HNPCC mutations in the human DNA mismatch repair gene hMLH1 influence assembly of hMutLα and hMLH1-hEXO1 complexes

Hereditary nonpolyposis colorectal cancer (HNPCC) is common inherited form of neoplasia caused by germline mutations in DNA mismatch repair (MMR) genes, MMR proteins have been reported to associate with several proteins, including the human exonuclease 1 (hEXO1). We report here novel HNPCC-hMLH1 mutant proteins (T117M, Q426X and 1813insA) in Danish HNPCC patients, We demonstrate that these mutant HNPCC-hMLH1 proteins are unable to form complexes with hEXO1 and hPMS2 in vivo. The results indicate that mutations found in HNPCC gene carriers disrupt hMLH1 - hEXO1 complex formation and hMutL alpha heterodimer assembly essential for MMR activity.