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The activation mechanisms of master kinases in the DNA damage response

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Abstract

DNA damage can be introduced by intrinsic or extrinsic stimuli and threaten the transmission of genetic information and ultimately, survival. Eukaryotes have evolved a sophisticated mechanism, DNA damage response (DDR), to counteract this threat posed by DNA damage. The DDR requires a series of proteins involved in multiple DNA repair pathways, of which ATM, ATR and DNA–PK serve as the three most critical kinases. The signaling mechanisms underlying these pathways have been extensively studied and these three master kinases structures determined by cryo-electron microscopy (cryo-EM) have led to tremendous progress in understanding the molecular mechanism of the DDR. In this review, we discuss the recent advances made in understanding the structures of ATM, ATR, and DNA–PK. We highlight the implications of these structures in terms of their function and regulation, and speculate on the critical role of PIKK regulatory domain (PRD) in their activation.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (31830107 and 31821002). We thank Dr Jessica Tamanini at Shenzhen University Health Science Center for editing the manuscript prior to submission. We would like to acknowledge the vast number of other highly valuable papers that could not be cited in this review due to space limitations.

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Authors and Affiliations

  1. Fudan University Shanghai Cancer Center, Institutes of Biomedical Sciences, State Key Laboratory of Genetic Engineering and Key Laboratory of Medical Epigenetics and Metabolism, Shanghai Medical College of Fudan University, Shanghai, 200032, China

    Jianxiong Xiao, Qinhui Rao & Yanhui Xu

  2. Department of Immunobiology, Yale School of Medicine, Yale University, New Haven, CT, 06515, USA

    Jianxiong Xiao

  3. Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, 06529, USA

    Qinhui Rao

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  1. Jianxiong Xiao
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  2. Qinhui Rao
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Correspondence to Jianxiong Xiao or Qinhui Rao.

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Xiao, J., Rao, Q. & Xu, Y. The activation mechanisms of master kinases in the DNA damage response. GENOME INSTAB. DIS. 2, 211–224 (2021). https://doi.org/10.1007/s42764-021-00045-y

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