Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTG9UYTW)

• DOT Name: V(D)J recombination-activating protein 2 (RAG2)
• Synonyms: RAG-2
• Gene Name: RAG2
• Related Disease:
  Recombinase activating gene 2 deficiency
  Acute lymphocytic leukaemia
  Adult lymphoma
  Advanced cancer
  Amyotrophic lateral sclerosis
  Arteriosclerosis
  Atherosclerosis
  Autoimmune disease
  Autoimmune haemolytic anaemia
  Breast carcinoma
  Classic Hodgkin lymphoma
  Clear cell renal carcinoma
  Colon carcinoma
  Epstein barr virus infection
  Graft-versus-host disease
  Hepatitis B virus infection
  HIV infectious disease
  Immunodeficiency
  Intellectual disability
  Leukemia
  Lymphoma
  Melanoma
  Metastatic malignant neoplasm
  Neoplasm
  Non-alcoholic fatty liver disease
  Non-alcoholic steatohepatitis
  Non-small-cell lung cancer
  Omenn syndrome
  Pancreatic cancer
  Pediatric lymphoma
  Plasma cell myeloma
  Renal cell carcinoma
  Rhabdomyosarcoma
  Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive
  Systemic lupus erythematosus
  Systemic sclerosis
  T-cell acute lymphoblastic leukaemia
  T-cell leukaemia
  Ulcerative colitis
  Colitis
  leukaemia
  Prostate cancer
  Prostate carcinoma
  Arthritis
  Breast cancer
  Inborn error of immunity
  Inflammatory bowel disease
  Rheumatoid arthritis
  Type-1 diabetes
  Type-1/2 diabetes
• UniProt ID: RAG2_HUMAN
• Pfam ID: PF03089 ; PF13341
• Sequence:
  MSLQMVTVSNNIALIQPGFSLMNFDGQVFFFGQKGWPKRSCPTGVFHLDVKHNHVKLKPT
  IFSKDSCYLPPLRYPATCTFKGSLESEKHQYIIHGGKTPNNEVSDKIYVMSIVCKNNKKV
  TFRCTEKDLVGDVPEARYGHSINVVYSRGKSMGVLFGGRSYMPSTHRTTEKWNSVADCLP
  CVFLVDFEFGCATSYILPELQDGLSFHVSIAKNDTIYILGGHSLANNIRPANLYRIRVDL
  PLGSPAVNCTVLPGGISVSSAILTQTNNDEFVIVGGYQLENQKRMICNIISLEDNKIEIR
  EMETPDWTPDIKHSKIWFGSNMGNGTVFLGIPGDNKQVVSEGFYFYMLKCAEDDTNEEQT
  TFTNSQTSTEDPGDSTPFEDSEEFCFSAEANSFDGDDEFDTYNEDDEEDESETGYWITCC
  PTCDVDINTWVPFYSTELNKPAMIYCSHGDGHWVHAQCMDLAERTLIHLSAGSNKYYCNE
  HVEIARALHTPQRVLPLKKPPMKSLRKKGSGKILTPAKKSFLRRLFD
• 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.
• Tissue Specificity: Cells of the B- and T-lymphocyte lineages.
• KEGG Pathway:
  FoxO sig.ling pathway (hsa04068)
  Primary immunodeficiency (hsa05340)
• Reactome Pathway:
  MAPK6/MAPK4 signaling (R-HSA-5687128)
  Interleukin-7 signaling (R-HSA-1266695)

Molecular Interaction Atlas (MIA) of This DOT

50 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Recombinase activating gene 2 deficiency	DISB4ZLM	Definitive	Autosomal recessive	[1]
Acute lymphocytic leukaemia	DISPX75S	Strong	Altered Expression	[2]
Adult lymphoma	DISK8IZR	Strong	Biomarker	[3]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[4]
Amyotrophic lateral sclerosis	DISF7HVM	Strong	Biomarker	[5]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[6]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[6]
Autoimmune disease	DISORMTM	Strong	Genetic Variation	[7]
Autoimmune haemolytic anaemia	DIS7MS3M	Strong	Genetic Variation	[8]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[9]
Classic Hodgkin lymphoma	DISV1LU6	Strong	Biomarker	[10]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[11]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[12]
Epstein barr virus infection	DISOO0WT	Strong	Genetic Variation	[13]
Graft-versus-host disease	DIS0QADF	Strong	Biomarker	[14]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[15]
HIV infectious disease	DISO97HC	Strong	Biomarker	[16]
Immunodeficiency	DIS093I0	Strong	Biomarker	[17]
Intellectual disability	DISMBNXP	Strong	Biomarker	[18]
Leukemia	DISNAKFL	Strong	Biomarker	[19]
Lymphoma	DISN6V4S	Strong	Biomarker	[3]
Melanoma	DIS1RRCY	Strong	Biomarker	[20]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[21]
Neoplasm	DISZKGEW	Strong	Biomarker	[22]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Biomarker	[23]
Non-alcoholic steatohepatitis	DIST4788	Strong	Biomarker	[23]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[24]
Omenn syndrome	DIS2C887	Strong	Autosomal recessive	[25]
Pancreatic cancer	DISJC981	Strong	Biomarker	[26]
Pediatric lymphoma	DIS51BK2	Strong	Biomarker	[3]
Plasma cell myeloma	DIS0DFZ0	Strong	Biomarker	[27]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[11]
Rhabdomyosarcoma	DISNR7MS	Strong	Altered Expression	[28]
Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	DIS6GFVU	Strong	Autosomal recessive	[29]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[30]
Systemic sclerosis	DISF44L6	Strong	Biomarker	[31]
T-cell acute lymphoblastic leukaemia	DIS17AI2	Strong	Biomarker	[32]
T-cell leukaemia	DISJ6YIF	Strong	Biomarker	[33]
Ulcerative colitis	DIS8K27O	Strong	Biomarker	[34]
Colitis	DISAF7DD	moderate	Biomarker	[35]
leukaemia	DISS7D1V	moderate	Biomarker	[19]
Prostate cancer	DISF190Y	moderate	Biomarker	[36]
Prostate carcinoma	DISMJPLE	moderate	Biomarker	[36]
Arthritis	DIST1YEL	Limited	Biomarker	[37]
Breast cancer	DIS7DPX1	Limited	Biomarker	[9]
Inborn error of immunity	DISNGCMN	Limited	Genetic Variation	[38]
Inflammatory bowel disease	DISGN23E	Limited	Biomarker	[39]
Rheumatoid arthritis	DISTSB4J	Limited	Altered Expression	[40]
Type-1 diabetes	DIS7HLUB	Limited	Biomarker	[41]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[42]

1 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of V(D)J recombination-activating protein 2 (RAG2).	[43]

References

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