Abstract 567: Dual functions of Mad1 in mitosis and DNA damage response.

Abstract

The spindle assembly checkpoint (SAC) and the DNA damage checkpoint are two evolutionarily conserved mechanisms by which the fidelity of chromosome segregation in response to various DNA lesions is protected. These checkpoints are believed to function independently. However, there is growing evidence showing that proteins involved in the two systems have overlapping functions. Here we show that the mitotic arrest-deficient protein 1 (Mad1), a critical component of the SAC, is also required for the DNA damage response (DDR). We found that depletion of Mad1 led to cellular hypersensitivity to ionizing radiation (IR) and prolonged persistence of the H2AX foci. Interestingly, we observed Mad1 to be hyperphosphorylated both in mitosis and in response to DNA damage induced by IR in an ATM (Ataxia Telangiectasia Mutated) dependent manner. ATM is an essential DDR kinase which is also activated in mitosis and required for the SAC. We found that ATM phosphorylated Mad1 on Serine 214 both in vitro and in-cell. We further demonstrated that ATM-mediated Mad1 Serine 214 phosphorylation was required for both SAC and optimal DDR. Collectively, these findings reveal the dual function of ATM-mediated Mad1 phosphorylation in mitosis and DDR.

Citation Format: Chunying Yang, Jianwei Hao, Dejuan Kong, Bo Xu. Dual functions of Mad1 in mitosis and DNA damage response. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 567. doi:10.1158/1538-7445.AM2013-567