Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7GM7MX)

• DOT Name: DNA-directed RNA polymerase III subunit RPC8 (POLR3H)
• Synonyms: RNA polymerase III subunit C8; DNA-directed RNA polymerase III subunit H; RNA polymerase III subunit 22.9 kDa subunit; RPC22.9
• Gene Name: POLR3H
• Related Disease:
  Female hypogonadism
  Movement disorder
  Ovarian dysgenesis 1
  46 XX gonadal dysgenesis
• UniProt ID: RPC8_HUMAN
• PDB ID: 7A6H; 7AE1; 7AE3; 7AEA; 7AST; 7D58; 7D59; 7DN3; 7DU2; 7FJI; 7FJJ; 8ITY; 8IUE; 8IUH
• Pfam ID: PF08292 ; PF03876
• Sequence:
  MFVLVEMVDTVRIPPWQFERKLNDSIAEELNKKLANKVVYNVGLCICLFDITKLEDAYVF
  PGDGASHTKVHFRCVVFHPFLDEILIGKIKGCSPEGVHVSLGFFDDILIPPESLQQPAKF
  DEAEQVWVWEYETEEGAHDLYMDTGEEIRFRVVDESFVDTSPTGPSSADATTSSEELPKK
  EAPYTLVGSISEPGLGLLSWWTSN
• Function: DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Specific peripheric component of RNA polymerase III (Pol III) which synthesizes small non-coding RNAs including 5S rRNA, snRNAs, tRNAs and miRNAs from at least 500 distinct genomic loci. With CRCP/RPC9 forms a mobile stalk that protrudes from Pol III core and functions primarily in transcription initiation. Pol III plays a key role in sensing and limiting infection by intracellular bacteria and DNA viruses. Acts as nuclear and cytosolic DNA sensor involved in innate immune response. Can sense non-self dsDNA that serves as template for transcription into dsRNA. The non-self RNA polymerase III transcripts, such as Epstein-Barr virus-encoded RNAs (EBERs) induce type I interferon and NF-kappa-B through the RIG-I pathway.
• KEGG Pathway:
  R. polymerase (hsa03020)
  Cytosolic D.-sensing pathway (hsa04623)
• Reactome Pathway:
  RNA Polymerase III Chain Elongation (R-HSA-73780)
  RNA Polymerase III Transcription Termination (R-HSA-73980)
  RNA Polymerase III Abortive And Retractive Initiation (R-HSA-749476)
  RNA Polymerase III Transcription Initiation From Type 1 Promoter (R-HSA-76061)
  RNA Polymerase III Transcription Initiation From Type 2 Promoter (R-HSA-76066)
  RNA Polymerase III Transcription Initiation From Type 3 Promoter (R-HSA-76071)
  Cytosolic sensors of pathogen-associated DNA (R-HSA-1834949)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Female hypogonadism	DISWASB4	Strong	Genetic Variation	[1]
Movement disorder	DISOJJ2D	Strong	CausalMutation	[2]
Ovarian dysgenesis 1	DISXIXHW	Strong	GermlineCausalMutation	[1]
46 XX gonadal dysgenesis	DISBB9HA	Supportive	Autosomal dominant	[1]

7 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-directed RNA polymerase III subunit RPC8 (POLR3H).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of DNA-directed RNA polymerase III subunit RPC8 (POLR3H).	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of DNA-directed RNA polymerase III subunit RPC8 (POLR3H).	[5]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of DNA-directed RNA polymerase III subunit RPC8 (POLR3H).	[6]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of DNA-directed RNA polymerase III subunit RPC8 (POLR3H).	[7]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of DNA-directed RNA polymerase III subunit RPC8 (POLR3H).	[8]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of DNA-directed RNA polymerase III subunit RPC8 (POLR3H).	[9]

References

• [1] Exome Sequencing Reveals the POLR3H Gene as a Novel Cause of Primary Ovarian Insufficiency. J Clin Endocrinol Metab. 2019 Jul 1;104(7):2827-2841. doi: 10.1210/jc.2018-02485.
• [2] Increased Survival and Partly Preserved Cognition in a Patient With ACO2-Related Disease Secondary to a Novel Variant. J Child Neurol. 2017 Aug;32(9):840-845. doi: 10.1177/0883073817711527. Epub 2017 May 25.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] 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.
• [5] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [6] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [7] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [8] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [9] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.