Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYO6F5P)

DOT Name	DNA dC->dU-editing enzyme APOBEC-3A (APOBEC3A)
Synonyms	A3A; EC 3.5.4.38; Phorbolin-1
Gene Name	APOBEC3A
Related Disease	Acute monocytic leukemia ( ) Acute myelogenous leukaemia ( ) Advanced cancer ( ) Benign neoplasm ( ) Bladder cancer ( ) Breast cancer ( ) Breast carcinoma ( ) Breast neoplasm ( ) Carcinoma of liver and intrahepatic biliary tract ( ) Cytomegalovirus infection ( ) Glioblastoma multiforme ( ) Hepatitis B virus infection ( ) Juvenile idiopathic arthritis ( ) Lentivirus infection ( ) leukaemia ( ) Leukemia ( ) Liver cancer ( ) Lung cancer ( ) Lung carcinoma ( ) Neoplasm ( ) Oral cancer ( ) Oropharyngeal cancer ( ) Prostate cancer ( ) Prostate carcinoma ( ) Psychotic disorder ( ) Skin cancer ( ) Systemic sclerosis ( ) Ulcerative colitis ( ) Urinary bladder cancer ( ) Urinary bladder neoplasm ( ) Wilms tumor ( ) Gastric cancer ( ) Nasopharyngeal carcinoma ( ) Niemann-Pick disease type C ( ) Stomach cancer ( ) Adenocarcinoma ( ) Gallbladder cancer ( ) Head-neck squamous cell carcinoma ( ) Hepatocellular carcinoma ( ) Human papillomavirus infection ( ) Metastatic malignant neoplasm ( ) Oropharyngeal carcinoma ( ) Squamous cell carcinoma ( )
UniProt ID	ABC3A_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	2M65; 4XXO; 5KEG; 5SWW; 7D3V; 7D3W; 7D3X; 8FII; 8FIJ; 8FIK; 8FIL; 8FIM
EC Number	3.5.4.38
Pfam ID	PF18782
Sequence	MEASPASGPRHLMDPHIFTSNFNNGIGRHKTYLCYEVERLDNGTSVKMDQHRGFLHNQAK NLLCGFYGRHAELRFLDLVPSLQLDPAQIYRVTWFISWSPCFSWGCAGEVRAFLQENTHV RLRIFAARIYDYDPLYKEALQMLRDAGAQVSIMTYDEFKHCWDTFVDHQGCPFQPWDGLD EHSQALSGRLRAILQNQGN
Function	DNA deaminase (cytidine deaminase) with restriction activity against viruses, foreign DNA and mobility of retrotransposons. Exhibits antiviral activity against adeno-associated virus (AAV) and human T-cell leukemia virus type 1 (HTLV-1) and may inhibit the mobility of LTR and non-LTR retrotransposons. Selectively targets single-stranded DNA and can deaminate both methylcytosine and cytosine in foreign DNA. Can induce somatic hypermutation in the nuclear and mitochondrial DNA. May also play a role in the epigenetic regulation of gene expression through the process of active DNA demethylation.
Tissue Specificity	Expressed in peripheral leukocytes with higher expression in CD14-positive phagocytic cells. Highly expressed in keratinocytes and in periphery blood monocytes. Also detected in non-lymphoid tissues including lung and adipose tissues. Found at high levels in colorectal adenocarcinoma, Burkitt's lymphoma and chronic myelogenous leukemia.
KEGG Pathway	Viral life cycle - HIV-1 (hsa03250 ) Human immunodeficiency virus 1 infection (hsa05170 )
Reactome Pathway	Formation of the Editosome (R-HSA-75094 ) mRNA Editing (R-HSA-72200 )

Molecular Interaction Atlas (MIA) of This DOT

43 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Acute monocytic leukemia	DIS28NEL	Strong	Altered Expression	[1]
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Benign neoplasm	DISDUXAD	Strong	Biomarker	[3]
Bladder cancer	DISUHNM0	Strong	Altered Expression	[4]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[5]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[5]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[6]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Altered Expression	[7]
Cytomegalovirus infection	DISCEMGC	Strong	Biomarker	[8]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[9]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[10]
Juvenile idiopathic arthritis	DISQZGBV	Strong	Biomarker	[11]
Lentivirus infection	DISX17PY	Strong	Biomarker	[12]
leukaemia	DISS7D1V	Strong	Biomarker	[1]
Leukemia	DISNAKFL	Strong	Biomarker	[1]
Liver cancer	DISDE4BI	Strong	Altered Expression	[7]
Lung cancer	DISCM4YA	Strong	Genetic Variation	[13]
Lung carcinoma	DISTR26C	Strong	Genetic Variation	[13]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[5]
Oral cancer	DISLD42D	Strong	Biomarker	[14]
Oropharyngeal cancer	DISDAMTJ	Strong	Biomarker	[15]
Prostate cancer	DISF190Y	Strong	Genetic Variation	[13]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[13]
Psychotic disorder	DIS4UQOT	Strong	Biomarker	[16]
Skin cancer	DISTM18U	Strong	Altered Expression	[17]
Systemic sclerosis	DISF44L6	Strong	Genetic Variation	[18]
Ulcerative colitis	DIS8K27O	Strong	Altered Expression	[19]
Urinary bladder cancer	DISDV4T7	Strong	Altered Expression	[4]
Urinary bladder neoplasm	DIS7HACE	Strong	Altered Expression	[4]
Wilms tumor	DISB6T16	Strong	Genetic Variation	[20]
Gastric cancer	DISXGOUK	moderate	Biomarker	[21]
Nasopharyngeal carcinoma	DISAOTQ0	moderate	Biomarker	[22]
Niemann-Pick disease type C	DIS492ZO	moderate	Biomarker	[22]
Stomach cancer	DISKIJSX	moderate	Biomarker	[21]
Adenocarcinoma	DIS3IHTY	Disputed	Biomarker	[23]
Gallbladder cancer	DISXJUAF	Disputed	Altered Expression	[23]
Head-neck squamous cell carcinoma	DISF7P24	Limited	Biomarker	[24]
Hepatocellular carcinoma	DIS0J828	Limited	Biomarker	[7]
Human papillomavirus infection	DISX61LX	Limited	Biomarker	[25]
Metastatic malignant neoplasm	DIS86UK6	Limited	Biomarker	[7]
Oropharyngeal carcinoma	DIS7K3AI	Limited	Biomarker	[15]
Squamous cell carcinoma	DISQVIFL	Limited	Altered Expression	[26]
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⏷ Show the Full List of 43 Disease(s)

Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of DNA dC->dU-editing enzyme APOBEC-3A (APOBEC3A).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of DNA dC->dU-editing enzyme APOBEC-3A (APOBEC3A).	[33]
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5 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of DNA dC->dU-editing enzyme APOBEC-3A (APOBEC3A).	[28]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of DNA dC->dU-editing enzyme APOBEC-3A (APOBEC3A).	[29]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of DNA dC->dU-editing enzyme APOBEC-3A (APOBEC3A).	[30]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of DNA dC->dU-editing enzyme APOBEC-3A (APOBEC3A).	[31]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of DNA dC->dU-editing enzyme APOBEC-3A (APOBEC3A).	[32]
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References

1	Cytosine Deaminase APOBEC3A Sensitizes Leukemia Cells to Inhibition of the DNA Replication Checkpoint.Cancer Res. 2017 Sep 1;77(17):4579-4588. doi: 10.1158/0008-5472.CAN-16-3394. Epub 2017 Jun 27.
2	A Tumor-Promoting Phorbol Ester Causes a Large Increase in APOBEC3A Expression and a Moderate Increase in APOBEC3B Expression in a Normal Human Keratinocyte Cell Line without Increasing Genomic Uracils.Mol Cell Biol. 2018 Dec 11;39(1):e00238-18. doi: 10.1128/MCB.00238-18. Print 2019 Jan 1.
3	An APOBEC3A hypermutation signature is distinguishable from the signature of background mutagenesis by APOBEC3B in human cancers.Nat Genet. 2015 Sep;47(9):1067-72. doi: 10.1038/ng.3378. Epub 2015 Aug 10.
4	Association of germline variants in the APOBEC3 region with cancer risk and enrichment with APOBEC-signature mutations in tumors.Nat Genet. 2016 Nov;48(11):1330-1338. doi: 10.1038/ng.3670. Epub 2016 Sep 19.
5	Integrative genomic analyses of APOBEC-mutational signature, expression and germline deletion of APOBEC3 genes, and immunogenicity in multiple cancer types.BMC Med Genomics. 2019 Sep 18;12(1):131. doi: 10.1186/s12920-019-0579-3.
6	Association of a germline copy number polymorphism of APOBEC3A and APOBEC3B with burden of putative APOBEC-dependent mutations in breast cancer.Nat Genet. 2014 May;46(5):487-91. doi: 10.1038/ng.2955. Epub 2014 Apr 13.
7	ARP3 promotes tumor metastasis and predicts a poor prognosis in hepatocellular carcinoma.Pathol Res Pract. 2018 Sep;214(9):1356-1361. doi: 10.1016/j.prp.2018.05.028. Epub 2018 Jun 7.
8	APOBEC3A Is Upregulated by Human Cytomegalovirus (HCMV) in the Maternal-Fetal Interface, Acting as an Innate Anti-HCMV Effector.J Virol. 2017 Nov 14;91(23):e01296-17. doi: 10.1128/JVI.01296-17. Print 2017 Dec 1.
9	RasGRP3 regulates the migration of glioma cells via interaction with Arp3.Oncotarget. 2015 Jan 30;6(3):1850-64. doi: 10.18632/oncotarget.2575.
10	A Functional Variant in Ubiquitin Conjugating Enzyme E2 L3 Contributes to Hepatitis B Virus Infection and Maintains Covalently Closed Circular DNA Stability by Inducing Degradation of Apolipoprotein B mRNA Editing Enzyme Catalytic Subunit 3A.Hepatology. 2019 May;69(5):1885-1902. doi: 10.1002/hep.30497. Epub 2019 Mar 15.
11	Gene expression signatures in polyarticular juvenile idiopathic arthritis demonstrate disease heterogeneity and offer a molecular classification of disease subsets.Arthritis Rheum. 2009 Jul;60(7):2113-23. doi: 10.1002/art.24534.
12	Interaction of Vpx and apolipoprotein B mRNA-editing catalytic polypeptide 3 family member A (APOBEC3A) correlates with efficient lentivirus infection of monocytes.J Biol Chem. 2010 Apr 16;285(16):12248-54. doi: 10.1074/jbc.M109.090977. Epub 2010 Feb 23.
13	APOBEC3A/B deletion polymorphism and cancer risk.Carcinogenesis. 2018 Feb 9;39(2):118-124. doi: 10.1093/carcin/bgx131.
14	APOBEC3A is an oral cancer prognostic biomarker in Taiwanese carriers of an APOBEC deletion polymorphism.Nat Commun. 2017 Sep 6;8(1):465. doi: 10.1038/s41467-017-00493-9.
15	Expression of estrogen receptor alpha is associated with pathogenesis and prognosis of human papillomavirus-positive oropharyngeal cancer.Int J Cancer. 2019 Sep 15;145(6):1547-1557. doi: 10.1002/ijc.32500. Epub 2019 Jun 22.
16	Upregulation of TET1 and downregulation of APOBEC3A and APOBEC3C in the parietal cortex of psychotic patients.Transl Psychiatry. 2012 Sep 4;2(9):e159. doi: 10.1038/tp.2012.86.
17	A biochemical analysis linking APOBEC3A to disparate HIV-1 restriction and skin cancer.J Biol Chem. 2013 Oct 11;288(41):29294-304. doi: 10.1074/jbc.M113.504175. Epub 2013 Aug 26.
18	Copy Number Variation of HLA-DQA1 and APOBEC3A/3B Contribute to the Susceptibility of Systemic Sclerosis in the Chinese Han Population.J Rheumatol. 2016 May;43(5):880-6. doi: 10.3899/jrheum.150945. Epub 2016 Apr 1.
19	Actin related protein 3 (ARP3) promotes apoptosis of intestinal epithelial cells in ulcerative colitis.Pathol Res Pract. 2019 Feb;215(2):235-242. doi: 10.1016/j.prp.2018.10.011. Epub 2018 Oct 24.
20	APOBEC3A is implicated in a novel class of G-to-A mRNA editing in WT1 transcripts.PLoS One. 2015 Mar 25;10(3):e0120089. doi: 10.1371/journal.pone.0120089. eCollection 2015.
21	Clinicopathological and prognostic significance of aberrant Arpin expression in gastric cancer.World J Gastroenterol. 2017 Feb 28;23(8):1450-1457. doi: 10.3748/wjg.v23.i8.1450.
22	Prevalent somatic BRCA1 mutations shape clinically relevant genomic patterns of nasopharyngeal carcinoma in Southeast Europe.Int J Cancer. 2018 Jan 1;142(1):66-80. doi: 10.1002/ijc.31023. Epub 2017 Sep 30.
23	CFL1 and Arp3 are biomarkers for metastasis and poor prognosis of squamous cell/adenosquamous carcinomas and adenocarcinomas of gallbladder.Cancer Invest. 2013 Feb;31(2):132-9. doi: 10.3109/07357907.2012.756113. Epub 2013 Jan 15.
24	Multi-modality analysis supports APOBEC as a major source of mutations in head and neck squamous cell carcinoma.Oral Oncol. 2017 Nov;74:8-14. doi: 10.1016/j.oraloncology.2017.09.002. Epub 2017 Sep 13.
25	Roles of APOBEC3A and APOBEC3B in Human Papillomavirus Infection and Disease Progression.Viruses. 2017 Aug 21;9(8):233. doi: 10.3390/v9080233.
26	APOBEC3A Expression in Penile Squamous Cell Carcinoma.Pathobiology. 2018;85(3):169-178. doi: 10.1159/000479007. Epub 2017 Nov 23.
27	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.
28	Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
29	Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
30	Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
31	Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
32	Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
33	DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.