FATC Domain Deletion Compromises ATM Protein Stability, Blocks Lymphocyte Development, and Promotes Lymphomagenesis.

Maja Milanovic, Zhengping Shao, Verna M Estes, Xiaobin S Wang, Demis Menolfi, Xiaohui Lin, Brian J Lee, Jun Xu, Olivia M Cupo, Dong Wang, Shan Zha

Journal of immunology (Baltimore, Md. : 1950) 2021 Mar 15

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Ataxia-telangiectasia mutated (ATM) kinase is a master regulator of the DNA damage response, and loss of ATM leads to primary immunodeficiency and greatly increased risk for lymphoid malignancies. The FATC domain is conserved in phosphatidylinositol-3-kinase-related protein kinases (PIKKs). Truncation mutation in the FATC domain (R3047X) selectively compromised reactive oxygen species-induced ATM activation in cell-free assays. In this article, we show that in mouse models, knock-in ATM-R3057X mutation (Atm⁠ RX ⁠, corresponding to R3047X in human ATM) severely compromises ATM protein stability and causes T cell developmental defects, B cell Ig class-switch recombination defects, and infertility resembling ATM-null. The residual ATM-R3057X protein retains minimal yet functional measurable DNA damage-induced checkpoint activation and significantly delays lymphomagenesis in Atm⁠ RX/RX ⁠ mice compared with Atm⁠ -/- ⁠. Together, these results support a physiological role of the FATC domain in ATM protein stability and show that the presence of minimal residual ATM-R3057X protein can prevent growth retardation and delay tumorigenesis without restoring lymphocyte development and fertility. Copyright © 2021 by The American Association of Immunologists, Inc.

Citation

Maja Milanovic, Zhengping Shao, Verna M Estes, Xiaobin S Wang, Demis Menolfi, Xiaohui Lin, Brian J Lee, Jun Xu, Olivia M Cupo, Dong Wang, Shan Zha. FATC Domain Deletion Compromises ATM Protein Stability, Blocks Lymphocyte Development, and Promotes Lymphomagenesis. Journal of immunology (Baltimore, Md. : 1950). 2021 Mar 15;206(6):1228-1239