RAG1

The protein encoded by this gene is involved in activation of immunoglobulin V-D-J recombination. The encoded protein is involved in recognition of the DNA substrate, but stable binding and cleavage activity also requires RAG2. Defects in this gene can be the cause of several diseases. [provided by RefSeq, Jul 2008]

Full Name

Recombination Activating 1

Function

Catalytic component of the RAG complex, a multiprotein complex that mediates the DNA cleavage phase during V(D)J recombination. V(D)J recombination assembles a diverse repertoire of immunoglobulin and T-cell receptor genes in developing B and T-lymphocytes through rearrangement of different V (variable), in some cases D (diversity), and J (joining) gene segments. In the RAG complex, RAG1 mediates the DNA-binding to the conserved recombination signal sequences (RSS) and catalyzes the DNA cleavage activities by introducing a double-strand break between the RSS and the adjacent coding segment. RAG2 is not a catalytic component but is required for all known catalytic activities. DNA cleavage occurs in 2 steps: a first nick is introduced in the top strand immediately upstream of the heptamer, generating a 3'-hydroxyl group that can attack the phosphodiester bond on the opposite strand in a direct transesterification reaction, thereby creating 4 DNA ends: 2 hairpin coding ends and 2 blunt, 5'-phosphorylated ends. The chromatin structure plays an essential role in the V(D)J recombination reactions and the presence of histone H3 trimethylated at 'Lys-4' (H3K4me3) stimulates both the nicking and haipinning steps. The RAG complex also plays a role in pre-B cell allelic exclusion, a process leading to expression of a single immunoglobulin heavy chain allele to enforce clonality and monospecific recognition by the B-cell antigen receptor (BCR) expressed on individual B-lymphocytes. The introduction of DNA breaks by the RAG complex on one immunoglobulin allele induces ATM-dependent repositioning of the other allele to pericentromeric heterochromatin, preventing accessibility to the RAG complex and recombination of the second allele. In addition to its endonuclease activity, RAG1 also acts as an E3 ubiquitin-protein ligase that mediates monoubiquitination of histone H3. Histone H3 monoubiquitination is required for the joining step of V(D)J recombination. Mediates polyubiquitination of KPNA1 (By similarity).

Biological Process

Biological Process adaptive immune responseManual Assertion Based On ExperimentIBA:GO_Central
Biological Process B cell differentiationISS:UniProtKB
Biological Process chromatin organizationIEA:UniProtKB-KW
Biological Process DNA recombinationManual Assertion Based On ExperimentTAS:ProtInc
Biological Process histone monoubiquitinationISS:UniProtKB
Biological Process immune responseManual Assertion Based On ExperimentTAS:ProtInc
Biological Process negative regulation of cysteine-type endopeptidase activity involved in apoptotic processIEA:Ensembl
Biological Process negative regulation of thymocyte apoptotic processIEA:Ensembl
Biological Process positive regulation of T cell differentiationIEA:Ensembl
Biological Process pre-B cell allelic exclusionISS:UniProtKB
Biological Process protein autoubiquitinationISS:UniProtKB
Biological Process regulation of behavioral fear responseIEA:Ensembl
Biological Process T cell differentiation in thymusISS:UniProtKB
Biological Process T cell homeostasisIEA:Ensembl
Biological Process thymus developmentIEA:Ensembl
Biological Process V(D)J recombinationManual Assertion Based On ExperimentIMP:CACAO
Biological Process visual learningIEA:Ensembl

Cellular Location

Nucleus

Involvement in disease

Combined cellular and humoral immune defects with granulomas (CHIDG):
Immunodeficiency disease with granulomas in the skin, mucous membranes, and internal organs. Other characteristics include hypogammaglobulinemia, a diminished number of T and B-cells, and sparse thymic tissue on ultrasonography.
Severe combined immunodeficiency autosomal recessive T-cell-negative/B-cell-negative/NK-cell-positive (T(-)B(-)NK(+) SCID):
A form of severe combined immunodeficiency (SCID), a genetically and clinically heterogeneous group of rare congenital disorders characterized by impairment of both humoral and cell-mediated immunity, leukopenia, and low or absent antibody levels. Patients present in infancy recurrent, persistent infections by opportunistic organisms. The common characteristic of all types of SCID is absence of T-cell-mediated cellular immunity due to a defect in T-cell development.
Omenn syndrome (OS):
Severe immunodeficiency characterized by the presence of activated, anergic, oligoclonal T-cells, hypereosinophilia, and high IgE levels.
Alpha/beta T-cell lymphopenia, with gamma/delta T-cell expansion, severe cytomegalovirus infection and autoimmunity (T-CMVA):
An immunological disorder characterized by oligoclonal expansion of TCR gamma/delta T-cells, TCR alpha/beta T-cell lymphopenia, severe, disseminated cytomegalovirus infection and autoimmune cytopenia.

PTM

Autoubiquitinated in the presence of CDC34/UBCH3.