Role of BRCA1, BRCA2 and ATR in Cancer Susceptibility
BRCA1 and BRCA2 were identified genetically as breast cancer susceptibility genes when a single copy of the gene is mutated and are involved in the cellular response to DNA damage, including blocking cell cycle progression and inducing DNA repair to preserve the integrity of the genome during cell division. BRCA1 and BRCA2 induce double-stranded repair of breaks using homologous recombination, in part through activation of RAD51. BRCA1 acts as a ubiquitin ligase targeting the protein FancD2 that activates checkpoint control, integrating the ATM response to ionizing radiation and the FA response to cross-linking agents like mitomycin C. Mutation of one of the several components of the FA complex involved in maintaining integrity of the genome leads to the condition Fanconi anemia. One member of the FA complex was recently identified as BRCA2, which leads to Fanconi anemia when both copies of the gene are mutated. Another related factor involved in the response of cells to DNA damage is the kinase ATM (see “ATM Signaling Pathway” and “cdc25 and chk1 Regulatory Pathway in response to DNA damage” pathway). ATM is mutated in patients with AT, a condition with many similar traits to Fanconi anemia. Like ATM, ATR serves as a checkpoint kinase that halts cell cycle progression and induces DNA repair when DNA is damaged. Loss of ATR results in a loss of checkpoint control in response to DNA damage, leading to cell death, and deletion of the ATR gene in mice is embryonic lethal. ATRIP is a protein that interacts with ATR and is a substrate for its kinase activity. ATRIP is required for ATR function, and removal of ATRIP also leads to a loss of checkpoint control of the cell cycle. ATR and ATM kinase targets include repair enzymes like Rad51, and the checkpoint kinases Chk1 and Chk2, as well as BRCA1 and BRCA2. The close relationship of the genes involved in breast cancer and Fanconi anemia has helped illuminate this signaling system, and may help lead to improved understanding and treatment of these conditions.
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