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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References
Ban C, Junop M, Yang W . 1999 Cell 97: 85–97
Baker SM, Bronner CE, Zhang L, Plug AW, Robatzek M, Warren G, Elliott EA, Yu J, Ashley T, Arnheim N, Flavell RA, Liskay RM . 1995 Cell 82: 309–319
Baker SM, Plug AW, Prolla TA, Bronner CE, Harris AC, Yao X, Christie DM, Monell C, Arnheim N, Bradley A, Ashley T, Liskay RM . 1996 Nat. Genet. 13: 336–342
Drummond JT, Li GM, Longley MJ, Modrich P . 1995 Science 268: 1909–1912
Drummond JT, Genschel J, Wolf E, Modrich P . 1997 Proc. Natl. Acad. Sci. USA 94: 10144–10149
Edelmann W, Cohen PE, Kane M, Lau K, Morrow B, Bennett S, Umar A, Kunkel T, Cattoretti G, Chaganti R, Pollard JW, Kolodner RD, Kucherlapti R . 1996 Cell 85: 1125–1134
Fiorentini P, Huang KN, Tishkoff DX, Kolodner RD, Symington LS . 1997 Mol. Cell. Biol. 17: 2764–2773
Guerrette S, Wilson T, Gradia S, Fishel R . 1998 Mol. Cell. Biol. 18: 6616–6623
Guerrette S, Acharya S, Fishel R . 1999 J. Biol. Chem. 274: 6336–6341
Jiricny J . 1998a Mutat. Res. 409: 107–121
Jiricny J . 1998b EMBO J. 17: 6427–6436
Jäger AC, Bisgaard ML, Myrhøj T, Bernstein I, Rehfeld JF, Nielsen FC . 1997 Am. J. Hum. Genet. 61: 129–138
Li GM, Modrich P . 1995 Proc. Natl. Acad. Sci. USA 92: 1950–1954
Lipkin SM, Wang V, Jacoby R, Banerjee-Basu S, Baxevanis AD, Lynch HT, Elliott RM, Collins FS . 2000 Nat. Genet. 24: 27–35
Nicholson A, Hendrix M, Jinks-Robertson S, Crouse GF . 2000 Genetics 154: 133–146
Palombo F, Gallinari P, Iaccarino I, Lettieri T, Hughes M, D'Arrigo A, Truong O, Hsuan JJ, Jiricny J . 1995 Science 268: 1912–1914
Papadopoulos N, Nicolaides NC, Liu B, Parsons R, Lengauer C, Palombo F, D'Arrigo A, Markowitz S, Willson JK, Kinzler KW, Jiricny J, Vogelstein B . 1995 Science 268: 1915–1917
Peltomäki P, Vasen HF . 1997 Gastroenterology 113: 1146–1158
Rasmussen LJ, Rasmussen M, Lee B-I, Rasmussen AK, Wilson III DM, Nielsen FC, Bisgaard HC . 2000 Mutat. Res. 460: 41–52
Risinger JI, Umar A, Glaab WE, Tindall KR, Kunkel TA, Barrett JC . 1998 Cancer Res. 58: 2978–2981
Räschle M, Marra G, Nyström LM, Schär P, Jiricny J . 1999 J. Biol. Chem. 274: 32368–32375
Saparbaev M, Prakash L, Prakash S . 1996 Genetics 142: 727–736
Schmutte C, Marinescu RC, Sadoff MM, Guerrette S, Overhauser J, Fischel R . 1998 Cancer Res. 58: 4537–4542
Shcherbakova PV, Kunkel TA . 1999 Mol. Cell. Biol. 19: 3177–3183
Shimodaira H, Filosi N, Shibata H, Suzuki T, Radice P, Kanamaru R, Friend SH, Kolodner RD, Ishioka C . 1998 Nat. Genet. 19: 384–389
Sugawara N, Pâques F, Colaiácovo M, Haber JE . 1997 Proc. Natl. Acad. Sci. USA 94: 9214–9219
Tishkoff DX, Berger AL, Bertrand P, Filosi N, Gaida GM, Kane MF, Kolodner RD . 1997 Proc. Natl. Acad. Sci. USA 94: 7487–7492
Tishkoff DX, Amin NS, Viars CS, Arden KC, Kolodner RD . 1998 Cancer Res. 58: 5027–5031
Tsubouchi H, Ogawa H . 2000 Mol. Biol. Cell. 11: 2221–2233
Wilson III DM, Carney JP, Coleman MA, Adamson AW, Christensen M, Lamerdin JE . 1998 Nucleic Acids Res. 26: 3762–3768
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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DOI: https://doi.org/10.1038/sj.onc.1204467
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