Adenosine nucleotide modulates the physical interaction between hMSH2 and BRCA1.
We have identified the physical interaction between the Breast Cancer susceptibility gene product BRCA1 and the Hereditary Non-Polyposis Colorectal Cancer (HNPCC) and DNA mismatch repair (MMR) gene product hMSH2, both in vitro and in vivo. The BRCA1-hMSH2 association involved several well-defined regions of both proteins which include the adenosine nucleotide ... binding domain of hMSH2. Moreover, the interaction of BRCA1 with purified hMSH2-hMSH6 appears to be modulated by adenosine nucleotide much like G protein downstream interaction/signaling is modulated by guanosine nucleotide. BARD1, another BRCA1-interacting protein, was also found to interact with hMSH2. In addition, BRCA1 was found to associate with both hMSH3 and hMSH6, the heterodimeric partners of hMSH2. These observations implicate BRCA1/BARD1 as downstream effectors of the adenosine nucleotide-activated hMSH2-hMSH6 signaling complex, and suggest a global role for BRCA1 in DNA damage processing. The functional interaction between BRCA1 and hMSH2 may provide a partial explanation for the background of gynecological and colorectal cancer in both HNPCC and BRCA1 kindreds, respectively.
Mesh Terms:
Adenosine Diphosphate, Adenosine Triphosphate, BRCA1 Protein, Binding Sites, Carrier Proteins, Cell Line, DNA-Binding Proteins, Humans, MutS Homolog 2 Protein, Protein Structure, Tertiary, Proto-Oncogene Proteins, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases
Adenosine Diphosphate, Adenosine Triphosphate, BRCA1 Protein, Binding Sites, Carrier Proteins, Cell Line, DNA-Binding Proteins, Humans, MutS Homolog 2 Protein, Protein Structure, Tertiary, Proto-Oncogene Proteins, Tumor Suppressor Proteins, Ubiquitin-Protein Ligases
Oncogene
Date: Aug. 02, 2001
PubMed ID: 11498787
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