MUC1-C oncoprotein interacts directly with ATM and promotes the DNA damage response to ionizing radiation

Abstract

The ataxia-telangiectasia mutated (ATM) kinase is activated in the cellular response to ionizing radiation (IR) and is of importance to the repair of DNA double-strand breaks (DSBs). The MUC1 oncoprotein is aberrantly overexpressed in human breast carcinomas. The present work demonstrates that the MUC1 C-terminal subunit (MUC1-C) constitutively interacts with ATM in human breast cancer cells. The authors show that the MUC1-C cytoplasmic domain binds directly to ATM HEAT repeats. The results also demonstrate that the MUC1-C cytoplasmic domain binds to the ATM substrate H2AX. The functional significance of these interactions is supported by the finding that MUC1-C promotes removal of IR-induced nuclear γH2AX foci. MUC1-C also protects against IR-induced chromosomal aberrations. In concert with these results, MUC1-C blocks IR-induced death by promoting repair of potentially lethal DNA damage. These findings indicate that the overexpression of MUC1 can protect against IR-induced DNA DSBs and may represent a physiologic response that has been exploited by malignant cells. © The Author(s) 2010.