Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT73B5MD)

• DOT Name: Nibrin (NBN)
• Synonyms: Cell cycle regulatory protein p95; Nijmegen breakage syndrome protein 1
• Gene Name: NBN
• Related Disease:
  Chromosomal disorder
  Nijmegen breakage syndrome
  Acute leukaemia
  Acute lymphocytic leukaemia
  Aplastic anemia
  Ataxia-telangiectasia
  Bladder cancer
  Cardiovascular disease
  Childhood acute lymphoblastic leukemia
  Fanconi anemia complementation group A
  Fanconi's anemia
  Gastric cancer
  Glioma
  Hepatocellular carcinoma
  Hereditary breast ovarian cancer syndrome
  Leukemia
  Lymphoma
  Lymphoma, non-Hodgkin, familial
  Medulloblastoma
  Non-small-cell lung cancer
  Oral mucositis
  Prostate carcinoma
  Renal cell carcinoma
  Squamous cell carcinoma
  Stomach cancer
  Urinary bladder cancer
  Urinary bladder neoplasm
  Breast neoplasm
  Colorectal carcinoma
  Familial prostate carcinoma
  Glioblastoma multiforme
  Isolated congenital microcephaly
  Rhabdomyosarcoma
  Adult glioblastoma
  Endometrial carcinoma
  Hereditary neoplastic syndrome
  Acute myelogenous leukaemia
  Head and neck cancer
  Head and neck carcinoma
  Head-neck squamous cell carcinoma
  Idiopathic aplastic anemia
  Intellectual disability-sparse hair-brachydactyly syndrome
  Laryngeal carcinoma
  leukaemia
  Lung cancer
  Lung carcinoma
  Pancreatic cancer
  Prostate cancer
  Prostate neoplasm
  T-cell lymphoma
  Hereditary breast carcinoma
• UniProt ID: NBN_HUMAN
• PDB ID: 5WQD; 7SID; 8BAH
• Pfam ID: PF00533 ; PF00498 ; PF08599 ; PF16508
• Sequence:
  MWKLLPAAGPAGGEPYRLLTGVEYVVGRKNCAILIENDQSISRNHAVLTANFSVTNLSQT
  DEIPVLTLKDNSKYGTFVNEEKMQNGFSRTLKSGDGITFGVFGSKFRIEYEPLVACSSCL
  DVSGKTALNQAILQLGGFTVNNWTEECTHLVMVSVKVTIKTICALICGRPIVKPEYFTEF
  LKAVESKKQPPQIESFYPPLDEPSIGSKNVDLSGRQERKQIFKGKTFIFLNAKQHKKLSS
  AVVFGGGEARLITEENEEEHNFFLAPGTCVVDTGITNSQTLIPDCQKKWIQSIMDMLQRQ
  GLRPIPEAEIGLAVIFMTTKNYCDPQGHPSTGLKTTTPGPSLSQGVSVDEKLMPSAPVNT
  TTYVADTESEQADTWDLSERPKEIKVSKMEQKFRMLSQDAPTVKESCKTSSNNNSMVSNT
  LAKMRIPNYQLSPTKLPSINKSKDRASQQQQTNSIRNYFQPSTKKRERDEENQEMSSCKS
  ARIETSCSLLEQTQPATPSLWKNKEQHLSENEPVDTNSDNNLFTDTDLKSIVKNSASKSH
  AAEKLRSNKKREMDDVAIEDEVLEQLFKDTKPELEIDVKVQKQEEDVNVRKRPRMDIETN
  DTFSDEAVPESSKISQENEIGKKRELKEDSLWSAKEISNNDKLQDDSEMLPKKLLLTEFR
  SLVIKNSTSRNPSGINDDYGQLKNFKKFKKVTYPGAGKLPHIIGGSDLIAHHARKNTELE
  EWLRQEMEVQNQHAKEESLADDLFRYNPYLKRRR
• Function: Component of the MRE11-RAD50-NBN (MRN complex) which plays a critical role in the cellular response to DNA damage and the maintenance of chromosome integrity. The complex is involved in double-strand break (DSB) repair, DNA recombination, maintenance of telomere integrity, cell cycle checkpoint control and meiosis. The complex possesses single-strand endonuclease activity and double-strand-specific 3'-5' exonuclease activity, which are provided by MRE11. RAD50 may be required to bind DNA ends and hold them in close proximity. NBN modulate the DNA damage signal sensing by recruiting PI3/PI4-kinase family members ATM, ATR, and probably DNA-PKcs to the DNA damage sites and activating their functions. It can also recruit MRE11 and RAD50 to the proximity of DSBs by an interaction with the histone H2AX. NBN also functions in telomere length maintenance by generating the 3' overhang which serves as a primer for telomerase dependent telomere elongation. NBN is a major player in the control of intra-S-phase checkpoint and there is some evidence that NBN is involved in G1 and G2 checkpoints. The roles of NBS1/MRN encompass DNA damage sensor, signal transducer, and effector, which enable cells to maintain DNA integrity and genomic stability. Forms a complex with RBBP8 to link DNA double-strand break sensing to resection. Enhances AKT1 phosphorylation possibly by association with the mTORC2 complex.
• Tissue Specificity: Ubiquitous . Expressed at high levels in testis .
• KEGG Pathway:
  Homologous recombi.tion (hsa03440)
  Cellular senescence (hsa04218)
• Reactome Pathway:
  HDR through Single Strand Annealing (SSA) (R-HSA-5685938)
  HDR through MMEJ (alt-NHEJ) (R-HSA-5685939)
  HDR through Homologous Recombination (HRR) (R-HSA-5685942)
  Sensing of DNA Double Strand Breaks (R-HSA-5693548)
  Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA) (R-HSA-5693554)
  Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks (R-HSA-5693565)
  Resolution of D-loop Structures through Holliday Junction Intermediates (R-HSA-5693568)
  Nonhomologous End-Joining (NHEJ) (R-HSA-5693571)
  Homologous DNA Pairing and Strand Exchange (R-HSA-5693579)
  Processing of DNA double-strand break ends (R-HSA-5693607)
  Presynaptic phase of homologous DNA pairing and strand exchange (R-HSA-5693616)
  Regulation of TP53 Activity through Phosphorylation (R-HSA-6804756)
  G2/M DNA damage checkpoint (R-HSA-69473)
  Meiotic recombination (R-HSA-912446)
  Defective homologous recombination repair (HRR) due to BRCA1 loss of function (R-HSA-9701192)
  Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function (R-HSA-9704331)
  Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function (R-HSA-9704646)
  Impaired BRCA2 binding to RAD51 (R-HSA-9709570)
  Impaired BRCA2 binding to PALB2 (R-HSA-9709603)
  DNA Damage/Telomere Stress Induced Senescence (R-HSA-2559586)

Molecular Interaction Atlas (MIA) of This DOT

51 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Chromosomal disorder	DISM5BB5	Definitive	Genetic Variation	[1]
Nijmegen breakage syndrome	DIS98HVL	Definitive	Autosomal recessive	[2]
Acute leukaemia	DISDQFDI	Strong	Genetic Variation	[3]
Acute lymphocytic leukaemia	DISPX75S	Strong	Genetic Variation	[4]
Aplastic anemia	DISJRSC0	Strong	Genetic Variation	[1]
Ataxia-telangiectasia	DISP3EVR	Strong	Biomarker	[5]
Bladder cancer	DISUHNM0	Strong	Genetic Variation	[6]
Cardiovascular disease	DIS2IQDX	Strong	Biomarker	[7]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Biomarker	[8]
Fanconi anemia complementation group A	DIS8PZLI	Strong	Biomarker	[9]
Fanconi's anemia	DISGW6Q8	Strong	Biomarker	[9]
Gastric cancer	DISXGOUK	Strong	Genetic Variation	[10]
Glioma	DIS5RPEH	Strong	Biomarker	[11]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[12]
Hereditary breast ovarian cancer syndrome	DISWDUGU	Strong	Genetic Variation	[13]
Leukemia	DISNAKFL	Strong	Biomarker	[14]
Lymphoma	DISN6V4S	Strong	Biomarker	[15]
Lymphoma, non-Hodgkin, familial	DISCXYIZ	Strong	Genetic Variation	[16]
Medulloblastoma	DISZD2ZL	Strong	Biomarker	[17]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Genetic Variation	[18]
Oral mucositis	DISS93V5	Strong	Genetic Variation	[19]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[20]
Renal cell carcinoma	DISQZ2X8	Strong	Genetic Variation	[21]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[22]
Stomach cancer	DISKIJSX	Strong	Genetic Variation	[10]
Urinary bladder cancer	DISDV4T7	Strong	Genetic Variation	[6]
Urinary bladder neoplasm	DIS7HACE	Strong	Genetic Variation	[6]
Breast neoplasm	DISNGJLM	moderate	Altered Expression	[23]
Colorectal carcinoma	DIS5PYL0	moderate	Genetic Variation	[24]
Familial prostate carcinoma	DISL9KNO	moderate	SusceptibilityMutation	[25]
Glioblastoma multiforme	DISK8246	moderate	Biomarker	[26]
Isolated congenital microcephaly	DISUXHZ6	moderate	Genetic Variation	[27]
Rhabdomyosarcoma	DISNR7MS	Moderate	Autosomal recessive	[28]
Adult glioblastoma	DISVP4LU	Disputed	Biomarker	[26]
Endometrial carcinoma	DISXR5CY	Disputed	Genetic Variation	[29]
Hereditary neoplastic syndrome	DISGXLG5	Disputed	CausalMutation	[30]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[31]
Head and neck cancer	DISBPSQZ	Limited	Genetic Variation	[32]
Head and neck carcinoma	DISOU1DS	Limited	Genetic Variation	[32]
Head-neck squamous cell carcinoma	DISF7P24	Limited	Biomarker	[33]
Idiopathic aplastic anemia	DISVFTJ9	Limited	Autosomal dominant	[34]
Intellectual disability-sparse hair-brachydactyly syndrome	DISEB2FS	Limited	Altered Expression	[35]
Laryngeal carcinoma	DISNHCIV	Limited	Genetic Variation	[36]
leukaemia	DISS7D1V	Limited	Biomarker	[14]
Lung cancer	DISCM4YA	Limited	Genetic Variation	[37]
Lung carcinoma	DISTR26C	Limited	Genetic Variation	[37]
Pancreatic cancer	DISJC981	Limited	Genetic Variation	[38]
Prostate cancer	DISF190Y	Limited	Autosomal dominant	[39]
Prostate neoplasm	DISHDKGQ	Limited	Biomarker	[40]
T-cell lymphoma	DISSXRTQ	Limited	Genetic Variation	[41]
Hereditary breast carcinoma	DISAEZT5	Refuted	Autosomal dominant	[2]

5 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 Nibrin (NBN).	[42]
Marinol	DM70IK5	Approved	Marinol increases the glycosylation of Nibrin (NBN).	[54]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Nibrin (NBN).	[60]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Nibrin (NBN).	[61]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid decreases the phosphorylation of Nibrin (NBN).	[64]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Nibrin (NBN).	[43]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Nibrin (NBN).	[44]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Nibrin (NBN).	[45]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Nibrin (NBN).	[46]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Nibrin (NBN).	[47]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Nibrin (NBN).	[48]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Nibrin (NBN).	[49]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Nibrin (NBN).	[50]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Nibrin (NBN).	[51]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Nibrin (NBN).	[52]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Nibrin (NBN).	[55]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Nibrin (NBN).	[52]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Nibrin (NBN).	[57]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Nibrin (NBN).	[58]
Delphinidin	DMS2WIN	Phase 2	Delphinidin increases the expression of Nibrin (NBN).	[59]
Celastrol	DMWQIJX	Preclinical	Celastrol decreases the expression of Nibrin (NBN).	[62]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Nibrin (NBN).	[63]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of Nibrin (NBN).	[65]
OXYBENZONE	DMMZYX6	Investigative	OXYBENZONE increases the expression of Nibrin (NBN).	[48]

2 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Decitabine	DMQL8XJ	Approved	Decitabine affects the localization of Nibrin (NBN).	[53]
Pentamidine	DMHZJCG	Approved	Pentamidine affects the localization of Nibrin (NBN).	[56]

References

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