Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWWP8Y6)

• DOT Name: DNA primase small subunit (PRIM1)
• Synonyms: EC 2.7.7.102; DNA primase 49 kDa subunit; p49
• Gene Name: PRIM1
• Related Disease:
  Advanced cancer
  Neoplasm
  Female hypogonadism
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Primordial dwarfism-immunodeficiency-lipodystrophy syndrome
• UniProt ID: PRI1_HUMAN
• PDB ID: 4BPU; 4BPW; 4BPX; 4LIK; 4LIL; 4MHQ; 4RR2; 5EXR; 6R4S; 6R4T; 6R4U; 6R5D; 6R5E; 6RB4; 7OPL; 7U5C; 8B9D; 8D0B; 8D0K; 8D9D
• EC Number: 2.7.7.102
• Pfam ID: PF01896
• Sequence:
  METFDPTELPELLKLYYRRLFPYSQYYRWLNYGGVIKNYFQHREFSFTLKDDIYIRYQSF
  NNQSDLEKEMQKMNPYKIDIGAVYSHRPNQHNTVKLGAFQAQEKELVFDIDMTDYDDVRR
  CCSSADICPKCWTLMTMAIRIIDRALKEDFGFKHRLWVYSGRRGVHCWVCDESVRKLSSA
  VRSGIVEYLSLVKGGQDVKKKVHLSEKIHPFIRKSINIIKKYFEEYALVNQDILENKESW
  DKILALVPETIHDELQQSFQKSHNSLQRWEHLKKVASRYQNNIKNDKYGPWLEWEIMLQY
  CFPRLDINVSKGINHLLKSPFSVHPKTGRISVPIDLQKVDQFDPFTVPTISFICRELDAI
  STNEEEKEENEAESDVKHRTRDYKKTSLAPYVKVFEHFLENLDKSRKGELLKKSDLQKDF
• Function: Catalytic subunit of the DNA primase complex and component of the DNA polymerase alpha complex (also known as the alpha DNA polymerase-primase complex - primosome/replisome) which play an essential role in the initiation of DNA synthesis. During the S phase of the cell cycle, the DNA polymerase alpha complex (composed of a catalytic subunit POLA1, an accessory subunit POLA2 and two primase subunits, the catalytic subunit PRIM1 and the regulatory subunit PRIM2) is recruited to DNA at the replicative forks via direct interactions with MCM10 and WDHD1. The primase subunit of the polymerase alpha complex initiates DNA synthesis by oligomerising short RNA primers on both leading and lagging strands. These primers are initially extended by the polymerase alpha catalytic subunit and subsequently transferred to polymerase delta and polymerase epsilon for processive synthesis on the lagging and leading strand, respectively. In the primase complex, both subunits are necessary for the initial di-nucleotide formation, but the extension of the primer depends only on the catalytic subunit. Synthesizes 9-mer RNA primers (also known as the 'unit length' RNA primers). Incorporates only ribonucleotides in the presence of ribo- and deoxy-nucleotide triphosphates (rNTPs, dNTPs). Requires template thymine or cytidine to start the RNA primer synthesis, with an adenine or guanine at its 5'-end. Binds single stranded DNA.
• KEGG Pathway: D. replication (hsa03030)
• Reactome Pathway:
  Polymerase switching on the C-strand of the telomere (R-HSA-174411)
  Telomere C-strand synthesis initiation (R-HSA-174430)
  DNA replication initiation (R-HSA-68952)
  Activation of the pre-replicative complex (R-HSA-68962)
  Polymerase switching (R-HSA-69091)
  Removal of the Flap Intermediate (R-HSA-69166)
  Processive synthesis on the lagging strand (R-HSA-69183)
  Defective pyroptosis (R-HSA-9710421)
  Inhibition of replication initiation of damaged DNA by RB1/E2F1 (R-HSA-113501)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Neoplasm	DISZKGEW	Strong	Altered Expression	[2]
Female hypogonadism	DISWASB4	moderate	Genetic Variation	[3]
Breast cancer	DIS7DPX1	Limited	Altered Expression	[2]
Breast carcinoma	DIS2UE88	Limited	Altered Expression	[2]
Breast neoplasm	DISNGJLM	Limited	Altered Expression	[2]
Primordial dwarfism-immunodeficiency-lipodystrophy syndrome	DISVW1OY	Limited	Autosomal recessive	[4]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	DNA primase small subunit (PRIM1) affects the response to substance of Fluorouracil.	[34]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of DNA primase small subunit (PRIM1).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of DNA primase small subunit (PRIM1).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of DNA primase small subunit (PRIM1).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of DNA primase small subunit (PRIM1).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of DNA primase small subunit (PRIM1).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of DNA primase small subunit (PRIM1).	[10]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of DNA primase small subunit (PRIM1).	[11]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of DNA primase small subunit (PRIM1).	[12]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of DNA primase small subunit (PRIM1).	[13]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of DNA primase small subunit (PRIM1).	[14]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of DNA primase small subunit (PRIM1).	[13]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of DNA primase small subunit (PRIM1).	[15]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of DNA primase small subunit (PRIM1).	[16]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of DNA primase small subunit (PRIM1).	[17]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of DNA primase small subunit (PRIM1).	[18]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of DNA primase small subunit (PRIM1).	[19]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of DNA primase small subunit (PRIM1).	[20]
Simvastatin	DM30SGU	Approved	Simvastatin decreases the expression of DNA primase small subunit (PRIM1).	[21]
Lucanthone	DMZLBUO	Approved	Lucanthone decreases the expression of DNA primase small subunit (PRIM1).	[22]
Palbociclib	DMD7L94	Approved	Palbociclib decreases the expression of DNA primase small subunit (PRIM1).	[23]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of DNA primase small subunit (PRIM1).	[24]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of DNA primase small subunit (PRIM1).	[25]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of DNA primase small subunit (PRIM1).	[11]
PEITC	DMOMN31	Phase 2	PEITC decreases the expression of DNA primase small subunit (PRIM1).	[26]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of DNA primase small subunit (PRIM1).	[27]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of DNA primase small subunit (PRIM1).	[28]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of DNA primase small subunit (PRIM1).	[29]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of DNA primase small subunit (PRIM1).	[30]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of DNA primase small subunit (PRIM1).	[31]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of DNA primase small subunit (PRIM1).	[32]
Manganese	DMKT129	Investigative	Manganese decreases the expression of DNA primase small subunit (PRIM1).	[33]

References

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• [2] DNA primase polypeptide 1 (PRIM1) involves in estrogen-induced breast cancer formation through activation of the G2/M cell cycle checkpoint.Int J Cancer. 2019 Feb 1;144(3):615-630. doi: 10.1002/ijc.31788. Epub 2018 Nov 21.
• [3] Variation analysis of PRIM1 gene in Chinese patients with primary ovarian insufficiency.Reprod Biomed Online. 2016 Nov;33(5):587-591. doi: 10.1016/j.rbmo.2016.08.017. Epub 2016 Aug 24.
• [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] 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.
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• [7] 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.
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• [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] Convergent transcriptional profiles induced by endogenous estrogen and distinct xenoestrogens in breast cancer cells. Carcinogenesis. 2006 Aug;27(8):1567-78.
• [12] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [13] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [14] 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.
• [15] Methotrexate modulates folate phenotype and inflammatory profile in EA.hy 926 cells. Eur J Pharmacol. 2014 Jun 5;732:60-7.
• [16] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [17] Cannabidiol-induced transcriptomic changes and cellular senescence in human Sertoli cells. Toxicol Sci. 2023 Feb 17;191(2):227-238. doi: 10.1093/toxsci/kfac131.
• [18] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [19] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [20] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [21] Simvastatin inactivates beta1-integrin and extracellular signal-related kinase signaling and inhibits cell proliferation in head and neck squamous cell carcinoma cells. Cancer Sci. 2007 Jun;98(6):890-9.
• [22] Lucanthone is a novel inhibitor of autophagy that induces cathepsin D-mediated apoptosis. J Biol Chem. 2011 Feb 25;286(8):6602-13.
• [23] Cdk4/6 inhibition induces epithelial-mesenchymal transition and enhances invasiveness in pancreatic cancer cells. Mol Cancer Ther. 2012 Oct;11(10):2138-48. doi: 10.1158/1535-7163.MCT-12-0562. Epub 2012 Aug 6.
• [24] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [25] Resveratrol-induced gene expression profiles in human prostate cancer cells. Cancer Epidemiol Biomarkers Prev. 2005 Mar;14(3):596-604. doi: 10.1158/1055-9965.EPI-04-0398.
• [26] Phenethyl isothiocyanate alters the gene expression and the levels of protein associated with cell cycle regulation in human glioblastoma GBM 8401 cells. Environ Toxicol. 2017 Jan;32(1):176-187.
• [27] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [28] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [29] 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.
• [30] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [31] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [32] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.
• [33] Gene expression profiling of human primary astrocytes exposed to manganese chloride indicates selective effects on several functions of the cells. Neurotoxicology. 2007 May;28(3):478-89.
• [34] Mechanistic and predictive profiling of 5-Fluorouracil resistance in human cancer cells. Cancer Res. 2004 Nov 15;64(22):8167-76. doi: 10.1158/0008-5472.CAN-04-0970.