Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRHTKG3)

• DOT Name: PAX-interacting protein 1 (PAXIP1)
• Synonyms: PAX transactivation activation domain-interacting protein
• Gene Name: PAXIP1
• Related Disease:
  Alzheimer disease
  Breast cancer
  Neoplasm
  Hepatocellular carcinoma
  Liver cirrhosis
  Advanced cancer
  Breast carcinoma
  Lung cancer
  Lung carcinoma
• UniProt ID: PAXI1_HUMAN
• PDB ID: 3SQD
• Pfam ID: PF00533 ; PF16589 ; PF12738 ; PF16770
• Sequence:
  MSDQAPKVPEEMFREVKYYAVGDIDPQVIQLLKAGKAKEVSYNALASHIISEDGDNPEVG
  EAREVFDLPVVKPSWVILSVQCGTLLPVNGFSPESCQIFFGITACLSQVSSEDRSALWAL
  VTFYGGDCQLTLNKKCTHLIVPEPKGEKYECALKRASIKIVTPDWVLDCVSEKTKKDEAF
  YHPRLIIYEEEEEEEEEEEEVENEEQDSQNEGSTDEKSSPASSQEGSPSGDQQFSPKSNT
  EKSKGELMFDDSSDSSPEKQERNLNWTPAEVPQLAAAKRRLPQGKEPGLINLCANVPPVP
  GNILPPEVRGNLMAAGQNLQSSERSEMIATWSPAVRTLRNITNNADIQQMNRPSNVAHIL
  QTLSAPTKNLEQQVNHSQQGHTNANAVLFSQVKVTPETHMLQQQQQAQQQQQQHPVLHLQ
  PQQIMQLQQQQQQQISQQPYPQQPPHPFSQQQQQQQQAHPHQFSQQQLQFPQQQLHPPQQ
  LHRPQQQLQPFQQQHALQQQFHQLQQHQLQQQQLAQLQQQHSLLQQQQQQQIQQQQLQRM
  HQQQQQQQMQSQTAPHLSQTSQALQHQVPPQQPPQQQQQQQPPPSPQQHQLFGHDPAVEI
  PEEGFLLGCVFAIADYPEQMSDKQLLATWKRIIQAHGGTVDPTFTSRCTHLLCESQVSSA
  YAQAIRERKRCVTAHWLNTVLKKKKMVPPHRALHFPVAFPPGGKPCSQHIISVTGFVDSD
  RDDLKLMAYLAGAKYTGYLCRSNTVLICKEPTGLKYEKAKEWRIPCVNAQWLGDILLGNF
  EALRQIQYSRYTAFSLQDPFAPTQHLVLNLLDAWRVPLKVSAELLMSIRLPPKLKQNEVA
  NVQPSSKRARIEDVPPPTKKLTPELTPFVLFTGFEPVQVQQYIKKLYILGGEVAESAQKC
  THLIASKVTRTVKFLTAISVVKHIVTPEWLEECFRCQKFIDEQNYILRDAEAEVLFSFSL
  EESLKRAHVSPLFKAKYFYITPGICPSLSTMKAIVECAGGKVLSKQPSFRKLMEHKQNSS
  LSEIILISCENDLHLCREYFARGIDVHNAEFVLTGVLTQTLDYESYKFN
• Function: Involved in DNA damage response and in transcriptional regulation through histone methyltransferase (HMT) complexes. Plays a role in early development. In DNA damage response is required for cell survival after ionizing radiation. In vitro shown to be involved in the homologous recombination mechanism for the repair of double-strand breaks (DSBs). Its localization to DNA damage foci requires RNF8 and UBE2N. Recruits TP53BP1 to DNA damage foci and, at least in particular repair processes, effective DNA damage response appears to require the association with TP53BP1 phosphorylated by ATM at 'Ser-25'. Together with TP53BP1 regulates ATM association. Proposed to recruit PAGR1 to sites of DNA damage and the PAGR1:PAXIP1 complex is required for cell survival in response to DNA damage; the function is probably independent of MLL-containing histone methyltransferase (HMT) complexes. However, this function has been questioned. Promotes ubiquitination of PCNA following UV irradiation and may regulate recruitment of polymerase eta and RAD51 to chromatin after DNA damage. Proposed to be involved in transcriptional regulation by linking MLL-containing histone methyltransferase (HMT) complexes to gene promoters by interacting with promoter-bound transcription factors such as PAX2. Associates with gene promoters that are known to be regulated by KMT2D/MLL2. During immunoglobulin class switching in activated B-cells is involved in trimethylation of histone H3 at 'Lys-4' and in transcription initiation of downstream switch regions at the immunoglobulin heavy-chain (Igh) locus; this function appears to involve the recruitment of MLL-containing HMT complexes. Conflictingly, its function in transcriptional regulation during immunoglobulin class switching is reported to be independent of the MLL2/MLL3 complex.
• Reactome Pathway:
  Nonhomologous End-Joining (NHEJ) (R-HSA-5693571)
  Formation of WDR5-containing histone-modifying complexes (R-HSA-9772755)
  Activation of anterior HOX genes in hindbrain development during early embryogenesis (R-HSA-5617472)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[1]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[2]
Neoplasm	DISZKGEW	Strong	Altered Expression	[2]
Hepatocellular carcinoma	DIS0J828	moderate	Biomarker	[3]
Liver cirrhosis	DIS4G1GX	moderate	Altered Expression	[3]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[4]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[5]
Lung cancer	DISCM4YA	Limited	Biomarker	[4]
Lung carcinoma	DISTR26C	Limited	Biomarker	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of PAX-interacting protein 1 (PAXIP1).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of PAX-interacting protein 1 (PAXIP1).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of PAX-interacting protein 1 (PAXIP1).	[8]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of PAX-interacting protein 1 (PAXIP1).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of PAX-interacting protein 1 (PAXIP1).	[10]
Menadione	DMSJDTY	Approved	Menadione affects the expression of PAX-interacting protein 1 (PAXIP1).	[11]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of PAX-interacting protein 1 (PAXIP1).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of PAX-interacting protein 1 (PAXIP1).	[13]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of PAX-interacting protein 1 (PAXIP1).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of PAX-interacting protein 1 (PAXIP1).	[15]

References

• [1] Establishment of TUSMi008-A, an induced pluripotent stem cell (iPSC) line from a 76-year old Alzheimer's disease (AD) patient with PAXIP1 gene mutation.Stem Cell Res. 2019 Apr;36:101391. doi: 10.1016/j.scr.2019.101391. Epub 2019 Jan 26.
• [2] DNA repair genes PAXIP1 and TP53BP1 expression is associated with breast cancer prognosis.Cancer Biol Ther. 2017 Jun 3;18(6):439-449. doi: 10.1080/15384047.2017.1323590. Epub 2017 May 5.
• [3] PTIP promotes recurrence and metastasis of hepatocellular carcinoma by regulating epithelial-mesenchymal transition.Oncotarget. 2017 Mar 22;8(35):58184-58198. doi: 10.18632/oncotarget.16436. eCollection 2017 Aug 29.
• [4] PAXIP1 Potentiates the Combination of WEE1 Inhibitor AZD1775 and Platinum Agents in Lung Cancer.Mol Cancer Ther. 2016 Jul;15(7):1669-81. doi: 10.1158/1535-7163.MCT-15-0182. Epub 2016 May 11.
• [5] Analysis of molecular markers as predictive factors of lymph node involvement in breast carcinoma.Oncol Lett. 2017 Jan;13(1):488-496. doi: 10.3892/ol.2016.5438. Epub 2016 Nov 28.
• [6] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [7] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [10] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [11] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [12] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [13] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [14] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [15] 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.