Recombination activating protein 1 (RAG1) (RAG1)

Recombination activating protein 1 (RAG1) is an essential endonuclease that, in complex with RAG2, initiates the process of V(D)J recombination within developing B and T lymphocytes [1, 16]. This process is critical for the adaptive immune system as it rearranges variable (V), diversity (D), and joining (J) gene segments to generate a vast repertoire of unique antigen receptors [3, 17]. RAG1 recognizes specific recombination signal sequences (RSS) and introduces double-strand breaks at the junctions of coding segments, which are subsequently repaired by the non-homologous end-joining (NHEJ) machinery to form functional genes [18, 21]. Beyond its nuclease activity, RAG1 also functions as an E3 ubiquitin-protein ligase, contributing to histone monoubiquitylation and the overall stability and regulation of the recombination complex [1, 4, 17]. Mutations in the RAG1 gene are the primary cause of several life-threatening immunodeficiencies, most notably RAG1-deficient severe combined immunodeficiency (SCID) and Omenn syndrome [3, 11]. While complete loss of function leads to a total absence of mature lymphocytes, hypomorphic mutations can result in dysregulated immune responses, autoimmunity, and the formation of granulomas [8, 11]. Current therapeutic development focuses on ex vivo gene therapy, such as the lentiviral vector product MB-110 (LV-RAG1), which aims to restore functional RAG1 expression in autologous hematopoietic stem cells [5, 14]. Despite the curative potential of these therapies, significant challenges remain, including the risk of off-target DNA cleavage leading to oncogenic translocations and the potential for insertional mutagenesis associated with viral vectors [12, 13].

Other names

V(D)J recombination-activating protein 1RNF74Ring finger protein 74Recombination activating 1RNF110RAG-1

Restoration of RAG1 protein expression through ex vivo lentiviral gene therapy in autologous hematopoietic stem cells, enabling functional V(D)J recombination and lymphocyte development.