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.
Wang
Q
Q
Department of Pathology and Laboratory Medicine, The Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, PA 19104, USA. qiang@reo.med.upenn.edu
Zhang
H
H
Guerrette
S
S
Chen
J
J
Mazurek
A
A
Wilson
T
T
Slupianek
A
A
Skorski
T
T
Fishel
R
R
Greene
M I
MI
D000244:Adenosine Diphosphate / Q000494:pharmacology*; D000255:Adenosine Triphosphate / Q000494:pharmacology*; D019313:BRCA1 Protein / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D004268:DNA-Binding Proteins; D006801:Humans; D051718:MutS Homolog 2 Protein; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000378:metabolism*; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases
D019313:BRCA1 Protein; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; C102449:BARD1 protein, human; D044767:Ubiquitin-Protein Ligases; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein