TISIDB

Summary
Symbol	RAG2
Name	recombination activating gene 2
Aliases	RAG-2; V(D)J recombination-activating protein 2
Chromosomal Location	11p13
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Basic function annotation. > Subcellular Location, Domain and Function > Gene Ontology > KEGG and Reactome Pathway

> Subcellular Location, Domain and Function [ TOP ]
Subcellular Location	Nucleus
Domain	PF03089 Recombination activating protein 2 PF13341 RAG2 PHD domain
Function	Core 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. DNA cleavage by the RAG complex 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 the RAG complex, RAG2 is not the catalytic component but is required for all known catalytic activities mediated by RAG1. It probably acts as a sensor of chromatin state that recruits the RAG complex to H3K4me3 (By similarity).

> Gene Ontology [ TOP ]
Biological Process	GO:0002200 somatic diversification of immune receptors GO:0002326 B cell lineage commitment GO:0002327 immature B cell differentiation GO:0002329 pre-B cell differentiation GO:0002331 pre-B cell allelic exclusion GO:0002358 B cell homeostatic proliferation GO:0002360 T cell lineage commitment GO:0002521 leukocyte differentiation GO:0002562 somatic diversification of immune receptors via germline recombination within a single locus GO:0006310 DNA recombination GO:0007159 leukocyte cell-cell adhesion GO:0016444 somatic cell DNA recombination GO:0030098 lymphocyte differentiation GO:0030183 B cell differentiation GO:0030217 T cell differentiation GO:0032943 mononuclear cell proliferation GO:0033077 T cell differentiation in thymus GO:0033151 V(D)J recombination GO:0035265 organ growth GO:0042100 B cell proliferation GO:0042110 T cell activation GO:0042113 B cell activation GO:0045165 cell fate commitment GO:0045927 positive regulation of growth GO:0046620 regulation of organ growth GO:0046622 positive regulation of organ growth GO:0046651 lymphocyte proliferation GO:0048638 regulation of developmental growth GO:0048639 positive regulation of developmental growth GO:0070486 leukocyte aggregation GO:0070489 T cell aggregation GO:0070661 leukocyte proliferation GO:0071593 lymphocyte aggregation GO:0071594 thymocyte aggregation
Molecular Function	GO:0003682 chromatin binding GO:0004842 ubiquitin-protein transferase activity GO:0005543 phospholipid binding GO:0005546 phosphatidylinositol-4,5-bisphosphate binding GO:0005547 phosphatidylinositol-3,4,5-trisphosphate binding GO:0019787 ubiquitin-like protein transferase activity GO:0035064 methylated histone binding GO:0035091 phosphatidylinositol binding GO:0042393 histone binding GO:0043168 anion binding GO:0043325 phosphatidylinositol-3,4-bisphosphate binding GO:0061630 ubiquitin protein ligase activity GO:0061659 ubiquitin-like protein ligase activity GO:0080025 phosphatidylinositol-3,5-bisphosphate binding GO:1901981 phosphatidylinositol phosphate binding GO:1902936 phosphatidylinositol bisphosphate binding
Cellular Component	-

> KEGG and Reactome Pathway [ TOP ]
KEGG	hsa04068 FoxO signaling pathway
Reactome	R-HSA-1280215: Cytokine Signaling in Immune system R-HSA-168256: Immune System R-HSA-1266695: Interleukin-7 signaling R-HSA-5683057: MAPK family signaling cascades R-HSA-5687128: MAPK6/MAPK4 signaling R-HSA-162582: Signal Transduction R-HSA-449147: Signaling by Interleukins

Summary
Symbol	RAG2
Name	recombination activating gene 2
Aliases	RAG-2; V(D)J recombination-activating protein 2
Chromosomal Location	11p13
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Literatures that report relations between RAG2 and anti-tumor immunity. The specific mechanism were also collected if the literature reports that a gene specifically promotes or inhibits the infiltration or function of T/NK cells.

> Text Mining

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Literatures describing the relation between RAG2 and anti-tumor immunity in human cancer.

PMID	Cancer type	Relation to immunity	Evidence sentences
16982889	mastocytoma	Inhibit immunity	An adoptive transfer model was developed in which tumor-specific 2C/RAG2(-/-) TCR transgenic CD8+ T cells were introduced either into the lymphopenic environment of RAG2(-/-) mice or into P14/RAG2(-/-) mice containing an irrelevant CD8+ TCR transgenic population. RAG2(-/-), but not P14/RAG2(-/-) recipients supported homeostatic proliferation of transferred T cells as well as tumor rejection.

Summary
Symbol	RAG2
Name	recombination activating gene 2
Aliases	RAG-2; V(D)J recombination-activating protein 2
Chromosomal Location	11p13
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	High-throughput screening data (e.g. CRISPR-Cas9, shRNA and RNAi) for T cell-mediated killing. Genetic screen techniques can identify mechanisms of tumor cell resistance (e.g., PTPN2) and sensitivity (e.g., APLNR) to killing by cytotoxic T cells, the central effectors of anti-tumor immunity. After comprehensively searching, eight groups of screening data sets were collected in the current database. In this tab, users can check whether their selected genes cause resistance or increase sensitivity to T cell-mediated killing in various data sets.

> High-throughput Screening

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Statistical results of RAG2 in screening data sets for detecting immune reponses.

PMID	Screening System	Cancer Type	Cell Line	Data Set	Statistical Results	Relation to immunity
29301958	CRISPR-Cas9	melanoma	B16F10	Pmel-1 T cell	NA/NS	NA/NS
29301958	CRISPR-Cas9	melanoma	B16F10	OT-1 T cell	NA/NS	NA/NS
28783722	CRISPR-Cas9	melanoma	Mel624	2CT-CRISPR	NA/NS	NA/NS
28723893	CRISPR-Cas9	melanoma	B16	GVAX+Anti-PD1	NA/NS	NA/NS
28723893	CRISPR-Cas9	melanoma	B16	GVAX	NA/NS	NA/NS
25691366	RNAi	Breast cancer	MCF7	Luc-CTL assay	NA/NS	NA/NS
24476824	shRNA	melanoma	B16	Primary screen	NA/NS	NA/NS
24476824	shRNA	melanoma	B16	Secondary screen	NA/NS	NA/NS

Summary
Symbol	RAG2
Name	recombination activating gene 2
Aliases	RAG-2; V(D)J recombination-activating protein 2
Chromosomal Location	11p13
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Transcriptomic and genomic profiling of pre-treated tumor biopsies from responders and non-responders to immunotherapy. These data were used to identify signatures and mechanisms of response to checkpoint blockade (e.g., anti-PDL1 and anti-PD1). One example is that mutations in the gene PBRM1 benefit clinical survival of patients with clear cell renal cell carcinoma. After comprehensively searching, we collected 5 and 6 of transcriptomic and genomic data sets, respectively. In this tab, users can check whether their selected genes have significant difference of expression or mutation between responders and non-responders in various data sets. > Expression difference between responders and non-responders > Mutation difference between responders and non-responders

> Expression difference between responders and non-responders

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Points in the above scatter plot represent the expression difference of RAG2 in various data sets.

No	PMID	Cancer type	Group	Drug	# Res	# NRes	Log2 (Fold Change)	P value
1	26997480	Melanoma	all	Anti-PD-1 (pembrolizumab and nivolumab)	14	12	0	1
2	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	6	5	0	1
3	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	7	0	1
4	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	-0.168	0.847
5	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	0.262	0.836
6	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	-0.707	0.623
7	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	26	23	0	1
8	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	15	11	0	1
9	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	11	12	0	1
10	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	4	8	0	1
11	29301960	Clear cell renal cell carcinoma (ccRCC)	VEGFRi	Anti-PD-1 (nivolumab)	2	0	0	1
12	29301960	Clear cell renal cell carcinoma (ccRCC)	non-VEGFRi	Anti-PD-1 (nivolumab)	2	8	0	1
13	29443960	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	68	230	0.135	0.485

> Mutation difference between responders and non-responders

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Points in the above scatter plot represent the mutation difference of RAG2 in various data sets.

No	PMID	Cancer type	Group	Drug	# Res	# NRes	% Mut/Res	% Mut/NRes	% Diff (R vs NR)	Pval
1	25765070	Non-small cell lung cancer (NSCLC)	all	Anti-PD-1 (pembrolizumab)	14	17	0	0	0	1
2	25765070	Non-small cell lung cancer (NSCLC)	smoking	Anti-PD-1 (pembrolizumab)	10	3	0	0	0	1
3	25765070	Non-small cell lung cancer (NSCLC)	non-smoking	Anti-PD-1 (pembrolizumab)	4	14	0	0	0	1
4	26359337	Melanoma	all	Anti-CTLA-4 (ipilimumab)	27	73	3.7	1.4	2.3	0.469
5	26359337	Melanoma	BRAFi	Anti-CTLA-4 (ipilimumab)	0	14	0	0	0	1
6	26359337	Melanoma	non-BRAFi	Anti-CTLA-4 (ipilimumab)	27	59	3.7	1.7	2	0.532
7	26997480	Melanoma	all	Anti-PD-1 (pembrolizumab and nivolumab)	21	17	4.8	23.5	-18.7	0.152
8	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	6	0	33.3	-33.3	0.165
9	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	13	11	7.7	18.2	-10.5	0.576
10	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	0	0	0	1
11	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	0	0	0	1
12	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	0	0	0	1
13	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	38	27	2.6	3.7	-1.1	1
14	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	22	13	4.5	0	4.5	1
15	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	16	14	0	7.1	-7.1	0.467
16	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	11	13	0	0	0	1
17	29301960	Clear cell renal cell carcinoma (ccRCC)	VEGFRi	Anti-PD-1 (nivolumab)	6	1	0	0	0	1
18	29301960	Clear cell renal cell carcinoma (ccRCC)	non-VEGFRi	Anti-PD-1 (nivolumab)	5	12	0	0	0	1

Summary
Symbol	RAG2
Name	recombination activating gene 2
Aliases	RAG-2; V(D)J recombination-activating protein 2
Chromosomal Location	11p13
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between abundance of tumor-infiltrating lymphocytes (TILs) and expression, copy number, methylation, or mutation of RAG2. The immune-related signatures of 28 TIL types from Charoentong's study, which can be viewed in the download page. For each cancer type, the relative abundance of TILs were inferred by using gene set variation analysis (GSVA) based on gene expression profile. In this tab, users can examine which kinds of TILs might be regulated by the current gene.

> Lymphocyte [ TOP ]

Summary
Symbol	RAG2
Name	recombination activating gene 2
Aliases	RAG-2; V(D)J recombination-activating protein 2
Chromosomal Location	11p13
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between three kinds of immunomodulators and expression, copy number, methylation, or mutation of RAG2. These immunomo-dulators were collected from Charoentong's study. In this tab, users can examine which immunomodulators might be regulated by RAG2. > Immunoinhibitor > Immunostimulator > MHC molecule

> Immunoinhibitor [ TOP ]

> Immunostimulator [ TOP ]

> MHC molecule [ TOP ]

Summary
Symbol	RAG2
Name	recombination activating gene 2
Aliases	RAG-2; V(D)J recombination-activating protein 2
Chromosomal Location	11p13
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between chemokines (or receptors) and expression, copy number, methylation, or mutation of RAG2. In this tab, users can examine which chemokines (or receptors) might be regulated by the current gene. > Chemokine > Receptor

> Chemokine [ TOP ]

> Receptor [ TOP ]

Summary
Symbol	RAG2
Name	recombination activating gene 2
Aliases	RAG-2; V(D)J recombination-activating protein 2
Chromosomal Location	11p13
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Distribution of RAG2 expression across immune and molecular subtypes. > Immune subtype > Molecular subtype

> Immune subtype [ TOP ]

> Molecular subtype [ TOP ]

Summary
Symbol	RAG2
Name	recombination activating gene 2
Aliases	RAG-2; V(D)J recombination-activating protein 2
Chromosomal Location	11p13
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Associations between RAG2 and clinical features. > Overall survival analysis > Cancer stage > Tumor grade

> Overall survival [ TOP ]

> Stage [ TOP ]

> Grade [ TOP ]

Summary
Symbol	RAG2
Name	recombination activating gene 2
Aliases	RAG-2; V(D)J recombination-activating protein 2
Chromosomal Location	11p13
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Drugs targeting RAG2 collected from DrugBank database.

> Drugs from DrugBank database [ TOP ]
There is no record.

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