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Abstract

Immunodeficiencies are typically caused by loss-of-function mutations in lymphocyte-specific genes. Occasionally, mutations in ubiquitous general-purpose factors, including those affecting essential components of the DNA polymerase epsilon (POLE) holoenzyme, have cell-type-specific consequences. POLE3, one of the four components of the POLE holoenzyme, features a histone fold domain and a unique acidic C terminus, making it a particularly attractive candidate mediating cell type-specific activities of POLE. Mice lacking Pole3 survive up to late embryonic stages, indicating that this subunit is dispensable for DNA replication. The phenotypes of viable hypomorphic and neomorphic alleles are surprisingly tissue restricted and reveal a stage-specific function of the histone fold domain of Pole3 during T and B cell development. Gradual introduction of positively charged residues into the acidic C terminus leads to peripheral lymphopenia of increasing severity. Our findings serve as a paradigm to understand the molecular basis of cell-type-specific non-replicative functions of the ubiquitous POLE complex.