TISIDB

Summary
Symbol	RAG1
Name	recombination activating gene 1
Aliases	RNF74; MGC43321; recombination activating protein 1; RING finger protein 74; V(D)J recombination-activating ......
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	PF12940 Recombination-activation protein 1 (RAG1) PF12560 RAG1 importin binding PF00097 Zinc finger PF10426 Recombination-activating protein 1 zinc-finger domain
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).

> Gene Ontology [ TOP ]
Biological Process	GO:0001776 leukocyte homeostasis GO:0002200 somatic diversification of immune receptors GO:0002250 adaptive immune response GO:0002260 lymphocyte homeostasis GO:0002327 immature B cell differentiation GO:0002329 pre-B cell differentiation GO:0002331 pre-B cell allelic exclusion GO:0002521 leukocyte differentiation GO:0002562 somatic diversification of immune receptors via germline recombination within a single locus GO:0002694 regulation of leukocyte activation GO:0002696 positive regulation of leukocyte activation GO:0006310 DNA recombination GO:0006513 protein monoubiquitination GO:0007159 leukocyte cell-cell adhesion GO:0010390 histone monoubiquitination GO:0010466 negative regulation of peptidase activity GO:0010951 negative regulation of endopeptidase activity GO:0016444 somatic cell DNA recombination GO:0016570 histone modification GO:0016574 histone ubiquitination GO:0022407 regulation of cell-cell adhesion GO:0022409 positive regulation of cell-cell adhesion GO:0030098 lymphocyte differentiation GO:0030183 B cell differentiation GO:0030217 T cell differentiation GO:0033077 T cell differentiation in thymus GO:0033151 V(D)J recombination GO:0042110 T cell activation GO:0042113 B cell activation GO:0043029 T cell homeostasis GO:0043154 negative regulation of cysteine-type endopeptidase activity involved in apoptotic process GO:0043281 regulation of cysteine-type endopeptidase activity involved in apoptotic process GO:0045580 regulation of T cell differentiation GO:0045582 positive regulation of T cell differentiation GO:0045619 regulation of lymphocyte differentiation GO:0045621 positive regulation of lymphocyte differentiation GO:0045785 positive regulation of cell adhesion GO:0045861 negative regulation of proteolysis GO:0048538 thymus development GO:0048732 gland development GO:0048872 homeostasis of number of cells GO:0050863 regulation of T cell activation GO:0050865 regulation of cell activation GO:0050867 positive regulation of cell activation GO:0050870 positive regulation of T cell activation GO:0051249 regulation of lymphocyte activation GO:0051251 positive regulation of lymphocyte activation GO:0051346 negative regulation of hydrolase activity GO:0051865 protein autoubiquitination GO:0052547 regulation of peptidase activity GO:0052548 regulation of endopeptidase activity GO:0070227 lymphocyte apoptotic process GO:0070228 regulation of lymphocyte apoptotic process GO:0070229 negative regulation of lymphocyte apoptotic process GO:0070231 T cell apoptotic process GO:0070232 regulation of T cell apoptotic process GO:0070233 negative regulation of T cell apoptotic process GO:0070242 thymocyte apoptotic process GO:0070243 regulation of thymocyte apoptotic process GO:0070244 negative regulation of thymocyte apoptotic process GO:0070486 leukocyte aggregation GO:0070489 T cell aggregation GO:0071593 lymphocyte aggregation GO:0071594 thymocyte aggregation GO:0071887 leukocyte apoptotic process GO:0090305 nucleic acid phosphodiester bond hydrolysis GO:1902105 regulation of leukocyte differentiation GO:1902107 positive regulation of leukocyte differentiation GO:1903037 regulation of leukocyte cell-cell adhesion GO:1903039 positive regulation of leukocyte cell-cell adhesion GO:1903706 regulation of hemopoiesis GO:1903708 positive regulation of hemopoiesis GO:2000106 regulation of leukocyte apoptotic process GO:2000107 negative regulation of leukocyte apoptotic process GO:2000116 regulation of cysteine-type endopeptidase activity GO:2000117 negative regulation of cysteine-type endopeptidase activity
Molecular Function	GO:0004518 nuclease activity GO:0004519 endonuclease activity GO:0004842 ubiquitin-protein transferase activity GO:0016874 ligase activity GO:0019787 ubiquitin-like protein transferase activity GO:0042393 histone binding GO:0061630 ubiquitin protein ligase activity GO:0061659 ubiquitin-like protein ligase activity
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	RAG1
Name	recombination activating gene 1
Aliases	RNF74; MGC43321; recombination activating protein 1; RING finger protein 74; V(D)J recombination-activating ......
Chromosomal Location	11p13
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Literatures that report relations between RAG1 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 RAG1 and anti-tumor immunity in human cancer.

PMID	Cancer type	Relation to immunity	Evidence sentences
29632726	Gastric Carcinoma	Promote immunity	Despite minimal in vitro cytotoxic activity, the adoptive transfer of CD8+ memory stem T cells into Rag1-/- tumor bearing mice enhanced tumor regression compared to CD8+ central or effector memory T cell counterparts.
29630898	Pancreatic ductal adenocarcinoma; melanoma; colon carcinoma	Promote immunity (T function); essential for immunotherapy	However, depletion of gut microbiome did not reduce tumor growth in Rag1-knockout mice, which lack mature T and B cells.

Summary
Symbol	RAG1
Name	recombination activating gene 1
Aliases	RNF74; MGC43321; recombination activating protein 1; RING finger protein 74; V(D)J recombination-activating ......
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 RAG1 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	RAG1
Name	recombination activating gene 1
Aliases	RNF74; MGC43321; recombination activating protein 1; RING finger protein 74; V(D)J recombination-activating ......
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 RAG1 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	0.104	0.531
2	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	6	5	0.156	0.697
3	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	7	0.064	0.834
4	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	-0.313	0.437
5	28552987	Urothelial cancer	smoking	Anti-PD-L1 (atezolizumab)	5	9	-0.284	0.793
6	28552987	Urothelial cancer	non-smoking	Anti-PD-L1 (atezolizumab)	4	7	-0.35	0.789
7	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	26	23	-0.048	0.872
8	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	15	11	0.303	0.625
9	29033130	Melanoma	NIV3-NAIVE	Anti-PD-1 (nivolumab)	11	12	-0.381	0.54
10	29301960	Clear cell renal cell carcinoma (ccRCC)	all	Anti-PD-1 (nivolumab)	4	8	0.381	0.466
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	0.274	0.692
13	29443960	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	68	230	-0.135	0.516

> Mutation difference between responders and non-responders

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Points in the above scatter plot represent the mutation difference of RAG1 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	5.9	-5.9	1
2	25765070	Non-small cell lung cancer (NSCLC)	smoking	Anti-PD-1 (pembrolizumab)	10	3	0	33.3	-33.3	0.231
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	11.1	4.1	7	0.339
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	11.1	5.1	6	0.373
7	26997480	Melanoma	all	Anti-PD-1 (pembrolizumab and nivolumab)	21	17	4.8	5.9	-1.1	1
8	26997480	Melanoma	MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	8	6	0	0	0	1
9	26997480	Melanoma	non-MAPKi	Anti-PD-1 (pembrolizumab and nivolumab)	13	11	7.7	9.1	-1.4	1
10	28552987	Urothelial cancer	all	Anti-PD-L1 (atezolizumab)	9	16	0	6.2	-6.2	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	14.3	-14.3	1
13	29033130	Melanoma	all	Anti-PD-1 (nivolumab)	38	27	5.3	3.7	1.6	1
14	29033130	Melanoma	NIV3-PROG	Anti-PD-1 (nivolumab)	22	13	9.1	0	9.1	0.519
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	9.1	0	9.1	0.458
17	29301960	Clear cell renal cell carcinoma (ccRCC)	VEGFRi	Anti-PD-1 (nivolumab)	6	1	16.7	0	16.7	1
18	29301960	Clear cell renal cell carcinoma (ccRCC)	non-VEGFRi	Anti-PD-1 (nivolumab)	5	12	0	0	0	1

Summary
Symbol	RAG1
Name	recombination activating gene 1
Aliases	RNF74; MGC43321; recombination activating protein 1; RING finger protein 74; V(D)J recombination-activating ......
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 RAG1. 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	RAG1
Name	recombination activating gene 1
Aliases	RNF74; MGC43321; recombination activating protein 1; RING finger protein 74; V(D)J recombination-activating ......
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 RAG1. These immunomo-dulators were collected from Charoentong's study. In this tab, users can examine which immunomodulators might be regulated by RAG1. > Immunoinhibitor > Immunostimulator > MHC molecule

> Immunoinhibitor [ TOP ]

> Immunostimulator [ TOP ]

> MHC molecule [ TOP ]

Summary
Symbol	RAG1
Name	recombination activating gene 1
Aliases	RNF74; MGC43321; recombination activating protein 1; RING finger protein 74; V(D)J recombination-activating ......
Chromosomal Location	11p13
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Relations between chemokines (or receptors) and expression, copy number, methylation, or mutation of RAG1. 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	RAG1
Name	recombination activating gene 1
Aliases	RNF74; MGC43321; recombination activating protein 1; RING finger protein 74; V(D)J recombination-activating ......
Chromosomal Location	11p13
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Distribution of RAG1 expression across immune and molecular subtypes. > Immune subtype > Molecular subtype

> Immune subtype [ TOP ]

> Molecular subtype [ TOP ]

Summary
Symbol	RAG1
Name	recombination activating gene 1
Aliases	RNF74; MGC43321; recombination activating protein 1; RING finger protein 74; V(D)J recombination-activating ......
Chromosomal Location	11p13
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Associations between RAG1 and clinical features. > Overall survival analysis > Cancer stage > Tumor grade

> Overall survival [ TOP ]

> Stage [ TOP ]

> Grade [ TOP ]

Summary
Symbol	RAG1
Name	recombination activating gene 1
Aliases	RNF74; MGC43321; recombination activating protein 1; RING finger protein 74; V(D)J recombination-activating ......
Chromosomal Location	11p13
External Links	HGNC, NCBI, Ensembl, Uniprot, GeneCards
Content	Drugs targeting RAG1 collected from DrugBank database.

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

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