RAG2: Difference between revisions
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'''Recombination activating gene 2''' also known as '''RAG-2''' is a [[protein]] | '''Recombination activating gene 2''' '''protein''' (also known as '''RAG-2''') is a [[lymphocyte]]-specific [[protein]] encoded by RAG2 [[gene]] on human [[chromosome 11]]. Together with [[RAG1]] protein, RAG2 forms a V(D)J recombinase, a protein complex required for the process of [[V(D)J recombination]] during which the variable regions of [[Antibody|immunoglobulin]] and [[T-cell receptor|T cell receptor]] genes are assembled in developing B and T lymphocytes. Therefore, RAG2 is essential for generation of mature B and T lymphocytes. | ||
== Structure == | |||
RAG2 is a 527-[[amino acid]] long protein. Its [[N-terminus|N-terminal]] part is thought to form a six-bladed propeller in the active core.<ref name="jbc.org">{{cite journal | vauthors = Zhang YH, Shetty K, Surleac MD, Petrescu AJ, Schatz DG | title = Mapping and Quantitation of the Interaction between the Recombination Activating Gene Proteins RAG1 and RAG2 | journal = The Journal of Biological Chemistry | volume = 290 | issue = 19 | pages = 11802–17 | date = May 2015 | pmid = 25745109 | doi = 10.1074/jbc.M115.638627 | url = http://www.jbc.org/content/290/19/11802 }}</ref><ref name="jbc.org"/> RAG2 is [[Conserved sequence|conserved]] among all species that carry out V(D)J recombination and its expression pattern correlates precisely with V(D)J recombinase activity.<ref>{{cite journal | vauthors = Oettinger MA, Schatz DG, Gorka C, Baltimore D | title = RAG-1 and RAG-2, adjacent genes that synergistically activate V(D)J recombination | journal = Science | volume = 248 | issue = 4962 | pages = 1517–23 | date = June 1990 | pmid = 2360047 }}</ref> RAG2 is expressed in immature lymphoid cells. While amount of RAG1 is constant during the [[cell cycle]], RAG2 accumulates mainly in [[G0 phase|G0]] and [[G1 phase|G1]] phase of cell cycle and it undergoes rapid degradation when the cell enters [[S phase]].<ref>{{cite journal | vauthors = Lin WC, Desiderio S | title = Cell cycle regulation of V(D)J recombination-activating protein RAG-2 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 91 | issue = 7 | pages = 2733–7 | date = March 1994 | pmid = 8146183 }}</ref><ref>{{Cite journal|last=Lee|first=Jinhak|last2=Desiderio|first2=Stephen|date=1999-12|title=Cyclin A/CDK2 Regulates V(D)J Recombination by Coordinating RAG-2 Accumulation and DNA Repair|url=http://dx.doi.org/10.1016/s1074-7613(00)80151-x|journal=Immunity|volume=11|issue=6|pages=771–781|doi=10.1016/s1074-7613(00)80151-x|issn=1074-7613}}</ref> This serves as an important regulatory mechanism of V(D)J recombination and a prevention of genomic instability. | |||
== Function == | == 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 [[DNA repair|double-strand breaks]] by cleaving [[DNA]] at conserved [[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.<ref>{{Cite journal|last=Landree|first=M. A.|last2=Wibbenmeyer|first2=J. A.|last3=Roth|first3=D. B.|date=1999-12-01|title=Mutational analysis of RAG1 and RAG2 identifies three catalytic amino acids in RAG1 critical for both cleavage steps of V(D)J recombination|url=http://dx.doi.org/10.1101/gad.13.23.3059|journal=Genes & Development|volume=13|issue=23|pages=3059–3069|doi=10.1101/gad.13.23.3059|issn=0890-9369}}</ref><ref>{{cite journal | vauthors = Kim DR, Dai Y, Mundy CL, Yang W, Oettinger MA | title = Mutations of acidic residues in RAG1 define the active site of the V(D)J recombinase | journal = Genes & Development | volume = 13 | issue = 23 | pages = 3070–80 | date = December 1999 | pmid = 10601033 }}</ref> Unlike RAG1, RAG2 protein does not appear to possess any [[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.<ref>{{Cite book|url=http://worldcat.org/oclc/679256409|title=RAG-2 Promotes Heptamer Occupancy by RAG-1 in the Assembly of a V(D)J Initiation Complex†|last=Stephen|first=Swanson, Patrick C. Desiderio,|publisher=American Society for Microbiology|oclc=679256409}}</ref><ref>{{cite journal | vauthors = Zhao S, Gwyn LM, De P, Rodgers KK | title = A non-sequence-specific DNA binding mode of RAG1 is inhibited by RAG2 | journal = Journal of Molecular Biology | volume = 387 | issue = 3 | pages = 744–58 | date = April 2009 | pmid = 19232525 | doi = 10.1016/j.jmb.2009.02.020 | url = http://dx.doi.org/10.1016/j.jmb.2009.02.020 }}</ref> The [[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]] plant [[homeodomain]] finger-like motif in this protein is necessary for interactions with [[chromatin]] components, specifically with [[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.<ref name=":0" /> Therefore, presence of both RAG1 and RAG2 is essential for generation of mature B and T lymphocytes. | |||
== Clinical significance == | == Clinical significance == | ||
As mentioned, RAG2 is crucial for maturation of B and T cells. Therefore, mutations of RAG2 gene can result in severe immune disorders such as [[Severe combined immunodeficiency|SCID]] (Severe Combined Immunodeficiency) or [[Omenn syndrome]].<ref name="entrez">{{cite web|url=https://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=retrieve&list_uids=5897|title=Entrez Gene: Recombination activating gene 2}}</ref> Omenn Syndrom is caused by a hypomorphic mutation of RAG2 gene, which leads to reduced but still present function of the RAG complex.<ref>{{cite journal | vauthors = Corneo B, Moshous D, Güngör T, Wulffraat N, Philippet P, Le Deist FL, Fischer A, de Villartay JP | title = Identical mutations in RAG1 or RAG2 genes leading to defective V(D)J recombinase activity can cause either T-B-severe combined immune deficiency or Omenn syndrome | journal = Blood | volume = 97 | issue = 9 | pages = 2772–6 | date = May 2001 | pmid = 11313270 }}</ref> Although patients do not have any circulating B cells, a small number of oligoclonal T cells is developed. | |||
== RAG2 knockout mice == | |||
In 1992, a RAG2 knockout mice strain was generated. Since then, it became a widely used mouse model in immunological research. This mice strain has an inactivated RAG2 gene, therefore [[Dominance (genetics)|homozygous]] mice are inable to initiate [[V(D)J recombination|V(D)J rearrangement]] and consequently fail to generate mature T and B [[lymphocyte]]s.<ref name=":0">{{cite journal | vauthors = Shinkai Y, Rathbun G, Lam KP, Oltz EM, Stewart V, Mendelsohn M, Charron J, Datta M, Young F, Stall AM | title = RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement | journal = Cell | volume = 68 | issue = 5 | pages = 855–67 | date = March 1992 | pmid = 1547487 | doi = 10.1016/0092-8674(92)90029-c }}</ref> As such RAG2 knockout mice represent a very valuable research tool used in transplantation experiments, [[vaccine]] development and [[Haematopoiesis|hematopoiesis]] research. Also, the RAG2 mutation can be combined with other mutations in order to develop further models useful for basic immunology research. | |||
== References == | == References == | ||
{{reflist}} | {{reflist}} | ||
{{NLM content}} | {{NLM content}} | ||
Latest revision as of 14:03, 21 October 2018
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Recombination activating gene 2 protein (also known as RAG-2) is a lymphocyte-specific protein encoded by RAG2 gene on human chromosome 11. Together with RAG1 protein, RAG2 forms a V(D)J recombinase, a protein complex required for the process of V(D)J recombination during which the variable regions of immunoglobulin and T cell receptor genes are assembled in developing B and T lymphocytes. Therefore, RAG2 is essential for generation of mature B and T lymphocytes.
Structure
RAG2 is a 527-amino acid long protein. Its N-terminal part is thought to form a six-bladed propeller in the active core.[1][1] RAG2 is conserved among all species that carry out V(D)J recombination and its expression pattern correlates precisely with V(D)J recombinase activity.[2] RAG2 is expressed in immature lymphoid cells. While amount of RAG1 is constant during the cell cycle, RAG2 accumulates mainly in G0 and G1 phase of cell cycle and it undergoes rapid degradation when the cell enters S phase.[3][4] 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 by cleaving DNA at conserved 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.[5][6] Unlike RAG1, RAG2 protein does not appear to possess any 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.[7][8] The 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 plant homeodomain finger-like motif in this protein is necessary for interactions with chromatin components, specifically with 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.[9] Therefore, presence of both RAG1 and RAG2 is essential for generation of mature B and T lymphocytes.
Clinical significance
As mentioned, RAG2 is crucial for maturation of B and T cells. Therefore, mutations of RAG2 gene can result in severe immune disorders such as SCID (Severe Combined Immunodeficiency) or Omenn syndrome.[10] Omenn Syndrom is caused by a hypomorphic mutation of RAG2 gene, which leads to reduced but still present function of the RAG complex.[11] Although patients do not have any circulating B cells, a small number of oligoclonal T cells is developed.
RAG2 knockout mice
In 1992, a RAG2 knockout mice strain was generated. Since then, it became a widely used mouse model in immunological research. This mice strain has an inactivated RAG2 gene, therefore homozygous mice are inable to initiate V(D)J rearrangement and consequently fail to generate mature T and B lymphocytes.[9] As such RAG2 knockout mice represent a very valuable research tool used in transplantation experiments, vaccine development and hematopoiesis research. Also, the RAG2 mutation can be combined with other mutations in order to develop further models useful for basic immunology research.
References
- ↑ 1.0 1.1 Zhang YH, Shetty K, Surleac MD, Petrescu AJ, Schatz DG (May 2015). "Mapping and Quantitation of the Interaction between the Recombination Activating Gene Proteins RAG1 and RAG2". The Journal of Biological Chemistry. 290 (19): 11802–17. doi:10.1074/jbc.M115.638627. PMID 25745109.
- ↑ 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. PMID 2360047.
- ↑ Lin WC, Desiderio S (March 1994). "Cell cycle regulation of V(D)J recombination-activating protein RAG-2". Proceedings of the National Academy of Sciences of the United States of America. 91 (7): 2733–7. PMID 8146183.
- ↑ Lee, Jinhak; Desiderio, Stephen (1999-12). "Cyclin A/CDK2 Regulates V(D)J Recombination by Coordinating RAG-2 Accumulation and DNA Repair". Immunity. 11 (6): 771–781. doi:10.1016/s1074-7613(00)80151-x. ISSN 1074-7613. Check date values in:
|date=(help) - ↑ Landree, M. A.; Wibbenmeyer, J. A.; Roth, D. B. (1999-12-01). "Mutational analysis of RAG1 and RAG2 identifies three catalytic amino acids in RAG1 critical for both cleavage steps of V(D)J recombination". Genes & Development. 13 (23): 3059–3069. doi:10.1101/gad.13.23.3059. ISSN 0890-9369.
- ↑ Kim DR, Dai Y, Mundy CL, Yang W, Oettinger MA (December 1999). "Mutations of acidic residues in RAG1 define the active site of the V(D)J recombinase". Genes & Development. 13 (23): 3070–80. PMID 10601033.
- ↑ Stephen, Swanson, Patrick C. Desiderio,. RAG-2 Promotes Heptamer Occupancy by RAG-1 in the Assembly of a V(D)J Initiation Complex†. American Society for Microbiology. OCLC 679256409.
- ↑ Zhao S, Gwyn LM, De P, Rodgers KK (April 2009). "A non-sequence-specific DNA binding mode of RAG1 is inhibited by RAG2". Journal of Molecular Biology. 387 (3): 744–58. doi:10.1016/j.jmb.2009.02.020. PMID 19232525.
- ↑ 9.0 9.1 Shinkai Y, Rathbun G, Lam KP, Oltz EM, Stewart V, Mendelsohn M, Charron J, Datta M, Young F, Stall AM (March 1992). "RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement". Cell. 68 (5): 855–67. doi:10.1016/0092-8674(92)90029-c. PMID 1547487.
- ↑ "Entrez Gene: Recombination activating gene 2".
- ↑ Corneo B, Moshous D, Güngör T, Wulffraat N, Philippet P, Le Deist FL, Fischer A, de Villartay JP (May 2001). "Identical mutations in RAG1 or RAG2 genes leading to defective V(D)J recombinase activity can cause either T-B-severe combined immune deficiency or Omenn syndrome". Blood. 97 (9): 2772–6. PMID 11313270.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.