The Role of Chk2 in Breast Cancer
Final rept. 1 Apr 2002-31 Mar 2006
BRIGHAM AND WOMEN'S HOSPITAL BOSTON MA
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DNA damage activates cellular responses that promote DNA repair, arrest the cell cycle, and in some cases, induce apoptosis 56. Cell cycle arrest allows time for the repair of damaged DNA while apoptosis eliminates cells harboring abnormal DNA. It is widely believed that these DNA damage responses are required for the maintenance of genomic stability and prevention of tumor development 20. The ataxia telangiectasia A-T mutated ATM gene, which is homologous to the yeast checkpoint gene Tel1, plays a critical role in sensing DNA double strand breaks DSBs in mammalian DNA. ATM is a kinase involved in activating the appropriate damage response pathway, leading to either cell cycle arrest or apoptosis, and is therefore a key checkpoint molecule in regulating cell cycle responses to DNA damage 37, 45. Indeed, the majority of phosphorylation events induced by ionizing radiation IR are carried out by ATM. Both A-T patients and ATM-deficient mice show defective cell cycle arrest, hypersensitivity to DNA DSBs, and tumor predisposition 4, 21, 52, 53. When cells are damaged by IR, ATM phosphorylates and activates the protein kinase Chk2 1, 35, 36, 55. Chk2 is a homologue of the Rad53 gene in budding yeast and of the Cds1 gene in fission yeast. Once phosphorylated, activated Chk2 phosphorylates multiple Cdc25 molecules which are thought to inhibit the activation of cyclindependent kinases 7, 10, 34. However, in response to damage induced by UV-irradiation or hydroxyurea, Chk2 is phosphorylated in an ATM-independent manner, possibly by A-T and rad3 related ATR 35, 46. Notably, ATM, ATR, and Chk2 are each able to phosphorylate the tumor suppressor gene p53 2, 9, 11, 26, 42, 49.
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