Details of Drug Off-Target (DOT)

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

• DOT Name: WW domain-containing adapter protein with coiled-coil
• Gene Name: WAC
• Related Disease:
  DeSanto-Shinawi syndrome
  DeSanto-Shinawi syndrome due to WAC point mutation
  Intellectual disability, autosomal dominant 40
• UniProt ID: WAC_HUMAN
• Pfam ID: PF00397
• Sequence:
  MVMYARKQQRLSDGCHDRRGDSQPYQALKYSSKSHPSSGDHRHEKMRDAGDPSPPNKMLR
  RSDSPENKYSDSTGHSKAKNVHTHRVRERDGGTSYSPQENSHNHSALHSSNSHSSNPSNN
  PSKTSDAPYDSADDWSEHISSSGKKYYYNCRTEVSQWEKPKEWLEREQRQKEANKMAVNS
  FPKDRDYRREVMQATATSGFASGMEDKHSSDASSLLPQNILSQTSRHNDRDYRLPRAETH
  SSSTPVQHPIKPVVHPTATPSTVPSSPFTLQSDHQPKKSFDANGASTLSKLPTPTSSVPA
  QKTERKESTSGDKPVSHSCTTPSTSSASGLNPTSAPPTSASAVPVSPVPQSPIPPLLQDP
  NLLRQLLPALQATLQLNNSNVDISKINEVLTAAVTQASLQSIIHKFLTAGPSAFNITSLI
  SQAAQLSTQAQPSNQSPMSLTSDASSPRSYVSPRISTPQTNTVPIKPLISTPPVSSQPKV
  STPVVKQGPVSQSATQQPVTADKQQGHEPVSPRSLQRSSSQRSPSPGPNHTSNSSNASNA
  TVVPQNSSARSTCSLTPALAAHFSENLIKHVQGWPADHAEKQASRLREEAHNMGTIHMSE
  ICTELKNLRSLVRVCEIQATLREQRILFLRQQIKELEKLKNQNSFMV
• Function: Acts as a linker between gene transcription and histone H2B monoubiquitination at 'Lys-120' (H2BK120ub1). Interacts with the RNA polymerase II transcriptional machinery via its WW domain and with RNF20-RNF40 via its coiled coil region, thereby linking and regulating H2BK120ub1 and gene transcription. Regulates the cell-cycle checkpoint activation in response to DNA damage. Positive regulator of amino acid starvation-induced autophagy. Also acts as a negative regulator of basal autophagy. Positively regulates MTOR activity by promoting, in an energy-dependent manner, the assembly of the TTT complex composed of TELO2, TTI1 and TTI2 and the RUVBL complex composed of RUVBL1 and RUVBL2 into the TTT-RUVBL complex. This leads to the dimerization of the mTORC1 complex and its subsequent activation. May negatively regulate the ubiquitin proteasome pathway.
• Reactome Pathway: E3 ubiquitin ligases ubiquitinate target proteins (R-HSA-8866654)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
DeSanto-Shinawi syndrome	DISY6ZH0	Definitive	Autosomal dominant	[1]
DeSanto-Shinawi syndrome due to WAC point mutation	DISK9PRN	Definitive	Autosomal dominant	[2]
Intellectual disability, autosomal dominant 40	DISAI0IH	Definitive	Autosomal dominant	[3]

5 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 WW domain-containing adapter protein with coiled-coil.	[4]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of WW domain-containing adapter protein with coiled-coil.	[10]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of WW domain-containing adapter protein with coiled-coil.	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of WW domain-containing adapter protein with coiled-coil.	[12]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of WW domain-containing adapter protein with coiled-coil.	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of WW domain-containing adapter protein with coiled-coil.	[5]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of WW domain-containing adapter protein with coiled-coil.	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of WW domain-containing adapter protein with coiled-coil.	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of WW domain-containing adapter protein with coiled-coil.	[8]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of WW domain-containing adapter protein with coiled-coil.	[9]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of WW domain-containing adapter protein with coiled-coil.	[13]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of WW domain-containing adapter protein with coiled-coil.	[14]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Clinical and molecular characterization of five new individuals with WAC-related intellectual disability: Evidence of pathogenicity for a novel splicing variant. Am J Med Genet A. 2022 May;188(5):1396-1406. doi: 10.1002/ajmg.a.62648. Epub 2022 Jan 12.
• [3] De novo loss-of-function mutations in WAC cause a recognizable intellectual disability syndrome and learning deficits in Drosophila. Eur J Hum Genet. 2016 Aug;24(8):1145-53. doi: 10.1038/ejhg.2015.282. Epub 2016 Jan 13.
• [4] 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.
• [5] 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.
• [6] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [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] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [9] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.