Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4DIMD0)

• DOT Name: Nucleus accumbens-associated protein 1 (NACC1)
• Synonyms: NAC-1; BTB/POZ domain-containing protein 14B
• Gene Name: NACC1
• Related Disease:
  NACC1-related neurodevelopmental disorder with epilepsy, cataracts and episodic irritability
  Neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination
• UniProt ID: NACC1_HUMAN
• PDB ID: 3GA1; 4U2N; 7BV9
• Pfam ID: PF10523 ; PF00651
• Sequence:
  MAQTLQMEIPNFGNSILECLNEQRLQGLYCDVSVVVKGHAFKAHRAVLAASSSYFRDLFN
  NSRSAVVELPAAVQPQSFQQILSFCYTGRLSMNVGDQFLLMYTAGFLQIQEIMEKGTEFF
  LKVSSPSCDSQGLHAEEAPSSEPQSPVAQTSGWPACSTPLPLVSRVKTEQQESDSVQCMP
  VAKRLWDSGQKEAGGGGNGSRKMAKFSTPDLAANRPHQPPPPQQAPVVAAAQPAVAAGAG
  QPAGGVAAAGGVVSGPSTSERTSPGTSSAYTSDSPGSYHNEEDEEEDGGEEGMDEQYRQI
  CNMYTMYSMMNVGQTAEKVEALPEQVAPESRNRIRVRQDLASLPAELINQIGNRCHPKLY
  DEGDPSEKLELVTGTNVYITRAQLMNCHVSAGTRHKVLLRRLLASFFDRNTLANSCGTGI
  RSSTNDPRRKPLDSRVLHAVKYYCQNFAPNFKESEMNAIAADMCTNARRVVRKSWMPKVK
  VLKAEDDAYTTFISETGKIEPDMMGVEHGFETASHEGEAGPSAEALQ
• Function: Functions as a transcriptional repressor. Seems to function as a transcriptional corepressor in neuronal cells through recruitment of HDAC3 and HDAC4. Contributes to tumor progression, and tumor cell proliferation and survival. This may be mediated at least in part through repressing transcriptional activity of GADD45GIP1. Required for recruiting the proteasome from the nucleus to the cytoplasm and dendritic spines.
• Tissue Specificity: Overexpressed in several types of carcinomas including ovarian serous carcinomas. Expression levels positively correlate with tumor recurrence in ovarian serous carcinomas, and intense immunoreactivity in primary ovarian tumors predicts early recurrence. Up-regulated in ovarian carcinomas after chemotherapy, suggesting a role in development of chemotherapy resistance in ovarian cancer.

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
NACC1-related neurodevelopmental disorder with epilepsy, cataracts and episodic irritability	DISD1B3A	Definitive	Autosomal dominant	[1]
Neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination	DISDGI3M	Strong	Autosomal dominant	[2]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Nucleus accumbens-associated protein 1 (NACC1) affects the response to substance of Cisplatin.	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Nucleus accumbens-associated protein 1 (NACC1).	[3]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Nucleus accumbens-associated protein 1 (NACC1).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Nucleus accumbens-associated protein 1 (NACC1).	[5]
Marinol	DM70IK5	Approved	Marinol increases the expression of Nucleus accumbens-associated protein 1 (NACC1).	[6]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Nucleus accumbens-associated protein 1 (NACC1).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Nucleus accumbens-associated protein 1 (NACC1).	[7]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Nucleus accumbens-associated protein 1 (NACC1).	[8]

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] Genome sequencing identifies major causes of severe intellectual disability. Nature. 2014 Jul 17;511(7509):344-7. doi: 10.1038/nature13394. Epub 2014 Jun 4.
• [3] 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.
• [4] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [5] 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.
• [6] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [7] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [8] 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.
• [9] 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.
• [10] NAC1 modulates sensitivity of ovarian cancer cells to cisplatin by altering the HMGB1-mediated autophagic response. Oncogene. 2012 Feb 23;31(8):1055-64. doi: 10.1038/onc.2011.290. Epub 2011 Jul 11.