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FATC domain deletion compromises ATM protein stability, lymphocyte development, and promotes lymphomagenesis

ABSTRACT: 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. Here we show that in mouse models, knock-in ATM-R3057X (AtmRX, corresponding to R3047X in human ATM) mutation severely compromises ATM protein stability, and causes T cell development and B cell immunoglobulin 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 AtmRX/RX mice compared to Atm-/-. Together, these results support a physiological role of the FATC domain in ATM protein stability and show that minimal ATM activity can prevent growth retardation and delay tumorigenesis without restoring lymphocyte development and fertility.

ORGANISM(S): Mus musculus

PROVIDER: GSE162568 | GEO | 2020/12/31

REPOSITORIES: GEO

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