14×10 −4  mutations/cell/generation in two independent clones) than scrambled controls (0 and 0.26×10 −4  mutations/cell/generation;  p <0.01). DNA sequencing confirmed the expected frameshift mutations with evidence for ongoing mutations of the constructs. Because EMAST-positive tumors are associated with inflammation, we subjected MMR-proficient cells to oxidative stress via H 2 O 2  to examine its effect on  hMSH3 . A reversible nuclear-to-cytosol shift of hMSH3 was observed upon H 2 O 2  treatment.    Conclusion  EMAST is dependent upon the MMR background, with  hMSH3 −/−   more prone to frameshift mutations than  hMSH6 −/−  , opposite to frameshift mutations observed for mononucleotide repeats.  hMSH3 −/−   mimics complete MMR failure ( hMLH1 −/−  ) in inducing EMAST. Given the observed heterogeneous expression of hMSH3 in CRCs with EMAST,  hMSH3 -deficiency appears to be the event that commences EMAST. Oxidative stress, which causes a shift of hMSH3’s subcellular location, may contribute to an hMSH3 loss-of-function phenotype by sequestering it to the cytosol.

Oxidative Stress Induces Nuclear-to-Cytosol Shift of hMSH3, a Potential Mechanism for EMAST in Colorectal Cancer Cells