Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6DNZC4)

• DOT Name: (E2-independent) E3 ubiquitin-conjugating enzyme FATS (C10ORF90)
• Synonyms: EC 2.3.2.-; Centrosomal protein C10orf90; E2/E3 hybrid ubiquitin-protein ligase FATS; Fragile-site associated tumor suppressor homolog; FATS
• Gene Name: C10ORF90
• Related Disease:
  Breast cancer
  Breast carcinoma
  Neoplasm
  Non-small-cell lung cancer
  Schizophrenia
  Acute myelogenous leukaemia
  Lymphoma
  Prostate carcinoma
• UniProt ID: CJ090_HUMAN
• EC Number: 2.3.2.-
• Pfam ID: PF15309 ; PF17730
• Sequence:
  MLKLSGEGLRDSYHSRRDQIALKNLQSDVTEAKSDFTKETLASQNTKMISSIVISQMIDE
  NKSRENRASLPLPCAIAQSRAHHAKQSLANRSGVNIHRAFALLPGRLGIPAPSDERGPEA
  ELPPKEERPCGGPRRGFASITITARRVGPPARALVWGTAGDSLCPKCRAEDTLFQAPPAL
  ANGAHPGRHQRSFACTEFSRNSSVVRLKVPEAHTGLCERRKYWVTHADDKETSFSPDTPL
  SGKSPLVFSSCVHLRVSQQCPDSIYYVDKSLSVPIEPPQIASPKMHRSVLSLNLNCSSHR
  LTADGVDGLVNREPISEALKQELLEGDQDLVGQRWNPGLQESHLKETPSLRRVHLGTGAC
  PWSGSFPLENTELANVGANQVTVRKGEKDHTTHCHASDHANQLSIHIPGWSYRAVHTKVF
  SGSSKRQQGEVCMTVSAPPVEQKPTRHFLPIGDSSPSDDCLSRDLSEPTERRHQSFLKPR
  ILFPGFLCPLQDVCASLQEDNGVQIESKFPKGDYTCCDLVVKIKECKKSEDPTTPEPSPA
  APSPAPRDGAGSPGLSEDCSESQQTPARSLTLQEALEVRKPQFISRSQERLKKLEHMVQQ
  RKAQRKEDLRQKQSLLPIRTSKKQFTIPHPLSDNLFKPKERCISEKEMHMRSKRIYDNLP
  EVKKKKEEQRKRVILQSNRLRAEVFKKQLLDQLLQRNAV
• Function: Tumor suppressor that is required to sustain G2/M checkpoint after DNA damage. Acts as a p53/TP53 activator by inhibiting MDM2 binding to p53/TP53 and stimulating non-proteolytic polyubiquitination of p53/TP53. Exhibits ubiquitin ligase (E3) activity and assemble ubiquitin polymers through 'Lys-11'- (K11-), 'Lys-29'- (K29-) and 'Lys-63'- (K63)-linkages, independently of the ubiquitin-conjugating enzyme (E2). Promotes p53/TP53-dependent transcription of CDKN1A/p21, leading to robust checkpoint response. Mediates CDKN1A/p21 protein stability in a ubiquitin-independent manner. Interacts with HDAC1 and prevents binding of HDAC1 to CDKN1A/p21 and facilitates the acetylation and stabilization of CDKN1A/p21. May have a role in the assembly of primary cilia (Probable).

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Altered Expression	[1]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[3]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[4]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[5]
Lymphoma	DISN6V4S	Limited	Biomarker	[6]
Prostate carcinoma	DISMJPLE	Limited	Genetic Variation	[7]

3 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 (E2-independent) E3 ubiquitin-conjugating enzyme FATS (C10ORF90).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin increases the expression of (E2-independent) E3 ubiquitin-conjugating enzyme FATS (C10ORF90).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of (E2-independent) E3 ubiquitin-conjugating enzyme FATS (C10ORF90).	[10]

1 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 decreases the methylation of (E2-independent) E3 ubiquitin-conjugating enzyme FATS (C10ORF90).	[11]

References

• [1] The value of FATS expression in predicting sensitivity to radiotherapy in breast cancer.Oncotarget. 2017 Jun 13;8(24):38491-38500. doi: 10.18632/oncotarget.16630.
• [2] Conjunctival melanoma copy number alterations and correlation with mutation status, tumor features, and clinical outcome.Pigment Cell Melanoma Res. 2019 Jul;32(4):564-575. doi: 10.1111/pcmr.12767. Epub 2019 Feb 19.
• [3] FATS expression is associated with cisplatin sensitivity in non small cell lung cancer.Lung Cancer. 2012 Jun;76(3):416-22. doi: 10.1016/j.lungcan.2011.11.009. Epub 2011 Dec 2.
• [4] Genome-wide association study identifies five new schizophrenia loci.Nat Genet. 2011 Sep 18;43(10):969-76. doi: 10.1038/ng.940.
• [5] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [6] An HDAC1-binding domain within FATS bridges p21 turnover to radiation-induced tumorigenesis.Oncogene. 2010 May 6;29(18):2659-71. doi: 10.1038/onc.2010.19. Epub 2010 Feb 15.
• [7] Meta-analysis of Genome Wide Association Studies Identifies Genetic Markers of Late Toxicity Following Radiotherapy for Prostate Cancer.EBioMedicine. 2016 Aug;10:150-63. doi: 10.1016/j.ebiom.2016.07.022. Epub 2016 Jul 20.
• [8] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [9] 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.
• [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] 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.