Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGT0KTF)

• DOT Name: DNA primase large subunit (PRIM2)
• Synonyms: DNA primase 58 kDa subunit; p58
• Gene Name: PRIM2
• Related Disease:
  Breast cancer
  Breast carcinoma
  Hepatitis C virus infection
  Non-insulin dependent diabetes
• UniProt ID: PRI2_HUMAN
• PDB ID: 3L9Q; 3Q36; 4BPU; 4BPW; 4BPX; 4RR2; 5DQO; 5EXR; 5F0Q; 5F0S; 5I7M; 6DHW; 7OPL; 7U5C; 8B9D; 8D0B; 8D0K; 8D96; 8D9D
• Pfam ID: PF04104
• Sequence:
  MEFSGRKWRKLRLAGDQRNASYPHCLQFYLQPPSENISLIEFENLAIDRVKLLKSVENLG
  VSYVKGTEQYQSKLESELRKLKFSYRENLEDEYEPRRRDHISHFILRLAYCQSEELRRWF
  IQQEMDLLRFRFSILPKDKIQDFLKDSQLQFEAISDEEKTLREQEIVASSPSLSGLKLGF
  ESIYKIPFADALDLFRGRKVYLEDGFAYVPLKDIVAIILNEFRAKLSKALALTARSLPAV
  QSDERLQPLLNHLSHSYTGQDYSTQGNVGKISLDQIDLLSTKSFPPCMRQLHKALRENHH
  LRHGGRMQYGLFLKGIGLTLEQALQFWKQEFIKGKMDPDKFDKGYSYNIRHSFGKEGKRT
  DYTPFSCLKIILSNPPSQGDYHGCPFRHSDPELLKQKLQSYKISPGGISQILDLVKGTHY
  QVACQKYFEMIHNVDDCGFSLNHPNQFFCESQRILNGGKDIKKEPIQPETPQPKPSVQKT
  KDASSALASLNSSLEMDMEGLEDYFSEDS
• Function: Regulatory subunit of the DNA primase complex and component of the DNA polymerase alpha complex (also known as the alpha DNA polymerase-primase complex) 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. Binds RNA:DNA duplex and coordinates the catalytic activities of PRIM1 and POLA2 during primase-to-polymerase switch.
• 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

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Altered Expression	[1]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[1]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[2]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[3]

14 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 large subunit (PRIM2).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of DNA primase large subunit (PRIM2).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of DNA primase large subunit (PRIM2).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of DNA primase large subunit (PRIM2).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of DNA primase large subunit (PRIM2).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of DNA primase large subunit (PRIM2).	[9]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of DNA primase large subunit (PRIM2).	[10]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of DNA primase large subunit (PRIM2).	[11]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of DNA primase large subunit (PRIM2).	[12]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of DNA primase large subunit (PRIM2).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of DNA primase large subunit (PRIM2).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of DNA primase large subunit (PRIM2).	[18]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of DNA primase large subunit (PRIM2).	[8]
Manganese	DMKT129	Investigative	Manganese decreases the expression of DNA primase large subunit (PRIM2).	[19]

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 DNA primase large subunit (PRIM2).	[15]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of DNA primase large subunit (PRIM2).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of DNA primase large subunit (PRIM2).	[17]

References

• [1] Increased susceptibility of breast cancer cells to stress mediated inhibition of protein synthesis.Cancer Res. 2008 Jun 15;68(12):4862-74. doi: 10.1158/0008-5472.CAN-08-0074.
• [2] Characterization of a Threonine-Rich Cluster in Hepatitis C Virus Nonstructural Protein 5A and Its Contribution to Hyperphosphorylation.J Virol. 2018 Nov 27;92(24):e00737-18. doi: 10.1128/JVI.00737-18. Print 2018 Dec 15.
• [3] Meta-analysis of genome-wide association studies identifies eight new loci for type 2 diabetes in east Asians.Nat Genet. 2011 Dec 11;44(1):67-72. doi: 10.1038/ng.1019.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [6] 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.
• [7] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [8] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] 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.
• [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] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [15] 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.
• [16] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [17] 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.
• [18] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [19] 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.