Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMO19ZD)

• DOT Name: RAD50-interacting protein 1 (RINT1)
• Synonyms: RAD50 interactor 1; HsRINT-1; RINT-1
• Gene Name: RINT1
• Related Disease:
  Advanced cancer
  Colorectal carcinoma
  Glioblastoma multiforme
  Infantile liver failure syndrome 3
  Neoplasm
  Acute liver failure
  Infantile liver failure syndrome 2
  Breast cancer
  Human papillomavirus infection
  Hereditary breast carcinoma
  Familial ovarian cancer
• UniProt ID: RINT1_HUMAN
• Pfam ID: PF04437
• Sequence:
  MLPAGEIGASPAAPCCSESGDERKNLEEKSDINVTVLIGSKQVSEGTDNGDLPSYVSAFI
  EKEVGNDLKSLKKLDKLIEQRTVSKMQLEEQVLTISSEIPKRIRSALKNAEESKQFLNQF
  LEQETHLFSAINSHLLTAQPWMDDLGTMISQIEEIERHLAYLKWISQIEELSDNIQQYLM
  TNNVPEAASTLVSMAELDIKLQESSCTHLLGFMRATVKFWHKILKDKLTSDFEEILAQLH
  WPFIAPPQSQTVGLSRPASAPEIYSYLETLFCQLLKLQTSDELLTEPKQLPEKYSLPASP
  SVILPIQVMLTPLQKRFRYHFRGNRQTNVLSKPEWYLAQVLMWIGNHTEFLDEKIQPILD
  KVGSLVNARLEFSRGLMMLVLEKLATDIPCLLYDDNLFCHLVDEVLLFERELHSVHGYPG
  TFASCMHILSEETCFQRWLTVERKFALQKMDSMLSSEAAWVSQYKDITDVDEMKVPDCAE
  TFMTLLLVITDRYKNLPTASRKLQFLELQKDLVDDFRIRLTQVMKEETRASLGFRYCAIL
  NAVNYISTVLADWADNVFFLQLQQAALEVFAENNTLSKLQLGQLASMESSVFDDMINLLE
  RLKHDMLTRQVDHVFREVKDAAKLYKKERWLSLPSQSEQAVMSLSSSACPLLLTLRDHLL
  QLEQQLCFSLFKIFWQMLVEKLDVYIYQEIILANHFNEGGAAQLQFDMTRNLFPLFSHYC
  KRPENYFKHIKEACIVLNLNVGSALLLKDVLQSASGQLPATAALNEVGIYKLAQQDVEIL
  LNLRTNWPNTGK
• Function: Involved in regulation of membrane traffic between the Golgi and the endoplasmic reticulum (ER); the function is proposed to depend on its association in the NRZ complex which is believed to play a role in SNARE assembly at the ER. May play a role in cell cycle checkpoint control. Essential for telomere length control.
• Reactome Pathway: COPI-dependent Golgi-to-ER retrograde traffic (R-HSA-6811434)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[1]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[2]
Infantile liver failure syndrome 3	DISELE52	Strong	Autosomal recessive	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[1]
Acute liver failure	DIS5EZKX	moderate	Genetic Variation	[3]
Infantile liver failure syndrome 2	DISGPJDM	Supportive	Autosomal recessive	[3]
Breast cancer	DIS7DPX1	Disputed	Autosomal dominant	[4]
Human papillomavirus infection	DISX61LX	Limited	Biomarker	[5]
Hereditary breast carcinoma	DISAEZT5	Refuted	Autosomal dominant	[6]
Familial ovarian cancer	DISGLR2C	No Known	Autosomal dominant	[6]

6 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 RAD50-interacting protein 1 (RINT1).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of RAD50-interacting protein 1 (RINT1).	[8]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of RAD50-interacting protein 1 (RINT1).	[10]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of RAD50-interacting protein 1 (RINT1).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of RAD50-interacting protein 1 (RINT1).	[13]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of RAD50-interacting protein 1 (RINT1).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of RAD50-interacting protein 1 (RINT1).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of RAD50-interacting protein 1 (RINT1).	[12]

References

• [1] Evaluation of Rint1 as a modifier of intestinal tumorigenesis and cancer risk.PLoS One. 2017 Mar 6;12(3):e0172247. doi: 10.1371/journal.pone.0172247. eCollection 2017.
• [2] Integrative functional genomics identifies RINT1 as a novel GBM oncogene.Neuro Oncol. 2012 Nov;14(11):1325-31. doi: 10.1093/neuonc/nos246. Epub 2012 Oct 16.
• [3] RINT1 Bi-allelic Variations Cause Infantile-Onset Recurrent Acute Liver Failure and Skeletal Abnormalities. Am J Hum Genet. 2019 Jul 3;105(1):108-121. doi: 10.1016/j.ajhg.2019.05.011. Epub 2019 Jun 13.
• [4] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [5] Association of Human Papillomavirus 16 E2 with Rad50-Interacting Protein 1 Enhances Viral DNA Replication.J Virol. 2017 Feb 14;91(5):e02305-16. doi: 10.1128/JVI.02305-16. Print 2017 Mar 1.
• [6] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [7] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [8] 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.
• [9] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [10] 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.
• [11] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [12] 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.
• [13] 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.
• [14] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.