Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVK6K9J)

• DOT Name: DNA-directed primase/polymerase protein (PRIMPOL)
• Synonyms: hPrimpol1; EC 2.7.7.-; Coiled-coil domain-containing protein 111
• Gene Name: PRIMPOL
• Related Disease:
  Invasive breast carcinoma
  Progressive external ophthalmoplegia
• UniProt ID: PRIPO_HUMAN
• PDB ID: 5L2X; 5N85; 5N8A; 7JK1; 7JKL; 7JKP; 7JL8; 7JLG
• EC Number: 2.7.7.-
• Pfam ID: PF01896 ; PF03121
• Sequence:
  MNRKWEAKLKQIEERASHYERKPLSSVYRPRLSKPEEPPSIWRLFHRQAQAFNFVKSCKE
  DVHVFALECKVGDGQRIYLVTTYAEFWFYYKSRKNLLHCYEVIPENAVCKLYFDLEFNKP
  ANPGADGKKMVALLIEYVCKALQELYGVNCSAEDVLNLDSSTDEKFSRHLIFQLHDVAFK
  DNIHVGNFLRKILQPALDLLGSEDDDSAPETTGHGFPHFSEAPARQGFSFNKMFTEKATE
  ESWTSNSKKLERLGSAEQSSPDLSFLVVKNNMGEKHLFVDLGVYTRNRNFRLYKSSKIGK
  RVALEVTEDNKFFPIQSKDVSDEYQYFLSSLVSNVRFSDTLRILTCEPSQNKQKGVGYFN
  SIGTSVETIEGFQCSPYPEVDHFVLSLVNKDGIKGGIRRWNYFFPEELLVYDICKYRWCE
  NIGRAHKSNNIMILVDLKNEVWYQKCHDPVCKAENFKSDCFPLPAEVCLLFLFKEEEEFT
  TDEADETRSNETQNPHKPSPSRLSTGASADAVWDNGIDDAYFLEATEDAELAEAAENSLL
  SYNSEVDEIPDELIIEVLQE
• Function: DNA primase and DNA polymerase required to tolerate replication-stalling lesions by bypassing them. Required to facilitate mitochondrial and nuclear replication fork progression by initiating de novo DNA synthesis using dNTPs and acting as an error-prone DNA polymerase able to bypass certain DNA lesions. Shows a high capacity to tolerate DNA damage lesions such as 8oxoG and abasic sites in DNA. Provides different translesion synthesis alternatives when DNA replication is stalled: able to synthesize DNA primers downstream of lesions, such as ultraviolet (UV) lesions, R-loops and G-quadruplexes, to allow DNA replication to continue. Can also realign primers ahead of 'unreadable lesions' such as abasic sites and 6-4 photoproduct (6-4 pyrimidine-pyrimidinone), thereby skipping the lesion. Also able to incorporate nucleotides opposite DNA lesions such as 8oxoG, like a regular translesion synthesis DNA polymerase. Also required for reinitiating stalled forks after UV damage during nuclear DNA replication. Required for mitochondrial DNA (mtDNA) synthesis and replication, by reinitiating synthesis after UV damage or in the presence of chain-terminating nucleotides. Prevents APOBEC family-mediated DNA mutagenesis by repriming downstream of abasic site to prohibit error-prone translesion synthesis. Has non-overlapping function with POLH. In addition to its role in DNA damage response, also required to maintain efficient nuclear and mitochondrial DNA replication in unperturbed cells ; Involved in adaptive response to cisplatin, a chemotherapeutic that causes reversal of replication forks, in cancer cells: reinitiates DNA synthesis past DNA lesions in BRCA1-deficient cancer cells treated with cisplatin via its de novo priming activity. Repriming rescues fork degradation while leading to accumulation of internal ssDNA gaps behind the forks. ATR regulates adaptive response to cisplatin.

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Invasive breast carcinoma	DISANYTW	Definitive	Altered Expression	[1]
Progressive external ophthalmoplegia	DISX4ATI	Definitive	Genetic Variation	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of DNA-directed primase/polymerase protein (PRIMPOL).	[3]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of DNA-directed primase/polymerase protein (PRIMPOL).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of DNA-directed primase/polymerase protein (PRIMPOL).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of DNA-directed primase/polymerase protein (PRIMPOL).	[5]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of DNA-directed primase/polymerase protein (PRIMPOL).	[6]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of DNA-directed primase/polymerase protein (PRIMPOL).	[6]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of DNA-directed primase/polymerase protein (PRIMPOL).	[7]

References

• [1] PrimPol prevents APOBEC/AID family mediated DNA mutagenesis.Nucleic Acids Res. 2016 Jun 2;44(10):4734-44. doi: 10.1093/nar/gkw123. Epub 2016 Feb 28.
• [2] A PRIMPOL mutation and variants in multiple genes may contribute to phenotypes in a familial case with chronic progressive external ophthalmoplegia symptoms.Neurosci Res. 2020 Aug;157:58-63. doi: 10.1016/j.neures.2019.07.006. Epub 2019 Jul 23.
• [3] 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.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] 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.
• [6] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [7] 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.
• [8] 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.