Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTADQ0OA)

• DOT Name: E3 ubiquitin-protein ligase MARCHF2 (MARCHF2)
• Synonyms: EC 2.3.2.27; Membrane-associated RING finger protein 2; Membrane-associated RING-CH protein II; MARCH-II; RING finger protein 172; RING-type E3 ubiquitin transferase MARCHF2
• Gene Name: MARCHF2
• Related Disease:
  Bacteremia
  Advanced cancer
  Cervical cancer
  Cervical carcinoma
  Colon cancer
  Colon carcinoma
  Hepatitis C virus infection
  Liver cirrhosis
  Ankylosing spondylitis
• UniProt ID: MARH2_HUMAN
• EC Number: 2.3.2.27
• Pfam ID: PF12906
• Sequence:
  MTTGDCCHLPGSLCDCSGSPAFSKVVEATGLGPPQYVAQVTSRDGRLLSTVIRALDTPSD
  GPFCRICHEGANGECLLSPCGCTGTLGAVHKSCLEKWLSSSNTSYCELCHTEFAVEKRPR
  PLTEWLKDPGPRTEKRTLCCDMVCFLFITPLAAISGWLCLRGAQDHLRLHSQLEAVGLIA
  LTIALFTIYVLWTLVSFRYHCQLYSEWRKTNQKVRLKIREADSPEGPQHSPLAAGLLKKV
  AEETPV
• Function: E3 ubiquitin-protein ligase that may mediate ubiquitination of TFRC and CD86, and promote their subsequent endocytosis and sorting to lysosomes via multivesicular bodies. E3 ubiquitin ligases accept ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfer the ubiquitin to targeted substrates. Together with GOPC/CAL mediates the ubiquitination and lysosomal degradation of CFTR. Ubiquitinates and therefore mediates the degradation of DLG1. Regulates the intracellular trafficking and secretion of alpha1-antitrypsin/SERPINA1 and HP/haptoglobin via ubiquitination and degradation of the cargo receptor ERGIC3. Negatively regulates the antiviral and antibacterial immune response by repression of the NF-kB and type 1 IFN signaling pathways, via MARCHF2-mediated K48-linked polyubiquitination of IKBKG/NEMO, resulting in its proteasomal degradation. May be involved in endosomal trafficking through interaction with STX6 ; (Microbial infection) Positively regulates the degradation of Vesicular stomatitis virus (VSV) G protein via the lysosomal degradation pathway. Represses HIV-1 viral production and may inhibit the translocation of HIV-1 env to the cell surface, resulting in decreased viral cell-cell transmission.
• Tissue Specificity: Broadly expressed.

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bacteremia	DIS6N9RZ	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Cervical cancer	DISFSHPF	Strong	Altered Expression	[3]
Cervical carcinoma	DIST4S00	Strong	Altered Expression	[3]
Colon cancer	DISVC52G	Strong	Biomarker	[4]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[4]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[5]
Liver cirrhosis	DIS4G1GX	Strong	Biomarker	[6]
Ankylosing spondylitis	DISRC6IR	Limited	Biomarker	[7]

1 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 E3 ubiquitin-protein ligase MARCHF2 (MARCHF2).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of E3 ubiquitin-protein ligase MARCHF2 (MARCHF2).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of E3 ubiquitin-protein ligase MARCHF2 (MARCHF2).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of E3 ubiquitin-protein ligase MARCHF2 (MARCHF2).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of E3 ubiquitin-protein ligase MARCHF2 (MARCHF2).	[12]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of E3 ubiquitin-protein ligase MARCHF2 (MARCHF2).	[13]
Selenium	DM25CGV	Approved	Selenium increases the expression of E3 ubiquitin-protein ligase MARCHF2 (MARCHF2).	[14]
Pantothenic acid	DM091H2	Approved	Pantothenic acid increases the expression of E3 ubiquitin-protein ligase MARCHF2 (MARCHF2).	[15]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of E3 ubiquitin-protein ligase MARCHF2 (MARCHF2).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of E3 ubiquitin-protein ligase MARCHF2 (MARCHF2).	[9]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of E3 ubiquitin-protein ligase MARCHF2 (MARCHF2).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of E3 ubiquitin-protein ligase MARCHF2 (MARCHF2).	[18]
CH-223191	DMMJZYC	Investigative	CH-223191 decreases the expression of E3 ubiquitin-protein ligase MARCHF2 (MARCHF2).	[19]

References

• [1] Serratia marcescens Bacteremia: Nosocomial Cluster Following Narcotic Diversion.Infect Control Hosp Epidemiol. 2017 Sep;38(9):1027-1031. doi: 10.1017/ice.2017.137. Epub 2017 Jul 6.
• [2] Systems biology: confronting the complexity of cancer.Cancer Res. 2011 Sep 15;71(18):5961-4. doi: 10.1158/0008-5472.CAN-11-1569. Epub 2011 Sep 6.
• [3] Cervical cancer screening service utilization and associated factors among HIV positive women attending adult ART clinic in public health facilities, Hawassa town, Ethiopia: a cross-sectional study.BMC Health Serv Res. 2019 Nov 19;19(1):847. doi: 10.1186/s12913-019-4718-5.
• [4] Knockout of MARCH2 inhibits the growth of HCT116 colon cancer cells by inducing endoplasmic reticulum stress.Cell Death Dis. 2017 Jul 27;8(7):e2957. doi: 10.1038/cddis.2017.347.
• [5] Treatment of acute hepatitis C genotypes 1 and 4 with 8 weeks of grazoprevir plus elbasvir (DAHHS2): an open-label, multicentre, single-arm, phase 3b trial.Lancet Gastroenterol Hepatol. 2019 Apr;4(4):269-277. doi: 10.1016/S2468-1253(18)30414-X. Epub 2019 Jan 17.
• [6] Efficacy of Sofosbuvir, Velpatasvir, and GS-9857 in Patients WithGenotype 1 Hepatitis C Virus Infection in an Open-Label, Phase 2 Trial.Gastroenterology. 2016 Nov;151(5):893-901.e1. doi: 10.1053/j.gastro.2016.07.039. Epub 2016 Jul 30.
• [7] Quality and readability of online information on ankylosing spondylitis.Clin Rheumatol. 2019 Nov;38(11):3269-3274. doi: 10.1007/s10067-019-04706-y. Epub 2019 Aug 1.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [12] 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.
• [13] Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
• [14] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [15] Calcium pantothenate modulates gene expression in proliferating human dermal fibroblasts. Exp Dermatol. 2009 Nov;18(11):969-78. doi: 10.1111/j.1600-0625.2009.00884.x. Epub 2009 Apr 8.
• [16] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [17] 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.
• [18] 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.
• [19] Adaptive changes in global gene expression profile of lung carcinoma A549 cells acutely exposed to distinct types of AhR ligands. Toxicol Lett. 2018 Aug;292:162-174.