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

Oncogene. 2001 Jun 14;20(27):3590-5. doi: 10.1038/sj.onc.1204467.

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 hMutLalpha heterodimer assembly essential for MMR activity.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Adenosine Triphosphatases*
  • Amino Acid Sequence
  • Amino Acid Substitution
  • Bacterial Proteins / chemistry
  • Bacterial Proteins / metabolism*
  • Base Pair Mismatch*
  • Carrier Proteins
  • Colorectal Neoplasms, Hereditary Nonpolyposis / genetics*
  • DNA Repair Enzymes*
  • DNA Repair*
  • DNA Transposable Elements
  • DNA-Binding Proteins*
  • Denmark
  • Escherichia coli
  • Escherichia coli Proteins*
  • Exodeoxyribonucleases / metabolism*
  • Humans
  • Mismatch Repair Endonuclease PMS2
  • Molecular Sequence Data
  • MutL Protein Homolog 1
  • MutL Proteins
  • Mutation*
  • Mutation, Missense
  • Neoplasm Proteins / chemistry
  • Neoplasm Proteins / genetics*
  • Neoplasm Proteins / metabolism*
  • Nuclear Proteins
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / metabolism
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • White People

Substances

  • Adaptor Proteins, Signal Transducing
  • Bacterial Proteins
  • Carrier Proteins
  • DNA Transposable Elements
  • DNA-Binding Proteins
  • Escherichia coli Proteins
  • MLH1 protein, human
  • MutL protein, E coli
  • Neoplasm Proteins
  • Nuclear Proteins
  • Recombinant Fusion Proteins
  • EXO1 protein, human
  • Exodeoxyribonucleases
  • exodeoxyribonuclease I
  • Adenosine Triphosphatases
  • PMS2 protein, human
  • Mismatch Repair Endonuclease PMS2
  • MutL Protein Homolog 1
  • MutL Proteins
  • DNA Repair Enzymes