Adenosine nucleotide modulates the physical interaction between hMSH2 and BRCA1

We have identified the physical interaction between the Breast Cancer susce ptibility gene product BRCA1 and the Hereditary Non-Polyposis Colorectal Ca ncer (HNPCC) and DNA mismatch repair (MMR) gene product hMSH2, both in vitr o and in vivo. The BRCA1-hMSH2 association involved several well-defined re gions of both proteins which include the adenosine nucleotide binding domai n of hMSH2. Moreover, the interaction of BRCA1 with purified hMSH2-hMSH6 ap pears to be modulated by adenosine nucleotide much like G protein downstrea m interaction/signaling is modulated by guanosine nucleotide. BARD1, anothe r BRCA1-interacting protein, was also found to interact with hMSH2. In addi tion, BRCA1 was found to associate with both hMSH3 and hMSH6, the heterodim eric partners of IMSH2. These observations implicate BRCA1/BARD1 as downstr eam effectors of the adenosine nucleotide-activated hMSH2-hMSH6 signaling c omplex, and suggest a global role for BRCA1 in DNA damage processing. The f unctional interaction between BRCA1 and hMSH2 may provide a partial explana tion for the background of gynecological and colorectal cancer in both HNPC C and BRCA1 kindreds, respectively.