RAG2 : recombination activating 2

Description

The RAG2 (recombination activating 2) is a protein-coding gene located on chromosome 11.

The RAG2 gene provides instructions for making a protein that is part of a complex called the RAG complex. This complex is important for immune system cells called B cells and T cells. These cells have special proteins on their surface that recognize foreign invaders and help protect the body from infection. To recognize a wide variety of substances, these proteins need to be diverse. The genes that make these proteins have segments called variable (V), diversity (D), and joining (J) segments. During protein production within lymphocytes, these gene segments are rearranged in different combinations to increase the variability of the resulting proteins. The RAG complex is involved in this process, known as V(D)J recombination. During V(D)J recombination, the RAG complex binds to a specific DNA sequence called a recombination signal sequence (RSS) next to a V, D, or J segment. The RAG complex makes cuts in the DNA between the segment and the RSS, allowing the segment to be separated and moved to a different location within the gene. This DNA rearrangement process within B cells and T cells is repeated multiple times, creating various combinations of V, D, and J segments. The resulting diversity of proteins produced throughout life following V(D)J recombination allows the body to effectively recognize and fight off a wide range of foreign invaders.

RAG2 is a core component of the RAG complex, a multiprotein complex that orchestrates DNA cleavage during V(D)J recombination. This process generates a diverse repertoire of immunoglobulin and T-cell receptor genes in developing B and T-lymphocytes. RAG2 works in conjunction with RAG1, the catalytic component of the RAG complex, to facilitate DNA rearrangement by recognizing specific sequences flanking the variable, diversity, and joining gene segments. This process involves a two-step DNA cleavage mechanism resulting in 4 distinct DNA ends: 2 hairpin coding ends and 2 blunt, 5'-phosphorylated ends. RAG2, although not directly catalyzing the DNA cleavage, is essential for all known catalytic activities of RAG1. It likely acts as a chromatin state sensor, recruiting the RAG complex to regions enriched in histone H3 trimethylated at Lys-4 (H3K4me3), which stimulates both the nicking and hairpin formation steps. RAG2 also contributes to pre-B cell allelic exclusion, ensuring that only one immunoglobulin heavy chain allele is expressed in a B-cell, promoting clonality and specific antigen recognition. Upon DNA cleavage by the RAG complex on one allele, the other immunoglobulin allele undergoes ATM-dependent repositioning to pericentromeric heterochromatin, restricting accessibility to the RAG complex and preventing recombination of the second allele. RAG2, in summary, plays a critical role in maintaining the fidelity and specificity of V(D)J recombination, a crucial process for generating the immune system's diversity and functionality.

RAG2 is also known as RAG-2.

Associated Diseases

• Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive
• Omenn syndrome
• Severe combined immunodeficiency due to complete RAG1/2 deficiency
• Combined cellular and humoral immune defects with granulomas