Details of Drug Off-Target (DOT)

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

• DOT Name: Protein DBF4 homolog B (DBF4B)
• Synonyms: Activator of S phase kinase-like protein 1; ASK-like protein 1; Chiffon homolog B; Dbf4-related factor 1
• Gene Name: DBF4B
• Related Disease:
  Advanced cancer
  Colon cancer
  Colon carcinoma
• UniProt ID: DBF4B_HUMAN
• Pfam ID: PF07535
• Sequence:
  MSEPGKGDDCLELESSMAESRLRAPDLGVSRCLGKCQKNSPGARKHPFSGKSFYLDLPAG
  KNLQFLTGAIQQLGGVIEGFLSKEVSYIVSSRREVKAESSGKSHRGCPSPSPSEVRVETS
  AMVDPKGSHPRPSRKPVDSVPLSRGKELLQKAIRNQGSISGGGSGGSSSLLTNARSWGVR
  ILHVDEMMMHVQQLSLASLCVKKQQPKKPEGTCPAAESRTRKVARLKAPFLKIEDESRKF
  RPFHHQFKSFPEISFLGPKDASPFEAPTTLGSMHHTRESKDGEPSPRSAAHTMPRRKKGY
  CECCQEAFEELHVHLQSAQHRSFALEAHLYAEVDRIIAQLSHSFADIPFQAGLPRWSGSP
  ASDCDPLCPETLHPHQPSHPRAASPRIRKEDSCQASVTQGRAAGQQRWTESLDGVMGPPA
  SHTCVSATTLLPALPKGSREQGCLCPCPASFTQSHLVTSLALLPGEWSPAEDMPLHPSQE
  NSFAPADIPVKGPLLFPEARPWLMSARCWVRPFPFVTWGCLIPHDTTPLHEEVSPCPCLR
  LGYLYLLLTQSLWCRVRVPSLSTAGPIPRTSHPCTLAFPSYLNDHDLGHLCQAKPQGWNT
  PQPFLHCGFLAVDSG
• Function: Regulatory subunit for CDC7 which activates its kinase activity thereby playing a central role in DNA replication and cell proliferation. Required for progression of S and M phases. The complex CDC7-DBF4B selectively phosphorylates MCM2 subunit at 'Ser-40' and then is involved in regulating the initiation of DNA replication during cell cycle.
• Tissue Specificity: Widely expressed. Highly expressed in testis.
• KEGG Pathway: Cell cycle (hsa04110)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Disputed	Biomarker	[1]
Colon cancer	DISVC52G	Disputed	Altered Expression	[1]
Colon carcinoma	DISJYKUO	Disputed	Altered Expression	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Protein DBF4 homolog B (DBF4B).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein DBF4 homolog B (DBF4B).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Protein DBF4 homolog B (DBF4B).	[4]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Protein DBF4 homolog B (DBF4B).	[5]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Protein DBF4 homolog B (DBF4B).	[5]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Protein DBF4 homolog B (DBF4B).	[6]
Permethrin	DMZ0Q1G	Approved	Permethrin increases the expression of Protein DBF4 homolog B (DBF4B).	[7]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Protein DBF4 homolog B (DBF4B).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Protein DBF4 homolog B (DBF4B).	[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 affects the methylation of Protein DBF4 homolog B (DBF4B).	[8]

References

• [1] SRSF1 Prevents DNA Damage and Promotes Tumorigenesis through Regulation of DBF4B Pre-mRNA Splicing.Cell Rep. 2017 Dec 19;21(12):3406-3413. doi: 10.1016/j.celrep.2017.11.091.
• [2] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [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] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [5] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [6] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [7] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [8] 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.
• [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] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.