Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTV131E4)

• DOT Name: V(D)J recombination-activating protein 1 (RAG1)
• Synonyms: RAG-1; RING finger protein 74
• Gene Name: RAG1
• Related Disease:
  Omenn syndrome
  Recombinase activating gene 1 deficiency
  Arteriosclerosis
  Atherosclerosis
  Autoimmune disease
  B-cell acute lymphoblastic leukaemia
  Chronic diarrhoea
  Classic Hodgkin lymphoma
  Colitis
  Colon cancer
  Colon carcinoma
  Common variable immunodeficiency
  Cytomegalovirus infection
  Exfoliative dermatitis
  Hepatitis B virus infection
  High blood pressure
  Hyperinsulinemia
  leukaemia
  Lung carcinoma
  Lymphoma
  Melanoma
  Myelodysplastic syndrome
  Nervous system inflammation
  Non-insulin dependent diabetes
  Pneumonia
  Prostate carcinoma
  Prostate neoplasm
  Pyoderma gangrenosum
  Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive
  Small lymphocytic lymphoma
  Systemic lupus erythematosus
  Acute lymphocytic leukaemia
  Advanced cancer
  Combined immunodeficiency due to partial RAG1 deficiency
  Acute myelogenous leukaemia
  Adult lymphoma
  Asthma
  Childhood acute lymphoblastic leukemia
  Inborn error of immunity
  Neuroblastoma
  Pediatric lymphoma
  Prostate cancer
  Rheumatoid arthritis
  Stroke
• UniProt ID: RAG1_HUMAN
• EC Number: 2.3.2.27; 3.1.-.-
• Pfam ID: PF12940 ; PF12560 ; PF00097 ; PF10426
• Sequence:
  MAASFPPTLGLSSAPDEIQHPHIKFSEWKFKLFRVRSFEKTPEEAQKEKKDSFEGKPSLE
  QSPAVLDKADGQKPVPTQPLLKAHPKFSKKFHDNEKARGKAIHQANLRHLCRICGNSFRA
  DEHNRRYPVHGPVDGKTLGLLRKKEKRATSWPDLIAKVFRIDVKADVDSIHPTEFCHNCW
  SIMHRKFSSAPCEVYFPRNVTMEWHPHTPSCDICNTARRGLKRKSLQPNLQLSKKLKTVL
  DQARQARQHKRRAQARISSKDVMKKIANCSKIHLSTKLLAVDFPEHFVKSISCQICEHIL
  ADPVETNCKHVFCRVCILRCLKVMGSYCPSCRYPCFPTDLESPVKSFLSVLNSLMVKCPA
  KECNEEVSLEKYNHHISSHKESKEIFVHINKGGRPRQHLLSLTRRAQKHRLRELKLQVKA
  FADKEEGGDVKSVCMTLFLLALRARNEHRQADELEAIMQGKGSGLQPAVCLAIRVNTFLS
  CSQYHKMYRTVKAITGRQIFQPLHALRNAEKVLLPGYHHFEWQPPLKNVSSSTDVGIIDG
  LSGLSSSVDDYPVDTIAKRFRYDSALVSALMDMEEDILEGMRSQDLDDYLNGPFTVVVKE
  SCDGMGDVSEKHGSGPVVPEKAVRFSFTIMKITIAHSSQNVKVFEEAKPNSELCCKPLCL
  MLADESDHETLTAILSPLIAEREAMKSSELMLELGGILRTFKFIFRGTGYDEKLVREVEG
  LEASGSVYICTLCDATRLEASQNLVFHSITRSHAENLERYEVWRSNPYHESVEELRDRVK
  GVSAKPFIETVPSIDALHCDIGNAAEFYKIFQLEIGEVYKNPNASKEERKRWQATLDKHL
  RKKMNLKPIMRMNGNFARKLMTKETVDAVCELIPSEERHEALRELMDLYLKMKPVWRSSC
  PAKECPESLCQYSFNSQRFAELLSTKFKYRYEGKITNYFHKTLAHVPEIIERDGSIGAWA
  SEGNESGNKLFRRFRKMNARQSKCYEMEDVLKHHWLYTSKYLQKFMNAHNALKTSGFTMN
  PQASLGDPLGIEDSLESQDSMEF
• 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.
• Tissue Specificity: Maturing lymphoid cells.
• 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

44 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Omenn syndrome	DIS2C887	Definitive	Autosomal recessive	[1]
Recombinase activating gene 1 deficiency	DIS3QXVN	Definitive	Autosomal recessive	[2]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[3]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[3]
Autoimmune disease	DISORMTM	Strong	Genetic Variation	[4]
B-cell acute lymphoblastic leukaemia	DISKLOKC	Strong	Biomarker	[5]
Chronic diarrhoea	DISH3PX3	Strong	Biomarker	[6]
Classic Hodgkin lymphoma	DISV1LU6	Strong	Biomarker	[7]
Colitis	DISAF7DD	Strong	Biomarker	[8]
Colon cancer	DISVC52G	Strong	Biomarker	[9]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[9]
Common variable immunodeficiency	DISHE7JQ	Strong	Genetic Variation	[10]
Cytomegalovirus infection	DISCEMGC	Strong	Genetic Variation	[11]
Exfoliative dermatitis	DISQEWIW	Strong	Genetic Variation	[12]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[13]
High blood pressure	DISY2OHH	Strong	Biomarker	[14]
Hyperinsulinemia	DISIDWT6	Strong	Biomarker	[15]
leukaemia	DISS7D1V	Strong	Biomarker	[16]
Lung carcinoma	DISTR26C	Strong	Biomarker	[17]
Lymphoma	DISN6V4S	Strong	Biomarker	[16]
Melanoma	DIS1RRCY	Strong	Biomarker	[17]
Myelodysplastic syndrome	DISYHNUI	Strong	Genetic Variation	[18]
Nervous system inflammation	DISB3X5A	Strong	Biomarker	[19]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[20]
Pneumonia	DIS8EF3M	Strong	Biomarker	[6]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[15]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[21]
Pyoderma gangrenosum	DIS8QVTT	Strong	Genetic Variation	[6]
Severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive	DIS6GFVU	Strong	Autosomal recessive	[1]
Small lymphocytic lymphoma	DIS30POX	Strong	Altered Expression	[22]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[23]
Acute lymphocytic leukaemia	DISPX75S	moderate	Altered Expression	[24]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[25]
Combined immunodeficiency due to partial RAG1 deficiency	DISH1G6J	Supportive	Autosomal recessive	[26]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[27]
Adult lymphoma	DISK8IZR	Limited	Biomarker	[16]
Asthma	DISW9QNS	Limited	Biomarker	[28]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Limited	Genetic Variation	[29]
Inborn error of immunity	DISNGCMN	Limited	Genetic Variation	[30]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[31]
Pediatric lymphoma	DIS51BK2	Limited	Biomarker	[16]
Prostate cancer	DISF190Y	Limited	Biomarker	[21]
Rheumatoid arthritis	DISTSB4J	Limited	Altered Expression	[32]
Stroke	DISX6UHX	Limited	Biomarker	[33]

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of V(D)J recombination-activating protein 1 (RAG1).	[34]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of V(D)J recombination-activating protein 1 (RAG1).	[40]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of V(D)J recombination-activating protein 1 (RAG1).	[41]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of V(D)J recombination-activating protein 1 (RAG1).	[35]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of V(D)J recombination-activating protein 1 (RAG1).	[36]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of V(D)J recombination-activating protein 1 (RAG1).	[37]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of V(D)J recombination-activating protein 1 (RAG1).	[38]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of V(D)J recombination-activating protein 1 (RAG1).	[39]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of V(D)J recombination-activating protein 1 (RAG1).	[42]

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