Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT24XM7T)

• DOT Name: DDB1- and CUL4-associated factor 12 (DCAF12)
• Synonyms: Centrosome-related protein TCC52; Testis cancer centrosome-related protein; WD repeat-containing protein 40A
• Gene Name: DCAF12
• Related Disease:
  Cholangiocarcinoma
  Laryngeal carcinoma
  Lung cancer
  Lung carcinoma
  Neoplasm
  Prostate cancer
  Prostate carcinoma
  Testicular cancer
• UniProt ID: DCA12_HUMAN
• PDB ID: 3I7P; 8AJM; 8AJN; 8AJO
• Pfam ID: PF00400
• Sequence:
  MARKVVSRKRKAPASPGAGSDAQGPQFGWDHSLHKRKRLPPVKRSLVYYLKNREVRLQNE
  TSYSRVLHGYAAQQLPSLLKEREFHLGTLNKVFASQWLNHRQVVCGTKCNTLFVVDVQTS
  QITKIPILKDREPGGVTQQGCGIHAIELNPSRTLLATGGDNPNSLAIYRLPTLDPVCVGD
  DGHKDWIFSIAWISDTMAVSGSRDGSMGLWEVTDDVLTKSDARHNVSRVPVYAHITHKAL
  KDIPKEDTNPDNCKVRALAFNNKNKELGAVSLDGYFHLWKAENTLSKLLSTKLPYCRENV
  CLAYGSEWSVYAVGSQAHVSFLDPRQPSYNVKSVCSRERGSGIRSVSFYEHIITVGTGQG
  SLLFYDIRAQRFLEERLSACYGSKPRLAGENLKLTTGKGWLNHDETWRNYFSDIDFFPNA
  VYTHCYDSSGTKLFVAGGPLPSGLHGNYAGLWS
• Function: Substrate-recognition component of a DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complex of the DesCEND (destruction via C-end degrons) pathway, which recognizes a C-degron located at the extreme C terminus of target proteins, leading to their ubiquitination and degradation. The C-degron recognized by the DesCEND pathway is usually a motif of less than ten residues and can be present in full-length proteins, truncated proteins or proteolytically cleaved forms. The DCX(DCAF12) complex specifically recognizes proteins with a diglutamate (Glu-Glu) at the C-terminus, such as MAGEA3, MAGEA6 and CCT5, leading to their ubiquitination and degradation. Ubiquitination of MAGEA3, MAGEA6 by DCX(DCAF12) complex is required for starvation-induced autophagy. Also directly recognizes the C-terminal glutamate-leucine (Glu-Leu) degron as an alternative degron in proteins such as MOV10, leading to their ubiquitination and degradation. Controls the protein level of MOV10 during spermatogenesis and in T cells, especially after their activation.
• Tissue Specificity: Highly expressed in lung cancer tissues and some cancer cell lines . Restricted expression in normal testis .

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cholangiocarcinoma	DIS71F6X	Strong	Biomarker	[1]
Laryngeal carcinoma	DISNHCIV	Strong	Biomarker	[1]
Lung cancer	DISCM4YA	Strong	Biomarker	[1]
Lung carcinoma	DISTR26C	Strong	Biomarker	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Prostate cancer	DISF190Y	Strong	Biomarker	[1]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[1]
Testicular cancer	DIS6HNYO	Strong	Biomarker	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Chlorpyrifos	DMKPUI6	Investigative	DDB1- and CUL4-associated factor 12 (DCAF12) decreases the response to substance of Chlorpyrifos.	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of DDB1- and CUL4-associated factor 12 (DCAF12).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of DDB1- and CUL4-associated factor 12 (DCAF12).	[4]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of DDB1- and CUL4-associated factor 12 (DCAF12).	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of DDB1- and CUL4-associated factor 12 (DCAF12).	[6]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of DDB1- and CUL4-associated factor 12 (DCAF12).	[6]

References

• [1] Novel centrosome protein, TCC52, is a cancer-testis antigen.Cancer Sci. 2008 Nov;99(11):2274-9. doi: 10.1111/j.1349-7006.2008.00937.x. Epub 2008 Oct 14.
• [2] Curative Multicycle Radioimmunotherapy Monitored by Quantitative SPECT/CT-Based Theranostics, Using Bispecific Antibody Pretargeting Strategy in Colorectal Cancer.J Nucl Med. 2017 Nov;58(11):1735-1742. doi: 10.2967/jnumed.117.193250. Epub 2017 Jul 13.
• [3] 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.
• [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] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [6] 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.
• [7] Application of human haploid cell genetic screening model in identifying the genes required for resistance to environmental toxicants: Chlorpyrifos as a case study. J Pharmacol Toxicol Methods. 2015 Nov-Dec;76:76-82. doi: 10.1016/j.vascn.2015.08.154. Epub 2015 Aug 20.