Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQQ0QXT)

• DOT Name: DDB1- and CUL4-associated factor 13 (DCAF13)
• Synonyms: WD repeat and SOF domain-containing protein 1
• Gene Name: DCAF13
• Related Disease:
  Neoplasm
  Advanced cancer
  Bone osteosarcoma
  Epilepsy
  Hepatocellular carcinoma
  Osteoporosis
  Osteosarcoma
• UniProt ID: DCA13_HUMAN
• PDB ID: 7MQ8; 7MQ9; 7MQA
• Pfam ID: PF08662 ; PF04158 ; PF00400
• Sequence:
  MKVKMLSRNPDNYVRETKLDLQRVPRNYDPALHPFEVPREYIRALNATKLERVFAKPFLA
  SLDGHRDGVNCLAKHPEKLATVLSGACDGEVRIWNLTQRNCIRTIQAHEGFVRGICTRFC
  GTSFFTVGDDKTVKQWKMDGPGYGDEEEPLHTILGKTVYTGIDHHWKEAVFATCGQQVDI
  WDEQRTNPICSMTWGFDSISSVKFNPIETFLLGSCASDRNIVLYDMRQATPLKKVILDMR
  TNTICWNPMEAFIFTAANEDYNLYTFDMRALDTPVMVHMDHVSAVLDVDYSPTGKEFVSA
  SFDKSIRIFPVDKSRSREVYHTKRMQHVICVKWTSDSKYIMCGSDEMNIRLWKANASEKL
  GVLTSREKAAKDYNQKLKEKFQHYPHIKRIARHRHLPKSIYSQIQEQRIMKEARRRKEVN
  RIKHSKPGSVPLVSEKKKHVVAVVK
• Function: Part of the small subunit (SSU) processome, first precursor of the small eukaryotic ribosomal subunit. During the assembly of the SSU processome in the nucleolus, many ribosome biogenesis factors, an RNA chaperone and ribosomal proteins associate with the nascent pre-rRNA and work in concert to generate RNA folding, modifications, rearrangements and cleavage as well as targeted degradation of pre-ribosomal RNA by the RNA exosome. Participates in the 18S rRNA processing in growing oocytes, being essential for oocyte nonsurrounded nucleolus (NSN) to surrounded nucleolus (SN) transition ; Substrate-recognition component of a DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complex that plays a key role in embryo preimplantation and is required for normal meiotic cycle progression in oocytes. Acts as a maternal factor that regulates oocyte and zygotic chromatin tightness during maternal to zygotic transition. Also involved in the transformation of the endometrium into the decidua, known as decidualization, providing a solid foundation for implantation of blastocysts. Recognizes the histone methyltransferases SUV39H1 and SUV39H2 and directs them to polyubiquitination and proteasomal degradation, which facilitates the H3K9me3 removal and early zygotic gene expression, essential steps for progressive genome reprogramming and the establishment of pluripotency during preimplantation embryonic development. Supports the spindle assembly and chromosome condensation during oocyte meiotic division by targeting the polyubiquitination and degradation of PTEN, a lipid phosphatase that inhibits PI3K pathway as well as oocyte growth and maturation. Targets PMP22 for polyubiquitination and proteasomal degradation.
• Tissue Specificity: Expressed in the endometrium during decidualization. Expression is down-regulated in preeclampsia decidual tissues.
• Reactome Pathway:
  Major pathway of rRNA processing in the nucleolus and cytosol (R-HSA-6791226)
  Neddylation (R-HSA-8951664)
  rRNA modification in the nucleus and cytosol (R-HSA-6790901)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[3]
Epilepsy	DISBB28L	Strong	Genetic Variation	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[2]
Osteoporosis	DISF2JE0	Strong	Genetic Variation	[5]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of DDB1- and CUL4-associated factor 13 (DCAF13).	[6]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of DDB1- and CUL4-associated factor 13 (DCAF13).	[13]

8 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 DDB1- and CUL4-associated factor 13 (DCAF13).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of DDB1- and CUL4-associated factor 13 (DCAF13).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of DDB1- and CUL4-associated factor 13 (DCAF13).	[9]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of DDB1- and CUL4-associated factor 13 (DCAF13).	[10]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of DDB1- and CUL4-associated factor 13 (DCAF13).	[11]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of DDB1- and CUL4-associated factor 13 (DCAF13).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of DDB1- and CUL4-associated factor 13 (DCAF13).	[14]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of DDB1- and CUL4-associated factor 13 (DCAF13).	[15]

References

• [1] MicroRNA-300 Regulates the Ubiquitination of PTEN through the CRL4B(DCAF13) E3 Ligase in Osteosarcoma Cells.Mol Ther Nucleic Acids. 2018 Mar 2;10:254-268. doi: 10.1016/j.omtn.2017.12.010. Epub 2017 Dec 22.
• [2] The overexpression and prognostic role of DCAF13 in hepatocellular carcinoma.Tumour Biol. 2017 Jun;39(6):1010428317705753. doi: 10.1177/1010428317705753.
• [3] Small molecule TSC01682 inhibits osteosarcoma cell growth by specifically disrupting the CUL4B-DDB1 interaction and decreasing the ubiquitination of CRL4B E3 ligase substrates.Am J Cancer Res. 2019 Sep 1;9(9):1857-1870. eCollection 2019.
• [4] Whole exome sequencing reveals novel NOV and DCAF13 variants in a Chinese pedigree with familial cortical myoclonic tremor with epilepsy.Neurosci Lett. 2018 Sep 25;684:115-120. doi: 10.1016/j.neulet.2018.07.014. Epub 2018 Jul 9.
• [5] Identification of non-synonymous polymorphisms in the WDSOF1 gene as novel susceptibility markers for low bone mineral density in Japanese postmenopausal women.Bone. 2010 Sep;47(3):636-42. doi: 10.1016/j.bone.2010.06.017. Epub 2010 Jun 23.
• [6] 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.
• [7] 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.
• [8] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [9] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [10] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [11] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [12] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [13] 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.
• [14] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [15] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.