Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXQVL4U)

• DOT Name: PWWP domain-containing DNA repair factor 3A (PWWP3A)
• Synonyms: PWWP3A; Mutated melanoma-associated antigen 1; MUM-1; PWWP domain-containing protein MUM1; Protein expandere
• Gene Name: PWWP3A
• Related Disease:
  Adult lymphoma
  Adult T-cell leukemia/lymphoma
  Advanced cancer
  Anaplastic large cell lymphoma
  Burkitt lymphoma
  Central nervous system lymphoma
  Gonorrhea
  Lymphoma
  Mycosis fungoides
  Neoplasm
  Non-alcoholic fatty liver disease
  Pediatric lymphoma
  Plasma cell myeloma
  Primary cutaneous peripheral T-cell lymphoma not otherwise specified
  T-cell lymphoma
  Epstein barr virus infection
  MALT lymphoma
  AIDS-related lymphoma
  Angioimmunoblastic T-cell Lymphoma
  Kaposi sarcoma
  Lymphoproliferative syndrome
  Small lymphocytic lymphoma
• UniProt ID: PWP3A_HUMAN
• PDB ID: 3PMI
• Pfam ID: PF20884 ; PF20886 ; PF20887
• Sequence:
  MADAKYVLCRWEKRLWPAKVLARTATSTKNKRRKEYFLAVQILSLEEKIKVKSTEVEILE
  KSQIEAIASSLASQNEVPAAPLEELAYRRSLRVALDVLSEGSIWSQESSAGTGRADRSLR
  GKPMEHVSSPCDSNSSSLPRGDVLGSSRPHRRRPCVQQSLSSSFTCEKDPECKVDHKKGL
  RKSENPRGPLVLPAGGGAQDESGSRIHHKNWTLASKRGGNSAQKASLCLNGSSLSEDDTE
  RDMGSKGGSWAAPSLPSGVREDDPCANAEGHDPGLPLGSLTAPPAPEPSACSEPGECPAK
  KRPRLDGSQRPPAVQLEPMAAGAAPSPGPGPGPRESVTPRSTARLGPPPSHASADATRCL
  PCPDSQKLEKECQSSEESMGSNSMRSILEEDEEDEEPPRVLLYHEPRSFEVGMLVWHKHK
  KYPFWPAVVKSVRQRDKKASVLYIEGHMNPKMKGFTVSLKSLKHFDCKEKQTLLNQARED
  FNQDIGWCVSLITDYRVRLGCGSFAGSFLEYYAADISYPVRKSIQQDVLGTKLPQLSKGS
  PEEPVVGCPLGQRQPCRKMLPDRSRAARDRANQKLVEYIVKAKGAESHLRAILKSRKPSR
  WLQTFLSSSQYVTCVETYLEDEGQLDLVVKYLQGVYQEVGAKVLQRTNGDRIRFILDVLL
  PEAIICAISAVDEVDYKTAEEKYIKGPSLSYREKEIFDNQLLEERNRRRR
• Function: Involved in the DNA damage response pathway by contributing to the maintenance of chromatin architecture. Recruited to the vicinity of DNA breaks by TP53BP1 and plays an accessory role to facilitate damage-induced chromatin changes and promoting chromatin relaxation. Required for efficient DNA repair and cell survival following DNA damage.

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult lymphoma	DISK8IZR	Strong	Altered Expression	[1]
Adult T-cell leukemia/lymphoma	DIS882XU	Strong	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Anaplastic large cell lymphoma	DISP4D1R	Strong	Biomarker	[3]
Burkitt lymphoma	DIS9D5XU	Strong	Genetic Variation	[4]
Central nervous system lymphoma	DISBYQTA	Strong	Biomarker	[5]
Gonorrhea	DISQ5AO6	Strong	Altered Expression	[6]
Lymphoma	DISN6V4S	Strong	Altered Expression	[1]
Mycosis fungoides	DIS62RB8	Strong	Altered Expression	[7]
Neoplasm	DISZKGEW	Strong	Altered Expression	[8]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Genetic Variation	[9]
Pediatric lymphoma	DIS51BK2	Strong	Altered Expression	[1]
Plasma cell myeloma	DIS0DFZ0	Strong	Biomarker	[10]
Primary cutaneous peripheral T-cell lymphoma not otherwise specified	DIS5OHQF	Strong	Altered Expression	[11]
T-cell lymphoma	DISSXRTQ	Strong	Biomarker	[2]
Epstein barr virus infection	DISOO0WT	moderate	Posttranslational Modification	[12]
MALT lymphoma	DIS1AVVE	moderate	Altered Expression	[10]
AIDS-related lymphoma	DISSLRAU	Limited	Altered Expression	[13]
Angioimmunoblastic T-cell Lymphoma	DISZPFTL	Limited	Biomarker	[14]
Kaposi sarcoma	DISC1H1Z	Limited	Altered Expression	[15]
Lymphoproliferative syndrome	DISMVL8O	Limited	Biomarker	[15]
Small lymphocytic lymphoma	DIS30POX	Limited	Altered Expression	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of PWWP domain-containing DNA repair factor 3A (PWWP3A).	[17]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of PWWP domain-containing DNA repair factor 3A (PWWP3A).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of PWWP domain-containing DNA repair factor 3A (PWWP3A).	[28]

12 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 PWWP domain-containing DNA repair factor 3A (PWWP3A).	[18]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of PWWP domain-containing DNA repair factor 3A (PWWP3A).	[19]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of PWWP domain-containing DNA repair factor 3A (PWWP3A).	[20]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of PWWP domain-containing DNA repair factor 3A (PWWP3A).	[21]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of PWWP domain-containing DNA repair factor 3A (PWWP3A).	[23]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of PWWP domain-containing DNA repair factor 3A (PWWP3A).	[24]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of PWWP domain-containing DNA repair factor 3A (PWWP3A).	[25]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of PWWP domain-containing DNA repair factor 3A (PWWP3A).	[26]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of PWWP domain-containing DNA repair factor 3A (PWWP3A).	[27]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of PWWP domain-containing DNA repair factor 3A (PWWP3A).	[29]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of PWWP domain-containing DNA repair factor 3A (PWWP3A).	[26]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of PWWP domain-containing DNA repair factor 3A (PWWP3A).	[30]

References

• [1] IFR4/MUM1-positive lymphoma in Waldeyer ring with co-expression of CD5 and CD10.Pediatr Blood Cancer. 2017 Feb;64(2):311-314. doi: 10.1002/pbc.26236. Epub 2016 Sep 12.
• [2] MUM1/IRF4 expression as a frequent event in mature lymphoid malignancies.Leukemia. 2000 Mar;14(3):449-56. doi: 10.1038/sj.leu.2401696.
• [3] CD30-positive peripheral T-cell lymphomas share molecular and phenotypic features.Haematologica. 2013 Aug;98(8):1250-8. doi: 10.3324/haematol.2012.081935. Epub 2013 May 28.
• [4] Burkitt lymphoma in Iraqi children: A distinctive form of sporadic disease with high incidence of EBV(+) cases and more frequent expression of MUM1/IRF4 protein in cases with head and neck presentation.Pediatr Blood Cancer. 2018 Dec;65(12):e27399. doi: 10.1002/pbc.27399. Epub 2018 Sep 11.
• [5] Prognostic Significance of High Ki-67 Index and Histogenetic Subclassification in Primary Central Nervous System Lymphoma.Appl Immunohistochem Mol Morphol. 2018 Apr;26(4):254-262. doi: 10.1097/PAI.0000000000000424.
• [6] BCL3 rearrangement, amplification and expression in diffuse large B-cell lymphoma.Eur J Haematol. 2011 Dec;87(6):480-5. doi: 10.1111/j.1600-0609.2011.01684.x. Epub 2011 Aug 19.
• [7] Mycosis fungoides in Taiwan shows a relatively high frequency of large cell transformation and CD56 expression.Pathology. 2018 Dec;50(7):718-724. doi: 10.1016/j.pathol.2018.08.008. Epub 2018 Oct 20.
• [8] A cyclin D1-positive diffuse large B-cell lymphoma of germinal center B-cell-like subtype in the right tonsil: A rare case report.Medicine (Baltimore). 2017 Mar;96(11):e6311. doi: 10.1097/MD.0000000000006311.
• [9] Risk estimation model for nonalcoholic fatty liver disease in the Japanese using multiple genetic markers.PLoS One. 2018 Jan 31;13(1):e0185490. doi: 10.1371/journal.pone.0185490. eCollection 2018.
• [10] Immunohistochemical expression of cereblon and MUM1 as potential predictive markers of response to lenalidomide in extranodal marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT lymphoma).Hematol Oncol. 2018 Feb;36(1):62-67. doi: 10.1002/hon.2472. Epub 2017 Aug 22.
• [11] IRF4/MUM1 expression is associated with poor survival outcomes in patients with peripheral T-cell lymphoma.J Cancer. 2017 Mar 29;8(6):1018-1024. doi: 10.7150/jca.17358. eCollection 2017.
• [12] Post-transplant lymphoproliferative disorders. Molecular analysis of histogenesis and pathogenesis.Minerva Med. 2004 Feb;95(1):53-64.
• [13] Expression of MUM1/IRF4 selectively clusters with primary effusion lymphoma among lymphomatous effusions: implications for disease histogenesis and pathogenesis.Br J Haematol. 2000 Oct;111(1):247-57. doi: 10.1046/j.1365-2141.2000.02329.x.
• [14] MUM-1 expression differentiates AITL with HRS-like cells from cHL.Int J Clin Exp Pathol. 2015 Sep 1;8(9):11372-8. eCollection 2015.
• [15] Lymph node-based disease and HHV-8/KSHV infection in HIV seronegative patients: report of three new cases of a heterogeneous group of diseases.Int J Hematol. 2011 Jun;93(6):795-801. doi: 10.1007/s12185-011-0849-0. Epub 2011 Apr 21.
• [16] MUM1/IRF4 expression in the circulating compartment of chronic lymphocytic leukemia.Leuk Lymphoma. 2008 Feb;49(2):273-80. doi: 10.1080/10428190701760037.
• [17] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [18] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [19] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [20] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [21] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [22] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [23] 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.
• [24] Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
• [25] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [26] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [27] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [28] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [29] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [30] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.