Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIU3F9Y)

• DOT Name: Germ cell nuclear acidic protein (GCNA)
• Synonyms: Acidic repeat-containing protein; Germ cell nuclear acidic peptidase; Germ cell nuclear antigen
• Gene Name: GCNA
• Related Disease:
  Germ cell tumor
  Alpha-1 antitrypsin deficiency
  Asthma
  Dystonia
  Parkinsonian disorder
• UniProt ID: GCNA_HUMAN
• Pfam ID: PF10263
• Sequence:
  MDGCKKELPRLQEPEEDEDCYILNVQSSSDDTSGSSVARRAPKRQASCILNVQSRSGDTS
  GSSVARRAPKRQASSVVVIDSDSDEECHTHEEKKAKLLEINSDDESPECCHVKPAIQEPP
  IVISDDDNDDDNGNDLEVPDDNSDDSEAPDDNSDDSEAPDDNSDDSEAPDDNSDDSEAPD
  DNSDDSDVPDDNSDDSSDDNSDDSSDDNSDDSDVPDDKSDDSDVPDDSSDDSDVPDDSSD
  DSEAPDDSSDDSEAPDDSSDDSEAPDDSSDDSEAPDDSSDDSEASDDSSDDSEASDDSSD
  DSEAPDDKSDDSDVPEDKSDDSDVPDDNSDDLEVPVPAEDLCNEGQIASDEEELVEAAAA
  VSQHDSSDDAGEQDLGENLSKPPSDPEANPEVSERKLPTEEEPAPVVEQSGKRKSKTKTI
  VEPPRKRQTKTKNIVEPPRKRQTKTKNIVEPLRKRKAKTKNVSVTPGHKKRGPSKKKPGA
  AKVEKRKTRTPKCKVPGCFLQDLEKSKKYSGKNLKRNKDELVQRIYDLFNRSVCDKKLPE
  KLRIGWNNKMVKTAGLCSTGEMWYPKWRRFAKIQIGLKVCDSADRIRDTLIHEMCHAASW
  LIDGIHDSHGDAWKYYARKSNRIHPELPRVTRCHNYKINYKVHYECTGCKTRIGCYTKSL
  DTSRFICAKCKGSLVMVPLTQKDGTRIVPHV
• Function: May play a role in DNA-protein cross-links (DPCs) clearance through a SUMO-dependent recruitment to sites of DPCs, ensuring the genomic stability by protecting germ cells and early embryos from various sources of damage. Can resolve the topoisomerase II (TOP2A) DPCs.
• Tissue Specificity: Expressed in germ cells of the testis (at protein level) . Detected in skeletal muscle, liver, kidney, pancreas, heart, lung and brain . Expressed throughout spermatogenesis, from spermatogonia to elongated spermatids, in normal adult testis (at protein level) .

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Germ cell tumor	DIS62070	Strong	Biomarker	[1]
Alpha-1 antitrypsin deficiency	DISQKEHW	moderate	Biomarker	[2]
Asthma	DISW9QNS	moderate	Biomarker	[2]
Dystonia	DISJLFGW	Limited	Biomarker	[3]
Parkinsonian disorder	DISHGY45	Limited	Biomarker	[3]

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 Germ cell nuclear acidic protein (GCNA).	[4]

13 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 Germ cell nuclear acidic protein (GCNA).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Germ cell nuclear acidic protein (GCNA).	[6]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Germ cell nuclear acidic protein (GCNA).	[7]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Germ cell nuclear acidic protein (GCNA).	[8]
Lindane	DMB8CNL	Approved	Lindane increases the expression of Germ cell nuclear acidic protein (GCNA).	[9]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Germ cell nuclear acidic protein (GCNA).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Germ cell nuclear acidic protein (GCNA).	[5]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Germ cell nuclear acidic protein (GCNA).	[11]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Germ cell nuclear acidic protein (GCNA).	[12]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Germ cell nuclear acidic protein (GCNA).	[13]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Germ cell nuclear acidic protein (GCNA).	[8]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of Germ cell nuclear acidic protein (GCNA).	[9]
crotylaldehyde	DMTWRQI	Investigative	crotylaldehyde increases the expression of Germ cell nuclear acidic protein (GCNA).	[14]

References

• [1] GCNA Preserves Genome Integrity and Fertility Across Species.Dev Cell. 2020 Jan 6;52(1):38-52.e10. doi: 10.1016/j.devcel.2019.11.007. Epub 2019 Dec 12.
• [2] Prevalence of alpha-1 antitrypsin deficiency in poorly controlled asthma--results from the ALA-ACRC low-dose theophylline trial. J Asthma. 2007 Oct;44(8):605-8. doi: 10.1080/02770900701540028.
• [3] ACRC codes for a novel nuclear protein with unusual acidic repeat tract and maps to DYT3 (dystonia parkinsonism) critical interval in xq13.1.Neurogenetics. 2001 Oct;3(4):207-13. doi: 10.1007/s100480100120.
• [4] 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.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [8] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [9] Transcriptome-based functional classifiers for direct immunotoxicity. Arch Toxicol. 2014 Mar;88(3):673-89.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] Loss of TRIM33 causes resistance to BET bromodomain inhibitors through MYC- and TGF-beta-dependent mechanisms. Proc Natl Acad Sci U S A. 2016 Aug 2;113(31):E4558-66.
• [12] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [13] Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides. J Biol Chem. 2018 Apr 13;293(15):5600-5612.
• [14] Gene expression profile and cytotoxicity of human bronchial epithelial cells exposed to crotonaldehyde. Toxicol Lett. 2010 Aug 16;197(2):113-22.