Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT38QBD4)

• DOT Name: Fanconi anemia group J protein (BRIP1)
• Synonyms: EC 3.6.4.12; BRCA1-associated C-terminal helicase 1; BRCA1-interacting protein C-terminal helicase 1; BRCA1-interacting protein 1
• Gene Name: BRIP1
• Related Disease:
  Familial ovarian cancer
  Fanconi anemia complementation group J
  Fanconi's anemia
  Hereditary breast carcinoma
  Colorectal adenoma
• UniProt ID: FANCJ_HUMAN
• PDB ID: 1T15; 1T29; 3AL3
• EC Number: 3.6.4.12
• Pfam ID: PF06733 ; PF13307
• Sequence:
  MSSMWSEYTIGGVKIYFPYKAYPSQLAMMNSILRGLNSKQHCLLESPTGSGKSLALLCSA
  LAWQQSLSGKPADEGVSEKAEVQLSCCCACHSKDFTNNDMNQGTSRHFNYPSTPPSERNG
  TSSTCQDSPEKTTLAAKLSAKKQASIYRDENDDFQVEKKRIRPLETTQQIRKRHCFGTEV
  HNLDAKVDSGKTVKLNSPLEKINSFSPQKPPGHCSRCCCSTKQGNSQESSNTIKKDHTGK
  SKIPKIYFGTRTHKQIAQITRELRRTAYSGVPMTILSSRDHTCVHPEVVGNFNRNEKCME
  LLDGKNGKSCYFYHGVHKISDQHTLQTFQGMCKAWDIEELVSLGKKLKACPYYTARELIQ
  DADIIFCPYNYLLDAQIRESMDLNLKEQVVILDEAHNIEDCARESASYSVTEVQLRFARD
  ELDSMVNNNIRKKDHEPLRAVCCSLINWLEANAEYLVERDYESACKIWSGNEMLLTLHKM
  GITTATFPILQGHFSAVLQKEEKISPIYGKEEAREVPVISASTQIMLKGLFMVLDYLFRQ
  NSRFADDYKIAIQQTYSWTNQIDISDKNGLLVLPKNKKRSRQKTAVHVLNFWCLNPAVAF
  SDINGKVQTIVLTSGTLSPMKSFSSELGVTFTIQLEANHIIKNSQVWVGTIGSGPKGRNL
  CATFQNTETFEFQDEVGALLLSVCQTVSQGILCFLPSYKLLEKLKERWLSTGLWHNLELV
  KTVIVEPQGGEKTNFDELLQVYYDAIKYKGEKDGALLVAVCRGKVSEGLDFSDDNARAVI
  TIGIPFPNVKDLQVELKRQYNDHHSKLRGLLPGRQWYEIQAYRALNQALGRCIRHRNDWG
  ALILVDDRFRNNPSRYISGLSKWVRQQIQHHSTFESALESLAEFSKKHQKVLNVSIKDRT
  NIQDNESTLEVTSLKYSTSPYLLEAASHLSPENFVEDEAKICVQELQCPKIITKNSPLPS
  SIISRKEKNDPVFLEEAGKAEKIVISRSTSPTFNKQTKRVSWSSFNSLGQYFTGKIPKAT
  PELGSSENSASSPPRFKTEKMESKTVLPFTDKCESSNLTVNTSFGSCPQSETIISSLKID
  ATLTRKNHSEHPLCSEEALDPDIELSLVSEEDKQSTSNRDFETEAEDESIYFTPELYDPE
  DTDEEKNDLAETDRGNRLANNSDCILAKDLFEIRTIKEVDSAREVKAEDCIDTKLNGILH
  IEESKIDDIDGNVKTTWINELELGKTHEIEIKNFKPSPSKNKGMFPGFK
• Function: DNA-dependent helicase and 5' to 3' DNA helicase required for the maintenance of chromosomal stability. Acts late in the Fanconi anemia pathway, after FANCD2 ubiquitination. Involved in the repair of DNA double-strand breaks by homologous recombination in a manner that depends on its association with BRCA1. Involved in the repair of abasic sites at replication forks by promoting the degradation of DNA-protein cross-links: acts by catalyzing unfolding of HMCES DNA-protein cross-link via its helicase activity, exposing the underlying DNA and enabling cleavage of the DNA-protein adduct by the SPRTN metalloprotease.
• Tissue Specificity: Ubiquitously expressed, with highest levels in testis.
• KEGG Pathway:
  Homologous recombi.tion (hsa03440)
  Fanconi anemia pathway (hsa03460)
• Reactome Pathway:
  HDR through Single Strand Annealing (SSA) (R-HSA-5685938)
  HDR through Homologous Recombination (HRR) (R-HSA-5685942)
  Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA) (R-HSA-5693554)
  Resolution of D-loop Structures through Holliday Junction Intermediates (R-HSA-5693568)
  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)
  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)
  Cytosolic iron-sulfur cluster assembly (R-HSA-2564830)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Familial ovarian cancer	DISGLR2C	Definitive	Autosomal dominant	[1]
Fanconi anemia complementation group J	DISWACKN	Definitive	Autosomal recessive	[1]
Fanconi's anemia	DISGW6Q8	Definitive	Autosomal recessive	[2]
Hereditary breast carcinoma	DISAEZT5	Strong	Autosomal dominant	[3]
Colorectal adenoma	DISTSVHM	Moderate	Autosomal dominant	[4]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Fanconi anemia group J protein (BRIP1) decreases the response to substance of Cisplatin.	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Fanconi anemia group J protein (BRIP1).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Fanconi anemia group J protein (BRIP1).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Fanconi anemia group J protein (BRIP1).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Fanconi anemia group J protein (BRIP1).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Fanconi anemia group J protein (BRIP1).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Fanconi anemia group J protein (BRIP1).	[10]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Fanconi anemia group J protein (BRIP1).	[11]
Arsenic	DMTL2Y1	Approved	Arsenic increases the mutagenesis of Fanconi anemia group J protein (BRIP1).	[12]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Fanconi anemia group J protein (BRIP1).	[13]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Fanconi anemia group J protein (BRIP1).	[13]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Fanconi anemia group J protein (BRIP1).	[14]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Fanconi anemia group J protein (BRIP1).	[15]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Fanconi anemia group J protein (BRIP1).	[16]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Fanconi anemia group J protein (BRIP1).	[17]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Fanconi anemia group J protein (BRIP1).	[18]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Fanconi anemia group J protein (BRIP1).	[14]
PEITC	DMOMN31	Phase 2	PEITC decreases the expression of Fanconi anemia group J protein (BRIP1).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Fanconi anemia group J protein (BRIP1).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Fanconi anemia group J protein (BRIP1).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Fanconi anemia group J protein (BRIP1).	[24]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of Fanconi anemia group J protein (BRIP1).	[25]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Fanconi anemia group J protein (BRIP1).	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Fanconi anemia group J protein (BRIP1).	[21]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Fanconi anemia group J protein (BRIP1).	[23]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Fanconi anemia group J protein (BRIP1).	[23]

References

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• [2] The DNA helicase BRIP1 is defective in Fanconi anemia complementation group J. Nat Genet. 2005 Sep;37(9):934-5. doi: 10.1038/ng1625. Epub 2005 Aug 21.
• [3] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
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• [21] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
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• [23] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [24] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [25] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.
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• [27] KIAA1018/FAN1 nuclease protects cells against genomic instability induced by interstrand cross-linking agents. Proc Natl Acad Sci U S A. 2010 Dec 14;107(50):21553-7. doi: 10.1073/pnas.1011081107. Epub 2010 Nov 29.