RoleofBRCA1,BRCA2andATRinCancerSusceptibility

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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REFERENCES: Cortez D, Guntuku S, Qin J, Elledge SJ. ATR and ATRIP: partners in checkpoint signaling. Science. 2001 Nov 23;294(5547):1713-6. Howlett NG, Taniguchi T, Olson S, Cox B, Waisfisz Q, De Die-Smulders C, Persky N, Grompe M, Joenje H, Pals G, Ikeda H, Fox EA, DAndrea AD. Biallelic inactivation of BRCA2 in Fanconi anemia. Science. 2002 Jul 26;297(5581):606-9. Lavin MF. An unlikely player joins the ATM signalling network. Nat Cell Biol. 2000 Dec;2(12):E215-7. Rouse J, Jackson SP. Interfaces between the detection, signaling, and repair of DNA damage. Science. 2002 Jul 26;297(5581):547-51. Taniguchi T, Garcia-Higuera I, Xu B, Andreassen PR, Gregory RC, Kim ST, Lane WS, Kastan MB, DAndrea AD. Convergence of the fanconi anemia and ataxia telangiectasia signaling pathways. Cell. 2002 May 17;109(4):459-72. Venkitaraman AR. Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell. 2002 Jan 25;108(2):171-82. Review. Zhou BB, Elledge SJ. The DNA damage response: putting checkpoints in perspective. Nature. 2000 Nov 23;408(6811):433-9. Review.