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

Abstract

Hereditary nonpolyposis colorectal cancer (HNPCC) is a 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 hMutLα heterodimer assembly essential for MMR activity.

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Acknowledgements

We are grateful to Dr Michael Liskay (Oregon Health Sciences) for hMLH1 cDNA, Dr J Carl Barrett (National Institute of Environmental Health Sciences, North Carolina) for hPMS2 cDNA, Anne Lützen (Roskilde University, Denmark) for pAL1, and Drs Byung-In Lee and David M Wilson III (Lawrence Livermore National Laboratory) for the hEXO1 two-hybrid constructs. We are also grateful to Dr David M Wilson III for critical reading of the manuscript. This work was supported by grants from the Danish Cancer Society and the Danish Research Council (LJ Rasmussen, HC Bisgaard), NIH R01 09714-02 (KK Singh), and the NOVO Nordisk Foundation and the Danish Pharmacy Foundation (AC Jäger, FC Nielsen).

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Jäger, A., Rasmussen, M., Bisgaard, H. et al. HNPCC mutations in the human DNA mismatch repair gene hMLH1 influence assembly of hMutLα and hMLH1–hEXO1 complexes. Oncogene 20, 3590–3595 (2001). https://doi.org/10.1038/sj.onc.1204467

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