Details of Drug Off-Target (DOT)

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

• DOT Name: Replication initiator 1 (REPIN1)
• Synonyms: 60 kDa origin-specific DNA-binding protein; 60 kDa replication initiation region protein; ATT-binding protein; DHFR oribeta-binding protein RIP60; Zinc finger protein 464
• Gene Name: REPIN1
• Related Disease:
  Metabolic disorder
  Breast cancer
  Breast carcinoma
  Cerebral palsy
  Fatty liver disease
  Glioma
  Neoplasm
  Non-alcoholic fatty liver disease
  Obesity
• UniProt ID: REPI1_HUMAN
• Pfam ID: PF00096
• Sequence:
  MLERRCRGPLAMGLAQPRLLSGPSQESPQTLGKESRGLRQQGTSVAQSGAQAPGRAHRCA
  HCRRHFPGWVALWLHTRRCQARLPLPCPECGRRFRHAPFLALHRQVHAAATPDLGFACHL
  CGQSFRGWVALVLHLRAHSAAKRPIACPKCERRFWRRKQLRAHLRRCHPPAPEARPFICG
  NCGRSFAQWDQLVAHKRVHVAEALEEAAAKALGPRPRGRPAVTAPRPGGDAVDRPFQCAC
  CGKRFRHKPNLIAHRRVHTGERPHQCPECGKRFTNKPYLTSHRRIHTGEKPYPCKECGRR
  FRHKPNLLSHSKIHKRSEGSAQAAPGPGSPQLPAGPQESAAEPTPAVPLKPAQEPPPGAP
  PEHPQDPIEAPPSLYSCDDCGRSFRLERFLRAHQRQHTGERPFTCAECGKNFGKKTHLVA
  HSRVHSGERPFACEECGRRFSQGSHLAAHRRDHAPDRPFVCPDCGKAFRHKPYLAAHRRI
  HTGEKPYVCPDCGKAFSQKSNLVSHRRIHTGERPYACPDCDRSFSQKSNLITHRKSHIRD
  GAFCCAICGQTFDDEERLLAHQKKHDV
• Function: Sequence-specific double-stranded DNA-binding protein required for initiation of chromosomal DNA replication. Binds on 5'-ATT-3' reiterated sequences downstream of the origin of bidirectional replication (OBR) and a second, homologous ATT sequence of opposite orientation situated within the OBR zone. Facilitates DNA bending.

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Metabolic disorder	DIS71G5H	Definitive	Altered Expression	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Cerebral palsy	DIS82ODL	Strong	Genetic Variation	[3]
Fatty liver disease	DIS485QZ	Strong	Biomarker	[4]
Glioma	DIS5RPEH	Strong	Biomarker	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[6]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Altered Expression	[6]
Obesity	DIS47Y1K	Strong	Biomarker	[4]

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 Replication initiator 1 (REPIN1).	[7]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid increases the phosphorylation of Replication initiator 1 (REPIN1).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Replication initiator 1 (REPIN1).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Replication initiator 1 (REPIN1).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Replication initiator 1 (REPIN1).	[10]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Replication initiator 1 (REPIN1).	[11]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate decreases the expression of Replication initiator 1 (REPIN1).	[12]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Replication initiator 1 (REPIN1).	[13]
Phenol	DM1QSM3	Phase 2/3	Phenol decreases the expression of Replication initiator 1 (REPIN1).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Replication initiator 1 (REPIN1).	[15]

References

• [1] Replication initiator 1 in adipose tissue function and human obesity.Vitam Horm. 2013;91:97-105. doi: 10.1016/B978-0-12-407766-9.00005-5.
• [2] The Transcription Factor AP4 Promotes Oncogenic Phenotypes and Cisplatin Resistance by Regulating LAPTM4B Expression.Mol Cancer Res. 2018 May;16(5):857-868. doi: 10.1158/1541-7786.MCR-17-0519. Epub 2018 Jan 29.
• [3] Genetic association study of adaptor protein complex 4 with cerebral palsy in a Han Chinese population.Mol Biol Rep. 2013 Nov;40(11):6459-67. doi: 10.1007/s11033-013-2761-6. Epub 2013 Sep 25.
• [4] Liver-specific Repin1 deficiency impairs transient hepatic steatosis in liver regeneration.Sci Rep. 2018 Nov 15;8(1):16858. doi: 10.1038/s41598-018-35325-3.
• [5] Hsa-mir-127 impairs survival of patients with glioma and promotes proliferation, migration and invasion of cancerous cells by modulating replication initiator 1.Neuroreport. 2018 Sep 26;29(14):1166-1173. doi: 10.1097/WNR.0000000000001089.
• [6] Repin1 deficiency in liver tissue alleviates NAFLD progression in mice.J Adv Res. 2018 Nov 22;16:99-111. doi: 10.1016/j.jare.2018.11.003. eCollection 2019 Mar.
• [7] 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.
• [8] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [11] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [12] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [13] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [14] Classification of heavy-metal toxicity by human DNA microarray analysis. Environ Sci Technol. 2007 May 15;41(10):3769-74.
• [15] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [16] Functional lipidomics: Palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism. Hepatology. 2017 Aug;66(2):432-448. doi: 10.1002/hep.29033. Epub 2017 Jun 16.