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

Affiliation

Milanovic M(1), Shao Z(1), Estes VM(1), Wang XS(1)(2), Menolfi D(1), Lin X(1), Lee BJ(1), Xu J(3), Cupo OM(1), Wang D(3), Zha S(4)(2)(5)(6).
Author information:
(1)Institute for Cancer Genetics, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032.
(2)Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032.
(3)Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093.
(4)Institute for Cancer Genetics, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032; [Email]
(5)Division of Pediatric Oncology, Hematology and Stem Cell Transplantation, Department of Pediatrics, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032; and.
(6)Department of Immunology and Microbiology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032.

Abstract

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.