Architecture of human DNA damage response regulator ATM kinase by cryo-EM
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AbstractAtaxia-telangiectasia mutated (ATM) kinase is an evolutionary conversed signaling protein responsible for activating the DNA double-stand breaks (DSBs) repair. Functional loss mutations in ATM lead to ataxia telangiectasia (AT), which is a multisystem disorder characterized by genome instability, cancer predisposition, progressive neurologic impairment and immune dysfunction [1]. Currently, there exists two well-studied pathways of ATM activation. DNA DSBs are sensed by Mre11/Rad/Nbs1 (MRN) complex, which then recruits ATM to DSBs. Upon autophosphorylation and monomerization, ATM becomes activated and are converted from a dimeric form to a monomeric form. A second activation pathway is called MRN independent pathway in which reactive oxygen species (ROS) oxidizes and activates ATM to form a covalently dimer [2]. Once activated by either DNA DSB or oxidative stress in the cell, ATM phosphorylates numerous downstream substrates including the tumor suppressor p53 to initiate DNA repair and arrest cell cycle progression. Recently, manganese (II) ions (Mn2+) was also suggested to activate ATM in vivo [3]. Our current understanding of the fundamental mechanism of ATM function and molecular pathology of AT is limited by the lack of the high-resolution structure of the active form of the enzyme. Traditional structural methods such as X-ray crystallography and nuclear magnetic resonance (NMR) have proven challenging for solving the structure of the intact ATM, which has molecular weight of 350 kDa. The aims of this study are to determine the atomic structure of the active ATM by single-particle cryo-electron microscopy (cryo-EM) and perform in vitro biochemical assays in order to have a better understanding of its Mn-dependent activation mechanism. Supported by Research Grants Council of Hong Kong (CUHK14105517 and AoE/M-05/12).

References
1. Shiloh, Yosef; Yael Ziv. (2013). The ATM protein kinase: regulating the cellular response to genotoxic stress, and more. Nature Reviews Molecular Cell Biology 14, no. 4
2. Paull, T. T. (2015). Mechanisms of ATM Activation. Annual Review of Biochemistry, 84(1): 711-738.
3. Tidball, A. M.; Bryan, M. R.; Uhouse, M. A.; Kumar, K. K.; Aboud, A. A.; Feist, J. E., … & Bowman, A. B. (2014). A novel manganese-dependent ATM-p53 signaling pathway is selectively impaired in patient-based neuroprogenitor and murine striatal models of Huntington's disease. Human Molecular Genetics, 24(7): 1929-1944.
Acceptance Date29/08/2018
All Author(s) ListJan Siu Kei Wong, Liwen Jiang, Wilson Chun Yu Lau
Name of ConferenceThe Cold Spring Harbor Asia Conference on Biology of Extracellular Vesicles
Start Date of Conference12/11/2018
End Date of Conference16/11/2018
Place of ConferenceSuzhou
Country/Region of ConferenceChina
Year2018
LanguagesEnglish-United States

Last updated on 2019-07-01 at 15:09