| First Author | Milanovic M | Year | 2021 |
| Journal | J Immunol | Volume | 206 |
| Issue | 6 | Pages | 1228-1239 |
| PubMed ID | 33536256 | Mgi Jnum | J:303892 |
| Mgi Id | MGI:6515405 | Doi | 10.4049/jimmunol.2000967 |
| Citation | Milanovic M, et al. (2021) FATC Domain Deletion Compromises ATM Protein Stability, Blocks Lymphocyte Development, and Promotes Lymphomagenesis. J Immunol 206(6):1228-1239 |
| abstractText | 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. |
