Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT25AGMB)

• DOT Name: Regulator of chromosome condensation (RCC1)
• Synonyms: Cell cycle regulatory protein; Chromosome condensation protein 1
• Gene Name: RCC1
• Related Disease:
  Advanced cancer
  Asthma
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Carcinoma
  Clear cell renal carcinoma
  Cryptococcosis
  Hereditary breast carcinoma
  Neoplasm
  Nephronophthisis
  Polycystic kidney disease
  Prostate cancer
  Prostate carcinoma
  Renal cell carcinoma
  Retinitis pigmentosa
  Stomach cancer
  Retinitis pigmentosa 3
  Thyroid cancer
  Thyroid gland carcinoma
• UniProt ID: RCC1_HUMAN
• PDB ID: 1A12; 1I2M; 5E1B; 5E1D; 5E1M; 5E1O; 5E2A; 5E2B; 5TBK; 6DUB; 8UX1
• Pfam ID: PF00415
• Sequence:
  MSPKRIAKRRSPPADAIPKSKKVKVSHRSHSTEPGLVLTLGQGDVGQLGLGENVMERKKP
  ALVSIPEDVVQAEAGGMHTVCLSKSGQVYSFGCNDEGALGRDTSVEGSEMVPGKVELQEK
  VVQVSAGDSHTAALTDDGRVFLWGSFRDNNGVIGLLEPMKKSMVPVQVQLDVPVVKVASG
  NDHLVMLTADGDLYTLGCGEQGQLGRVPELFANRGGRQGLERLLVPKCVMLKSRGSRGHV
  RFQDAFCGAYFTFAISHEGHVYGFGLSNYHQLGTPGTESCFIPQNLTSFKNSTKSWVGFS
  GGQHHTVCMDSEGKAYSLGRAEYGRLGLGEGAEEKSIPTLISRLPAVSSVACGASVGYAV
  TKDGRVFAWGMGTNYQLGTGQDEDAWSPVEMMGKQLENRVVLSVSSGGQHTVLLVKDKEQ
  S
• Function: Guanine-nucleotide releasing factor that promotes the exchange of Ran-bound GDP by GTP, and thereby plays an important role in RAN-mediated functions in nuclear import and mitosis. Contributes to the generation of high levels of chromosome-associated, GTP-bound RAN, which is important for mitotic spindle assembly and normal progress through mitosis. Via its role in maintaining high levels of GTP-bound RAN in the nucleus, contributes to the release of cargo proteins from importins after nuclear import. Involved in the regulation of onset of chromosome condensation in the S phase. Binds both to the nucleosomes and double-stranded DNA.
• Reactome Pathway:
  Nuclear import of Rev protein (R-HSA-180746)
  Postmitotic nuclear pore complex (NPC) reformation (R-HSA-9615933)
  Rev-mediated nuclear export of HIV RNA (R-HSA-165054)

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Asthma	DISW9QNS	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Breast neoplasm	DISNGJLM	Strong	Genetic Variation	[3]
Carcinoma	DISH9F1N	Strong	Biomarker	[4]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[5]
Cryptococcosis	DISDYDTK	Strong	Biomarker	[6]
Hereditary breast carcinoma	DISAEZT5	Strong	Genetic Variation	[3]
Neoplasm	DISZKGEW	Strong	Altered Expression	[7]
Nephronophthisis	DISXU4HY	Strong	Genetic Variation	[8]
Polycystic kidney disease	DISWS3UY	Strong	Biomarker	[8]
Prostate cancer	DISF190Y	Strong	Altered Expression	[9]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[9]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[5]
Retinitis pigmentosa	DISCGPY8	Strong	Genetic Variation	[10]
Stomach cancer	DISKIJSX	Strong	Biomarker	[7]
Retinitis pigmentosa 3	DIS4VBK1	Limited	Genetic Variation	[11]
Thyroid cancer	DIS3VLDH	Limited	Genetic Variation	[12]
Thyroid gland carcinoma	DISMNGZ0	Limited	Genetic Variation	[12]

13 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 Regulator of chromosome condensation (RCC1).	[13]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Regulator of chromosome condensation (RCC1).	[14]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Regulator of chromosome condensation (RCC1).	[15]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Regulator of chromosome condensation (RCC1).	[16]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Regulator of chromosome condensation (RCC1).	[17]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Regulator of chromosome condensation (RCC1).	[18]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Regulator of chromosome condensation (RCC1).	[19]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Regulator of chromosome condensation (RCC1).	[20]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Regulator of chromosome condensation (RCC1).	[21]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene decreases the expression of Regulator of chromosome condensation (RCC1).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Regulator of chromosome condensation (RCC1).	[24]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Regulator of chromosome condensation (RCC1).	[25]
AM251	DMTAWHL	Investigative	AM251 decreases the expression of Regulator of chromosome condensation (RCC1).	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Regulator of chromosome condensation (RCC1).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Regulator of chromosome condensation (RCC1).	[23]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid decreases the phosphorylation of Regulator of chromosome condensation (RCC1).	[26]

References

• [1] Novel Ran-RCC1 Inhibitory Peptide-Loaded Nanoparticles Have Anti-Cancer Efficacy In Vitro and In Vivo.Cancers (Basel). 2019 Feb 14;11(2):222. doi: 10.3390/cancers11020222.
• [2] RasGRP4, a new mast cell-restricted Ras guanine nucleotide-releasing protein with calcium- and diacylglycerol-binding motifs. Identification of defective variants of this signaling protein in asthma, mastocytosis, and mast cell leukemia patients and demonstration of the importance of RasGRP4 in mast cell development and function.J Biol Chem. 2002 Jul 12;277(28):25756-74. doi: 10.1074/jbc.M202575200. Epub 2002 Apr 15.
• [3] Exome sequencing and case-control analyses identify RCC1 as a candidate breast cancer susceptibility gene.Int J Cancer. 2018 Jun 15;142(12):2512-2517. doi: 10.1002/ijc.31273. Epub 2018 Feb 5.
• [4] Regulator of chromatin condensation 1 abrogates the G1 cell cycle checkpoint via Cdk1 in human papillomavirus E7-expressing epithelium and cervical cancer cells.Cell Death Dis. 2018 May 22;9(6):583. doi: 10.1038/s41419-018-0584-z.
• [5] Estrogen inhibits renal cell carcinoma cell progression through estrogen receptor- activation.PLoS One. 2013;8(2):e56667. doi: 10.1371/journal.pone.0056667. Epub 2013 Feb 27.
• [6] Role of clathrin-mediated endocytosis in the use of heme and hemoglobin by the fungal pathogen Cryptococcus neoformans.Cell Microbiol. 2019 Mar;21(3):e12961. doi: 10.1111/cmi.12961. Epub 2018 Nov 20.
• [7] Methylation-silencing RCC1 expression is associated with tumorigenesis and depth of invasion in gastric cancer.Int J Clin Exp Pathol. 2015 Nov 1;8(11):14257-69. eCollection 2015.
• [8] A novel mutation causing nephronophthisis in the Lewis polycystic kidney rat localises to a conserved RCC1 domain in Nek8.BMC Genomics. 2012 Aug 16;13:393. doi: 10.1186/1471-2164-13-393.
• [9] CHC1-L, a candidate gene for prostate carcinogenesis at 13q14.2, is frequently affected by loss of heterozygosity and underexpressed in human prostate cancer.Int J Cancer. 2002 Jun 10;99(5):689-96. doi: 10.1002/ijc.10393.
• [10] Interaction of retinitis pigmentosa GTPase regulator (RPGR) with RAB8A GTPase: implications for cilia dysfunction and photoreceptor degeneration.Hum Mol Genet. 2010 Sep 15;19(18):3591-8. doi: 10.1093/hmg/ddq275. Epub 2010 Jul 14.
• [11] A gene (RPGR) with homology to the RCC1 guanine nucleotide exchange factor is mutated in X-linked retinitis pigmentosa (RP3).Nat Genet. 1996 May;13(1):35-42. doi: 10.1038/ng0596-35.
• [12] A somatic mutation of RasGRP3 decreases Na(+)/I(-) symporter expression in metastases of radioactive iodine-refractory thyroid cancer by stimulating the Akt signaling pathway.Am J Cancer Res. 2018 Sep 1;8(9):1847-1855. eCollection 2018.
• [13] A genomic approach to predict synergistic combinations for breast cancer treatment. Pharmacogenomics J. 2013 Feb;13(1):94-104. doi: 10.1038/tpj.2011.48. Epub 2011 Nov 15.
• [14] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [15] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [16] 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.
• [17] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [18] 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.
• [19] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [20] Progesterone regulation of implantation-related genes: new insights into the role of oestrogen. Cell Mol Life Sci. 2007 Apr;64(7-8):1009-32.
• [21] Cellular response to 5-fluorouracil (5-FU) in 5-FU-resistant colon cancer cell lines during treatment and recovery. Mol Cancer. 2006 May 18;5:20. doi: 10.1186/1476-4598-5-20.
• [22] 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.
• [23] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [24] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [25] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [26] 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.
• [27] Cannabinoid derivatives induce cell death in pancreatic MIA PaCa-2 cells via a receptor-independent mechanism. FEBS Lett. 2006 Mar 20;580(7):1733-9.