A novel RAG1 mutation reveals a critical in vivo role for HMGB1/2 during V(D)J recombination.

ABSTRACT: The Recombination Activating Genes, RAG1 and RAG2, are essential for V(D)J recombination and adaptive immunity. Mutations in these genes often cause immunodeficiency, the severity of which reflects the importance of the altered residue or residues during recombination. Here, we describe a novel RAG1 mutation that causes immunodeficiency in an unexpected way: The mutated protein severely disrupts binding of the accessory protein, HMGB1. Although HMGB1 enhances RAG cutting in vitro, its role in vivo was controversial. We show here that reduced HMGB1 binding by the mutant protein dramatically reduces RAG cutting in vitro and almost completely eliminates recombination in vivo. The RAG1 mutation, R401W, places a bulky tryptophan opposite the binding site for HMG Box A at bo

SUBMITTER: Thwaites DT 

PROVIDER: S-EPMC6450058 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature