Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCMJ3K3)

• DOT Name: KRR1 small subunit processome component homolog (KRR1)
• Synonyms: HIV-1 Rev-binding protein 2; KRR-R motif-containing protein 1; Rev-interacting protein 1; Rip-1
• Gene Name: KRR1
• Related Disease:
  Neoplasm
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Gastric cancer
  Polycystic ovarian syndrome
  Stomach cancer
  Advanced cancer
  Gallbladder cancer
  Gallbladder carcinoma
  Lung cancer
  Lung carcinoma
• UniProt ID: KRR1_HUMAN
• PDB ID: 7MQ8; 7MQ9
• Pfam ID: PF17903 ; PF21800
• Sequence:
  MASPSLERPEKGAGKSEFRNQKPKPENQDESELLTVPDGWKEPAFSKEDNPRGLLEESSF
  ATLFPKYREAYLKECWPLVQKALNEHHVNATLDLIEGSMTVCTTKKTFDPYIIIRARDLI
  KLLARSVSFEQAVRILQDDVACDIIKIGSLVRNKERFVKRRQRLIGPKGSTLKALELLTN
  CYIMVQGNTVSAIGPFSGLKEVRKVVLDTMKNIHPIYNIKSLMIKRELAKDSELRSQSWE
  RFLPQFKHKNVNKRKEPKKKTVKKEYTPFPPPQPESQIDKELASGEYFLKANQKKRQKME
  AIKAKQAEAISKRQEERNKAFIPPKEKPIVKPKEASTETKIDVASIKEKVKKAKNKKLGA
  LTAEEIALKMEADEKKKKKKK
• Function: Part of the small subunit (SSU) processome, first precursor of the small eukaryotic ribosomal subunit. During the assembly of the SSU processome in the nucleolus, many ribosome biogenesis factors, an RNA chaperone and ribosomal proteins associate with the nascent pre-rRNA and work in concert to generate RNA folding, modifications, rearrangements and cleavage as well as targeted degradation of pre-ribosomal RNA by the RNA exosome.
• Reactome Pathway:
  Major pathway of rRNA processing in the nucleolus and cytosol (R-HSA-6791226)
  rRNA modification in the nucleus and cytosol (R-HSA-6790901)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Altered Expression	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[2]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[3]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Genetic Variation	[4]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[3]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[5]
Gallbladder cancer	DISXJUAF	moderate	Biomarker	[1]
Gallbladder carcinoma	DISD6ACL	moderate	Biomarker	[1]
Lung cancer	DISCM4YA	Limited	Biomarker	[6]
Lung carcinoma	DISTR26C	Limited	Biomarker	[6]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	KRR1 small subunit processome component homolog (KRR1) affects the response to substance of Methotrexate.	[18]
Mitoxantrone	DMM39BF	Approved	KRR1 small subunit processome component homolog (KRR1) affects the response to substance of Mitoxantrone.	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of KRR1 small subunit processome component homolog (KRR1).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of KRR1 small subunit processome component homolog (KRR1).	[8]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of KRR1 small subunit processome component homolog (KRR1).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of KRR1 small subunit processome component homolog (KRR1).	[10]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of KRR1 small subunit processome component homolog (KRR1).	[12]
Selenium	DM25CGV	Approved	Selenium decreases the expression of KRR1 small subunit processome component homolog (KRR1).	[13]
Piroxicam	DMTK234	Approved	Piroxicam increases the expression of KRR1 small subunit processome component homolog (KRR1).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of KRR1 small subunit processome component homolog (KRR1).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of KRR1 small subunit processome component homolog (KRR1).	[16]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of KRR1 small subunit processome component homolog (KRR1).	[17]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of KRR1 small subunit processome component homolog (KRR1).	[15]

References

• [1] Receptorinteracting serine/threonineprotein kinase 1 promotes the progress and lymph metastasis of gallbladder cancer.Oncol Rep. 2019 Dec;42(6):2435-2449. doi: 10.3892/or.2019.7331. Epub 2019 Sep 23.
• [2] Autoantibody Response to ZRF1 and KRR1 SEREX Antigens in Patients with Breast Tumors of Different Histological Types and Grades.Dis Markers. 2016;2016:5128720. doi: 10.1155/2016/5128720. Epub 2016 Oct 25.
• [3] Receptor-interacting protein-1 promotes the growth and invasion in gastric cancer.Int J Oncol. 2016 Jun;48(6):2387-98. doi: 10.3892/ijo.2016.3455. Epub 2016 Mar 24.
• [4] ERBB4 Confers Risk for Polycystic Ovary Syndrome in Han Chinese.Sci Rep. 2017 Feb 14;7:42000. doi: 10.1038/srep42000.
• [5] Expression of the RIP-1 gene and its role in growth and invasion of human gallbladder carcinoma.Cell Physiol Biochem. 2014;34(4):1152-65. doi: 10.1159/000366328. Epub 2014 Sep 22.
• [6] CYLD Promotes TNF--Induced Cell Necrosis Mediated by RIP-1 in Human Lung Cancer Cells.Mediators Inflamm. 2016;2016:1542786. doi: 10.1155/2016/1542786. Epub 2016 Sep 25.
• [7] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [10] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [11] Epigenetic changes in individuals with arsenicosis. Chem Res Toxicol. 2011 Feb 18;24(2):165-7. doi: 10.1021/tx1004419. Epub 2011 Feb 4.
• [12] 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.
• [13] 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.
• [14] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [15] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [16] 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.
• [17] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [18] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.