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Inactivation of DNA mismatch repair propels colorectal cancer (CRC) tumorigenesis. CRCs exhibiting levated icrosatellite lterations at elected etranucleotide repeats (EMAST) show reduced nuclear MutS homolog 3 (MSH3) expression with surrounding inflammation and portends poor patient outcomes. MSH3 reversibly exits from the nucleus to the cytosol in response to the pro-inflammatory cytokine interleukin-6 (IL-6), suggesting that MSH3 may be a shuttling protein. Here, we manipulated three putative nuclear localization (NLS1-3) and two potential nuclear export signals (NES1-2) within MSH3. We found that both NLS1 and NLS2 possess nuclear import function, with NLS1 responsible for nuclear localization within full-length MSH3. We also found that NES1 and NES2 work synergistically to maximize nuclear export, with both being required for IL-6-induced MSH3 export. We examined a 27-bp deletion (Δ27bp) within the polymorphic exon 1 that occurs frequently in human CRC cells and neighbors NLS1. With oxidative stress, Δ27bpMSH3 localizes to the cytoplasm, suggesting that NLS1 function in Δ27bpMSH3 is compromised. Overall, MSH3's shuttling in response to inflammation enables accumulation in the cytoplasm; reduced nuclear MSH3 increases EMAST and DNA damage. We suggest that polymorphic sequences adjacent to NLS1 may enhance cytosolic retention, which has clinical implications for inflammatory-driven neoplastic processes.

molecular and cellular biology

The Human DNA Mismatch Repair Protein MSH3 Contains Nuclear Localization and Export Signals That Enable Nuclear-Cytosolic Shuttling in Response to Inflammation