Functional alterations of human exonuclease 1 mutants identified in atypical hereditary nonpolyposis colorectal cancer syndrome.

Abstract	Hereditary Nonpolyposis Colorectal Cancer (HNPCC) is a genetically heterogeneous disorder caused by germ-line mutations in one of several DNA mismatch repair (MMR) genes, most commonly in hMSH2 and hMLH1. Human exonuclease 1 (hExo1) possesses both 5'exonuclease and flap endonuclease activities and plays a role in DNA repair, recombination, and replication. The enzyme interacts with MMR proteins, hMsh2, hMlh1, and hMsh3. Recently, eight missense mutations in hEXO1 were identified in atypical HNPCC patients, who have been screened to be negative for hMSH2, hMLH1, and hMSH6 mutations. To address the question of whether these mutations cause susceptibility to HNPCC, in vitro nuclease activity and protein-protein interaction assays were performed in this study. We found that two mutants, E109K and L410R, lost their exonuclease activities while retaining their capacity to bind to the DNA substrate. Three other mutants, P640S, G759E, and P770L, displayed a reduced capacity to interact with hMsh2. The combination of these three point mutations leads to the binding capacity with hMsh2 to nearly zero. Evidence made available in this study sheds light on the pathogenesis of HNPCC, perhaps initiated by an additional MMR gene, hEXO1.
Authors	Xuemin Sun, Li Zheng, Binghui Shen
Journal	Cancer research (Cancer Res) Vol. 62 Issue 21 Pg. 6026-30 (Nov 01 2002) ISSN: 0008-5472 [Print] United States
PMID	12414623 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
Chemical References	Adaptor Proteins, Signal Transducing Carrier Proteins DNA-Binding Proteins MLH1 protein, human Neoplasm Proteins Nuclear Proteins Proto-Oncogene Proteins Recombinant Proteins EXO1 protein, human Exodeoxyribonucleases MSH2 protein, human MutL Protein Homolog 1 MutS Homolog 2 Protein DNA Repair Enzymes
Topics	Adaptor Proteins, Signal Transducing Base Pair Mismatch (genetics) Carrier Proteins Colorectal Neoplasms, Hereditary Nonpolyposis (enzymology, genetics) DNA Repair Enzymes DNA-Binding Proteins Escherichia coli (enzymology, genetics) Exodeoxyribonucleases (genetics, metabolism) Genetic Predisposition to Disease Humans MutL Protein Homolog 1 MutS Homolog 2 Protein Neoplasm Proteins (genetics, metabolism) Nuclear Proteins Point Mutation Precipitin Tests Proto-Oncogene Proteins (genetics, metabolism) Recombinant Proteins (genetics, metabolism)

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