# RAG2

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Protein-coding gene in the species Homo sapiens

RAG2 Identifiers Aliases RAG2, RAG-2, recombination activating gene 2, recombination activating 2 External IDs OMIM: 179616; MGI: 97849; HomoloGene: 7507; GeneCards: RAG2; OMA:RAG2 - orthologs Gene location (Human) Chr. Chromosome 11 (human)[1] Band 11p12 Start 36,575,574 bp[1] End 36,598,279 bp[1] Gene location (Mouse) Chr. Chromosome 2 (mouse)[2] Band 2 E2|2 53.87 cM Start 101,455,063 bp[2] End 101,462,874 bp[2] RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in thymus bone marrow left lobe of thyroid gland right lobe of thyroid gland bone marrow cell corpus callosum granulocyte mucosa of transverse colon tonsil muscle tissue Top expressed in thymus granulocyte bone marrow heart cochlea exocrine gland hepatobiliary system liver embryo embryonic structure More reference expression data BioGPS n/a Gene ontology Molecular function DNA binding ubiquitin protein ligase activity zinc ion binding chromatin binding phosphatidylinositol-3,5-bisphosphate binding metal ion binding phosphatidylinositol-3,4-bisphosphate binding methylated histone binding phosphatidylinositol binding phosphatidylinositol-4,5-bisphosphate binding phosphatidylinositol-3,4,5-trisphosphate binding sequence-specific DNA binding Cellular component nucleoplasm nucleus DNA recombinase complex Biological process DNA recombination B cell homeostatic proliferation T cell differentiation in thymus positive regulation of organ growth T cell differentiation B cell lineage commitment protein ubiquitination V(D)J recombination pre-B cell allelic exclusion B cell differentiation T cell lineage commitment defense response to bacterium chromatin organization Sources:Amigo / QuickGO Orthologs Species Human Mouse Entrez 5897 19374 Ensembl ENSG00000175097 ENSMUSG00000032864 UniProt P55895 P21784 RefSeq (mRNA) NM_000536 NM_001243785 NM_001243786 NM_009020 RefSeq (protein) NP_000527 NP_001230714 NP_001230715 NP_033046 Location (UCSC) Chr 11: 36.58 – 36.6 Mb Chr 2: 101.46 – 101.46 Mb PubMed search [3] [4] Wikidata View/Edit Human View/Edit Mouse

**Recombination activating gene 2** **protein** (also known as **RAG-2**) is a [lymphocyte](/source/Lymphocyte)-specific [protein](/source/Protein) encoded by the RAG2 [gene](/source/Gene) on human [chromosome 11](/source/Chromosome_11). Together with the [RAG1](/source/RAG1) protein, RAG2 forms a V(D)J recombinase, a [protein complex](/source/Protein_complex) required for the process of [V(D)J recombination](/source/V(D)J_recombination) during which the variable regions of [immunoglobulin](/source/Antibody) and [T cell receptor](/source/T-cell_receptor) genes are assembled in developing [B](/source/B_cell) and [T lymphocytes](/source/T_cell). Therefore, RAG2 is essential for the generation of mature B and T lymphocytes.

## Structure

RAG2 is a 527-[amino acid](/source/Amino_acid) long protein. Its [N-terminal](/source/N-terminus) part is thought to form a six-bladed propeller in the active core.[5] RAG2 is [conserved](/source/Conserved_sequence) among all species that carry out V(D)J recombination and its expression pattern correlates precisely with V(D)J recombinase activity.[6] RAG2 is expressed in immature lymphoid cells. While the amount of RAG1 is constant during the [cell cycle](/source/Cell_cycle), the RAG2 accumulates mainly in the [G0](/source/G0_phase) and [G1](/source/G1_phase) phases of the cell cycle and it undergoes rapid degradation when the cell enters the [S phase](/source/S_phase).[7][8] This serves as an important regulatory mechanism of V(D)J recombination and a prevention of genomic instability.

## Function

RAG2 is one of the two core components of the RAG complex. RAG complex is a multiprotein complex that mediates the DNA cleavage phase during V(D)J recombination. This complex can make [double-strand breaks](/source/DNA_repair) by cleaving [DNA](/source/DNA) at conserved [recombination signal sequences](/source/Recombination_signal_sequences) (RSS).

The other core component of this complex is RAG1. This protein is thought to possess most of the catalytic activity of the RAG complex. The RAG1 protein is the component that actually binds to DNA and cleaves it.[9][10] Unlike RAG1, RAG2 protein does not appear to possess any [endonuclease](/source/Endonuclease) activity or to even bind to DNA strand. RAG2 plays a role of an accessory factor. Its primary function seems to be to interact with RAG1 protein and activate its endonuclease functions. RAG2 also enhances RSS recognition and thereby decreases nonspecific DNA binding by RAG complex.[11][12] The [N-terminal](/source/N-terminal) of the recombination activating gene 2 component is thought to form a six-bladed propeller in the active core that serves as a binding scaffold for the tight association of the complex with DNA. A [C-terminal](/source/C-terminal) plant [homeodomain](/source/Homeodomain) finger-like motif in this protein is necessary for interactions with [chromatin](/source/Chromatin) components, specifically with [histone H3](/source/Histone_H3) that is trimethylated at lysine 4.

As recombination does not occur in the absence of RAG2, its interactions with RAG1 are thought to be crucial for catalytic function of RAG1 protein.[13] Therefore, presence of both RAG1 and RAG2 is essential for the generation of mature B and T lymphocytes.

## Clinical significance

As mentioned, RAG2 is crucial for the maturation of B and T cells. Therefore, mutations of RAG2 gene can result in severe immune disorders such as [SCID](/source/Severe_combined_immunodeficiency) (Severe Combined Immunodeficiency) or [Omenn syndrome](/source/Omenn_syndrome).[14] Omenn Syndrom is caused by a hypomorphic mutation of RAG2 gene, which leads to reduced but still present function of the RAG complex.[15] Although patients do not have any circulating B cells, a small number of oligoclonal T cells is developed. Over fifty percent of RAG1 is conserved in humans. Therefore, functionally validating novel genetic findings is crucial for characterising human RAG deficiency. 71 RAG1 and 39 RAG2 variants have been functionally assayed. Variants that are most likely to occur and present as disease-causing have been predicted.[16] Combined with pathogenicity prediction, this application guides research to test the effect of top candidate variants in preparation for novel disease cases.

## RAG2 knockout mice

In 1992, a RAG2 knockout mice strain was generated. Since then, it has become a widely used mouse model in immunological research. This mice strain has an inactivated RAG2 gene. Therefore [homozygous](/source/Dominance_(genetics)) mice are unable to initiate [V(D)J rearrangement](/source/V(D)J_recombination) and consequently fail to generate mature T and B [lymphocytes](/source/Lymphocyte).[13] As such RAG2 knockout mice represent a very valuable research tool used in transplantation experiments, [vaccine](/source/Vaccine) development and [hematopoiesis](/source/Haematopoiesis) research. Also, the RAG2 mutation can be combined with other mutations in order to develop further models useful for basic immunology research. Furthermore, [methylcholantrene](/source/Methylcholanthrene) can be used to develop tumors in RAG2 knockout mice.[17]

## References

1. ^ [***a***](#cite_ref-refGRCh38Ensembl_1-0) [***b***](#cite_ref-refGRCh38Ensembl_1-1) [***c***](#cite_ref-refGRCh38Ensembl_1-2) [GRCh38: Ensembl release 89: ENSG00000175097](http://May2017.archive.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000175097) – [Ensembl](/source/Ensembl_genome_database_project), May 2017

1. ^ [***a***](#cite_ref-refGRCm38Ensembl_2-0) [***b***](#cite_ref-refGRCm38Ensembl_2-1) [***c***](#cite_ref-refGRCm38Ensembl_2-2) [GRCm38: Ensembl release 89: ENSMUSG00000032864](http://May2017.archive.ensembl.org/Mus_musculus/Gene/Summary?db=core;g=ENSMUSG00000032864) – [Ensembl](/source/Ensembl_genome_database_project), May 2017

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1. **[^](#cite_ref-6)** Oettinger MA, Schatz DG, Gorka C, Baltimore D (June 1990). "RAG-1 and RAG-2, adjacent genes that synergistically activate V(D)J recombination". *Science*. **248** (4962): 1517–23. [Bibcode](/source/Bibcode_(identifier)):[1990Sci...248.1517O](https://ui.adsabs.harvard.edu/abs/1990Sci...248.1517O). [doi](/source/Doi_(identifier)):[10.1126/science.2360047](https://doi.org/10.1126%2Fscience.2360047). [PMID](/source/PMID_(identifier)) [2360047](https://pubmed.ncbi.nlm.nih.gov/2360047).

1. **[^](#cite_ref-7)** Lin WC, Desiderio S (March 1994). ["Cell cycle regulation of V(D)J recombination-activating protein RAG-2"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC43444). *Proceedings of the National Academy of Sciences of the United States of America*. **91** (7): 2733–7. [Bibcode](/source/Bibcode_(identifier)):[1994PNAS...91.2733L](https://ui.adsabs.harvard.edu/abs/1994PNAS...91.2733L). [doi](/source/Doi_(identifier)):[10.1073/pnas.91.7.2733](https://doi.org/10.1073%2Fpnas.91.7.2733). [PMC](/source/PMC_(identifier)) [43444](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC43444). [PMID](/source/PMID_(identifier)) [8146183](https://pubmed.ncbi.nlm.nih.gov/8146183).

1. **[^](#cite_ref-8)** Lee, Jinhak; Desiderio, Stephen (December 1999). ["Cyclin A/CDK2 Regulates V(D)J Recombination by Coordinating RAG-2 Accumulation and DNA Repair"](https://doi.org/10.1016%2Fs1074-7613%2800%2980151-x). *Immunity*. **11** (6): 771–781. [doi](/source/Doi_(identifier)):[10.1016/s1074-7613(00)80151-x](https://doi.org/10.1016%2Fs1074-7613%2800%2980151-x). [ISSN](/source/ISSN_(identifier)) [1074-7613](https://search.worldcat.org/issn/1074-7613). [PMID](/source/PMID_(identifier)) [10626899](https://pubmed.ncbi.nlm.nih.gov/10626899).

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*This article incorporates text from the [United States National Library of Medicine](/source/United_States_National_Library_of_Medicine), which is in the [public domain](/source/Public_domain).*

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Adapted from the Wikipedia article [RAG2](https://en.wikipedia.org/wiki/RAG2) by Wikipedia contributors ([contributor history](https://en.wikipedia.org/wiki/RAG2?action=history)). Available under [Creative Commons Attribution-ShareAlike 4.0 International](https://creativecommons.org/licenses/by-sa/4.0/). Changes may have been made.