Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTL8879S)

• DOT Name: TP53-binding protein 1 (TP53BP1)
• Synonyms: 53BP1; p53-binding protein 1; p53BP1
• Gene Name: TP53BP1
• UniProt ID: TP53B_HUMAN
• PDB ID: 1GZH ; 1KZY ; 1XNI ; 2G3R ; 2IG0 ; 2LVM ; 2MWO ; 2MWP ; 3LGF ; 3LGL ; 3LH0 ; 4CRI ; 4RG2 ; 4X34 ; 5ECG ; 5J26 ; 5KGF ; 5Z78 ; 5ZCJ ; 6CO1 ; 6CO2 ; 6IU7 ; 6IUA ; 6MXX ; 6MXY ; 6MXZ ; 6MY0 ; 6RML ; 6RMM ; 6UPT ; 6VA5 ; 6VIP ; 7LIN ; 7LIO ; 7YQK ; 8EOM ; 8F0W ; 8HKW ; 8SWJ ; 8U4U
• Pfam ID: PF09038 ; PF18428
• Sequence:
  MDPTGSQLDSDFSQQDTPCLIIEDSQPESQVLEDDSGSHFSMLSRHLPNLQTHKENPVLD
  VVSNPEQTAGEERGDGNSGFNEHLKENKVADPVDSSNLDTCGSISQVIEQLPQPNRTSSV
  LGMSVESAPAVEEEKGEELEQKEKEKEEDTSGNTTHSLGAEDTASSQLGFGVLELSQSQD
  VEENTVPYEVDKEQLQSVTTNSGYTRLSDVDANTAIKHEEQSNEDIPIAEQSSKDIPVTA
  QPSKDVHVVKEQNPPPARSEDMPFSPKASVAAMEAKEQLSAQELMESGLQIQKSPEPEVL
  STQEDLFDQSNKTVSSDGCSTPSREEGGCSLASTPATTLHLLQLSGQRSLVQDSLSTNSS
  DLVAPSPDAFRSTPFIVPSSPTEQEGRQDKPMDTSVLSEEGGEPFQKKLQSGEPVELENP
  PLLPESTVSPQASTPISQSTPVFPPGSLPIPSQPQFSHDIFIPSPSLEEQSNDGKKDGDM
  HSSSLTVECSKTSEIEPKNSPEDLGLSLTGDSCKLMLSTSEYSQSPKMESLSSHRIDEDG
  ENTQIEDTEPMSPVLNSKFVPAENDSILMNPAQDGEVQLSQNDDKTKGDDTDTRDDISIL
  ATGCKGREETVAEDVCIDLTCDSGSQAVPSPATRSEALSSVLDQEEAMEIKEHHPEEGSS
  GSEVEEIPETPCESQGEELKEENMESVPLHLSLTETQSQGLCLQKEMPKKECSEAMEVET
  SVISIDSPQKLAILDQELEHKEQEAWEEATSEDSSVVIVDVKEPSPRVDVSCEPLEGVEK
  CSDSQSWEDIAPEIEPCAENRLDTKEEKSVEYEGDLKSGTAETEPVEQDSSQPSLPLVRA
  DDPLRLDQELQQPQTQEKTSNSLTEDSKMANAKQLSSDAEAQKLGKPSAHASQSFCESSS
  ETPFHFTLPKEGDIIPPLTGATPPLIGHLKLEPKRHSTPIGISNYPESTIATSDVMSESM
  VETHDPILGSGKGDSGAAPDVDDKLCLRMKLVSPETEASEESLQFNLEKPATGERKNGST
  AVAESVASPQKTMSVLSCICEARQENEARSEDPPTTPIRGNLLHFPSSQGEEEKEKLEGD
  HTIRQSQQPMKPISPVKDPVSPASQKMVIQGPSSPQGEAMVTDVLEDQKEGRSTNKENPS
  KALIERPSQNNIGIQTMECSLRVPETVSAATQTIKNVCEQGTSTVDQNFGKQDATVQTER
  GSGEKPVSAPGDDTESLHSQGEEEFDMPQPPHGHVLHRHMRTIREVRTLVTRVITDVYYV
  DGTEVERKVTEETEEPIVECQECETEVSPSQTGGSSGDLGDISSFSSKASSLHRTSSGTS
  LSAMHSSGSSGKGAGPLRGKTSGTEPADFALPSSRGGPGKLSPRKGVSQTGTPVCEEDGD
  AGLGIRQGGKAPVTPRGRGRRGRPPSRTTGTRETAVPGPLGIEDISPNLSPDDKSFSRVV
  PRVPDSTRRTDVGAGALRRSDSPEIPFQAAAGPSDGLDASSPGNSFVGLRVVAKWSSNGY
  FYSGKITRDVGAGKYKLLFDDGYECDVLGKDILLCDPIPLDTEVTALSEDEYFSAGVVKG
  HRKESGELYYSIEKEGQRKWYKRMAVILSLEQGNRLREQYGLGPYEAVTPLTKAADISLD
  NLVEGKRKRRSNVSSPATPTASSSSSTTPTRKITESPRASMGVLSGKRKLITSEEERSPA
  KRGRKSATVKPGAVGAGEFVSPCESGDNTGEPSALEEQRGPLPLNKTLFLGYAFLLTMAT
  TSDKLASRSKLPDGPTGSSEEEEEFLEIPPFNKQYTESQLRAGAGYILEDFNEAQCNTAY
  QCLLIADQHCRTRKYFLCLASGIPCVSHVWVHDSCHANQLQNYRNYLLPAGYSLEEQRIL
  DWQPRENPFQNLKVLLVSDQQQNFLELWSEILMTGGAASVKQHHSSAHNKDIALGVFDVV
  VTDPSCPASVLKCAEALQLPVVSQEWVIQCLIVGERIGFKQHPKYKHDYVSH
• Function: Double-strand break (DSB) repair protein involved in response to DNA damage, telomere dynamics and class-switch recombination (CSR) during antibody genesis. Plays a key role in the repair of double-strand DNA breaks (DSBs) in response to DNA damage by promoting non-homologous end joining (NHEJ)-mediated repair of DSBs and specifically counteracting the function of the homologous recombination (HR) repair protein BRCA1. In response to DSBs, phosphorylation by ATM promotes interaction with RIF1 and dissociation from NUDT16L1/TIRR, leading to recruitment to DSBs sites. Recruited to DSBs sites by recognizing and binding histone H2A monoubiquitinated at 'Lys-15' (H2AK15Ub) and histone H4 dimethylated at 'Lys-20' (H4K20me2), two histone marks that are present at DSBs sites. Required for immunoglobulin class-switch recombination (CSR) during antibody genesis, a process that involves the generation of DNA DSBs. Participates in the repair and the orientation of the broken DNA ends during CSR. In contrast, it is not required for classic NHEJ and V(D)J recombination. Promotes NHEJ of dysfunctional telomeres via interaction with PAXIP1.
• KEGG Pathway: NOD-like receptor sig.ling pathway (hsa04621)
• Reactome Pathway:
  Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks (R-HSA-5693565)
  Nonhomologous End-Joining (NHEJ) (R-HSA-5693571)
  Processing of DNA double-strand break ends (R-HSA-5693607)
  G2/M DNA damage checkpoint (R-HSA-69473)
  SUMOylation of transcription factors (R-HSA-3232118)

Molecular Interaction Atlas (MIA) of This DOT

17 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 TP53-binding protein 1 (TP53BP1).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of TP53-binding protein 1 (TP53BP1).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of TP53-binding protein 1 (TP53BP1).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of TP53-binding protein 1 (TP53BP1).	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of TP53-binding protein 1 (TP53BP1).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of TP53-binding protein 1 (TP53BP1).	[6]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of TP53-binding protein 1 (TP53BP1).	[7]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of TP53-binding protein 1 (TP53BP1).	[9]
Etoposide	DMNH3PG	Approved	Etoposide increases the expression of TP53-binding protein 1 (TP53BP1).	[10]
Gemcitabine	DMSE3I7	Approved	Gemcitabine increases the expression of TP53-binding protein 1 (TP53BP1).	[11]
Fenretinide	DMRD5SP	Phase 3	Fenretinide increases the expression of TP53-binding protein 1 (TP53BP1).	[12]
Itarnafloxin	DMCY9PO	Phase 2	Itarnafloxin increases the expression of TP53-binding protein 1 (TP53BP1).	[13]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of TP53-binding protein 1 (TP53BP1).	[16]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of TP53-binding protein 1 (TP53BP1).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of TP53-binding protein 1 (TP53BP1).	[1]
BRN-3548355	DM4KXT0	Investigative	BRN-3548355 increases the expression of TP53-binding protein 1 (TP53BP1).	[20]
OXYBENZONE	DMMZYX6	Investigative	OXYBENZONE increases the expression of TP53-binding protein 1 (TP53BP1).	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Quercetin	DM3NC4M	Approved	Quercetin increases the phosphorylation of TP53-binding protein 1 (TP53BP1).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of TP53-binding protein 1 (TP53BP1).	[14]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of TP53-binding protein 1 (TP53BP1).	[15]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of TP53-binding protein 1 (TP53BP1).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of TP53-binding protein 1 (TP53BP1).	[18]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of TP53-binding protein 1 (TP53BP1).	[8]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid affects the phosphorylation of TP53-binding protein 1 (TP53BP1).	[19]

References

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• [11] Gene expression profiling of breast cancer cells in response to gemcitabine: NF-kappaB pathway activation as a potential mechanism of resistance. Breast Cancer Res Treat. 2007 Apr;102(2):157-72.
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• [13] CX-5461 is a DNA G-quadruplex stabilizer with selective lethality in BRCA1/2 deficient tumours. Nat Commun. 2017 Feb 17;8:14432. doi: 10.1038/ncomms14432.
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• [15] 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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• [18] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [19] Functional lipidomics: Palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism. Hepatology. 2017 Aug;66(2):432-448. doi: 10.1002/hep.29033. Epub 2017 Jun 16.
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