ATM, mutation of which leads to the human autosomal recessive disorder Ataxia- Telangiectasia (A-T), plays a critical role in maintaining genetic stability and preventing cancer formation. ATM is a PI-3 like kinase that functions as a sensor and signal transducer in DNA damage responses. Currently, most of the functional studies of ATM focus on its essential role in the cellular response to ionizing radiation-induced DNA double strand breaks. However, because of the complexity of A-T phenotypes and many of the A-T phenotypes can not be simply explained by the lack of an optimal DNA damage response, functions of ATM in the absence of DNA damage must be further examined. We have found that ATM was required for the activation of the spindle checkpoint, a process that protects against chromosome missegregation by delaying sister chromatid separation. Our preliminary data demonstrated that ATM was activated during mitosis in the absence of DNA damage. The mitosis-dependent activation of ATM requires functional Aurora-B. Furthermore we found that Aurora-B phosphorylated ATM at Ser1403 both in vitro and in vivo. In depth studies have found that Aurora-B associated with ATM during mitosis and ATM was required for the activity of Bub1. Further we found that ATM phosphorylated Bub1 (at Ser314) and Mad 1(at Ser214). Our general hypothesis in this proposal is that mitotic activation of ATM is governed by Aurora-B and has functional significance in regulation of the spindle checkpoint. Therefore we propose to study the mechanisms of mitotic activation of ATM and to dissect the ATM pathways in the spindle checkpoint.
Three specific aims are proposed.
Aim 1 will focus on investigate the molecular mechanism of the ATM activation.
Aim 2 will study the role of ATM Ser1403 phosphorylation on mitotic progression and the spindle checkpoint.
Aim 3 will focus on studying the functional significance of mitotic- dependent ATM phosphorylation of its downstream target. Our long-term goal of this project is to better understand the role of ATM in mitotic cell cycle control as a basis for providing insights into general mechanisms of carcinogenesis, cell growth and cell death. Dissecting the important role of ATM in mitosis may help understand many A-T phenotypes and find a cure for the disease.

Public Health Relevance

The goal of this proposal is to study a novel role of ATM in the mitotic spindle checkpoint by determining the upstream and downstream regulatory pathways controlling the process. Elucidating the role of ATM in basic cell cycle control will help understand the cause of Ataxia-Telangiectasia. Further the study will provide novel insight into general mechanisms of tumorigenesis and shed light on cancer treatment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA133093-05
Application #
8461074
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Pelroy, Richard
Project Start
2009-03-05
Project End
2014-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
5
Fiscal Year
2013
Total Cost
$314,033
Indirect Cost
$110,115
Name
Methodist Hospital Research Institute
Department
Type
DUNS #
185641052
City
Houston
State
TX
Country
United States
Zip Code
77030
Zhang, Dan; Wang, Haibo; Sun, Mianen et al. (2014) Speckle-type POZ protein, SPOP, is involved in the DNA damage response. Carcinogenesis 35:1691-7
Yang, Chunying; Hao, Jianwei; Kong, Dejuan et al. (2014) ATM-mediated Mad1 Serine 214 phosphorylation regulates Mad1 dimerization and the spindle assembly checkpoint. Carcinogenesis 35:2007-13
Boohaker, Rebecca J; Xu, Bo (2014) The versatile functions of ATM kinase. Biomed J 37:3-9
Bian, Yang; Kitagawa, Risa; Bansal, Parmil K et al. (2014) Synthetic genetic array screen identifies PP2A as a therapeutic target in Mad2-overexpressing tumors. Proc Natl Acad Sci U S A 111:1628-33
Nair, B C; Krishnan, S R; Sareddy, G R et al. (2014) Proline, glutamic acid and leucine-rich protein-1 is essential for optimal p53-mediated DNA damage response. Cell Death Differ 21:1409-18
Kikuchi, Koji; Narita, Takeo; Pham, Van T et al. (2013) Structure-specific endonucleases xpf and mus81 play overlapping but essential roles in DNA repair by homologous recombination. Cancer Res 73:4362-71
Lee, Michael W; Parker, William B; Xu, Bo (2013) New insights into the synergism of nucleoside analogs with radiotherapy. Radiat Oncol 8:223
Guo, Xiaojing; Yang, Chunying; Qian, Xiaolong et al. (2013) Estrogen receptor * regulates ATM Expression through miRNAs in breast cancer. Clin Cancer Res 19:4994-5002
Liu, Jinping; Luo, Shukun; Zhao, Hongchang et al. (2012) Structural mechanism of the phosphorylation-dependent dimerization of the MDC1 forkhead-associated domain. Nucleic Acids Res 40:3898-912
Yang, Chunying; Wang, Haibo; Xu, Yiran et al. (2012) The kinetochore protein Bub1 participates in the DNA damage response. DNA Repair (Amst) 11:185-91

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