Abstract
Abstract Ataxia-telangiectasia mutated (ATM) is a protein kinase that plays a pivotal role in DNA damage-induced cell cycle checkpoints and DNA repair. Mutation of ATM leads to the autosomal recessive disorder ataxia-telangiectasia, characterized by comprehensive clinical phenotypes such as cancer predisposition and neurodegeneration. One of the cellular phenotypes of ATM-deficiency is the spindle assembly checkpoint (SAC) defect and aneuploidy, indicating that ATM has a functional role in mitosis. We have recently demonstrated that ATM is activated in mitosis and that ATM is required for SAC. The molecular mechanism of mitotic ATM activation has started to emerge. We show here using coimmunoprecipitation that ATM interacts with Aurora B in unsynchronized cells and that this interaction increases during mitosis. Aurora B is a protein kinase and mitotic chromosomal passenger involved in the progression of mitosis. Although regulation of the Aurora B activity in response to DNA damage is dependent on ATM, Aurora B appears to serve as an upstream element of the mitotic ATM activation pathway. Aurora B phosphorylates ATM at Ser1403 and this phosphorylation event is required for activation of the SAC. We also show that Ser1403 is dephosphorylated by Protein Phosphatase 1 (PP1), thus implicating PP1 in the regulation of mitosis and the SAC. We demonstrate that the interaction between ATM and Aurora B is partially dependent on the enzymatic activity of both proteins. We also characterize the protein domains essential for the interaction of ATM with Aurora B and study the functional significance of this interaction. These data expand to our understanding of the roles of ATM outside of DNA damage repair and link ATM to cell cycle control. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2990. doi:10.1158/1538-7445.AM2011-2990
Published Version
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