Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6CTWCB)

• DOT Name: PWWP domain-containing protein 2B (PWWP2B)
• Gene Name: PWWP2B
• Related Disease: Polycystic ovarian syndrome
• UniProt ID: PWP2B_HUMAN
• PDB ID: 4LD6
• Pfam ID: PF00855
• Sequence:
  MEPRAGCRLPVRVEQVVNGALVVTVSCGERSFAGILLDCTKKSGLFGLPPLAPLPQVDES
  PVNDSHGRAPEEGDAEVMQLGSSSPPPARGVQPPETTRPEPPPPLVPPLPAGSLPPYPPY
  FEGAPFPHPLWLRDTYKLWVPQPPPRTIKRTRRRLSRNRDPGRLILSTIRLRPRQVLCEK
  CKSTLSPPEASPGPPAAPRARRRLGSGPDRELRKPEEPENGEPTAAATARRSKRERREED
  RAPAEQVPRSPVIKISYSTPQGKGEVVKIPSRVHGSLEPFRPQQAPQDDGSQDPEVLDRE
  SRDRPSCAPSASIPKLKLTRPVPAGADLPPPKIRLKPHRLGDSEHEPVYRAELVGELNGY
  LRDSSPAPCADGPAGGLADLSSGSSGEDDDFKSCPQGPQGREGLAFLVSCPEGRADCASE
  SACSSDSLDEARSSGSEGTPADTGDLSPGHGASAPSVSREARQTVPPLTVRLHTQSVSEC
  ITEDGRTVAVGDIVWGKIHGFPWWPARVLDISLGQKEDGEPSWREAKVSWFGSPTTSFLS
  ISKLSPFSEFFKLRFNRKKKGMYRKAITEAANAARHVAPEIRELLTQFET
• Function: Chromatin-binding protein that acts as an adapter between distinct nucleosome components (H3K36me3 or H2A.Z) and chromatin-modifying complexes, contributing to the regulation of the levels of histone acetylation at actively transcribed genes. Competes with CHD4 and MBD3 for interaction with MTA1 to form a NuRD subcomplex, preventing the formation of full NuRD complex (containing CHD4 and MBD3), leading to recruitment of HDACs to gene promoters resulting in turn in the deacetylation of nearby H3K27 and H2A.Z. Plays a role in facilitating transcriptional elongation through regulation of histone acetylation. Negatively regulates brown adipocyte thermogenesis by interacting with and stabilizing HDAC1 at the UCP1 gene promoter, thereby promoting histone deacetylation at the promoter leading to the repression of UCP1 expression.

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Polycystic ovarian syndrome	DISZ2BNG	Strong	Biomarker	[1]

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 protein 2B (PWWP2B).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of PWWP domain-containing protein 2B (PWWP2B).	[7]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of PWWP domain-containing protein 2B (PWWP2B).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of PWWP domain-containing protein 2B (PWWP2B).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of PWWP domain-containing protein 2B (PWWP2B).	[4]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of PWWP domain-containing protein 2B (PWWP2B).	[5]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of PWWP domain-containing protein 2B (PWWP2B).	[6]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of PWWP domain-containing protein 2B (PWWP2B).	[8]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of PWWP domain-containing protein 2B (PWWP2B).	[10]

References

• [1] Progesterone resistance in PCOS endometrium: a microarray analysis in clomiphene citrate-treated and artificial menstrual cycles.J Clin Endocrinol Metab. 2011 Jun;96(6):1737-46. doi: 10.1210/jc.2010-2600. Epub 2011 Mar 16.
• [2] 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.
• [3] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [4] 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.
• [5] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [6] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [7] 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.
• [8] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [9] 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.
• [10] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.