Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8KHYFY)

• DOT Name: Ribonuclease H2 subunit B (RNASEH2B)
• Synonyms: RNase H2 subunit B; Aicardi-Goutieres syndrome 2 protein; AGS2; Deleted in lymphocytic leukemia 8; Ribonuclease HI subunit B
• Gene Name: RNASEH2B
• Related Disease:
  Aicardi-Goutieres syndrome 2
  Carcinoma
  Colorectal neoplasm
  Glioblastoma multiforme
  Glioma
  Hereditary spastic paraplegia
  Metastatic prostate carcinoma
  Prostate adenocarcinoma
  Prostate carcinoma
  Rheumatoid arthritis
  Aicardi-Goutieres syndrome
  Dystonia
  Intellectual disability
  Prostate cancer
• UniProt ID: RNH2B_HUMAN
• PDB ID: 3P56; 3P87; 3PUF
• Pfam ID: PF09468 ; PF17745
• Sequence:
  MAAGVDCGDGVGARQHVFLVSEYLKDASKKMKNGLMFVKLVNPCSGEGAIYLFNMCLQQL
  FEVKVFKEKHHSWFINQSVQSGGLLHFATPVDPLFLLLHYLIKADKEGKFQPLDQVVVDN
  VFPNCILLLKLPGLEKLLHHVTEEKGNPEIDNKKYYKYSKEKTLKWLEKKVNQTVAALKT
  NNVNVSSRVQSTAFFSGDQASTDKEEDYIRYAHGLISDYIPKELSDDLSKYLKLPEPSAS
  LPNPPSKKIKLSDEPVEAKEDYTKFNTKDLKTEKKNSKMTAAQKALAKVDKSGMKSIDTF
  FGVKNKKKIGKV
• Function: Non catalytic subunit of RNase H2, an endonuclease that specifically degrades the RNA of RNA:DNA hybrids. Participates in DNA replication, possibly by mediating the removal of lagging-strand Okazaki fragment RNA primers during DNA replication. Mediates the excision of single ribonucleotides from DNA:RNA duplexes.
• Tissue Specificity: Widely expressed.
• KEGG Pathway: D. replication (hsa03030)
• BioCyc Pathway: MetaCyc:HS13612-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Aicardi-Goutieres syndrome 2	DISOL1R1	Definitive	Autosomal recessive	[1]
Carcinoma	DISH9F1N	Strong	Genetic Variation	[2]
Colorectal neoplasm	DISR1UCN	Strong	Genetic Variation	[3]
Glioblastoma multiforme	DISK8246	Strong	Genetic Variation	[2]
Glioma	DIS5RPEH	Strong	Biomarker	[2]
Hereditary spastic paraplegia	DISGZQV1	Strong	Biomarker	[4]
Metastatic prostate carcinoma	DISVBEZ9	Strong	Genetic Variation	[5]
Prostate adenocarcinoma	DISBZYU8	Strong	Altered Expression	[6]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[2]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[7]
Aicardi-Goutieres syndrome	DIS1NH4X	Supportive	Autosomal dominant	[8]
Dystonia	DISJLFGW	Limited	Biomarker	[9]
Intellectual disability	DISMBNXP	Limited	Biomarker	[10]
Prostate cancer	DISF190Y	Limited	Autosomal dominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Ribonuclease H2 subunit B (RNASEH2B).	[11]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Ribonuclease H2 subunit B (RNASEH2B).	[12]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Ribonuclease H2 subunit B (RNASEH2B).	[13]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Ribonuclease H2 subunit B (RNASEH2B).	[15]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Ribonuclease H2 subunit B (RNASEH2B).	[16]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Ribonuclease H2 subunit B (RNASEH2B).	[17]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Ribonuclease H2 subunit B (RNASEH2B).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Ribonuclease H2 subunit B (RNASEH2B).	[18]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Ribonuclease H2 subunit B (RNASEH2B).	[19]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Ribonuclease H2 subunit B (RNASEH2B).	[20]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Ribonuclease H2 subunit B (RNASEH2B).	[21]
CH-223191	DMMJZYC	Investigative	CH-223191 decreases the expression of Ribonuclease H2 subunit B (RNASEH2B).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Ribonuclease H2 subunit B (RNASEH2B).	[14]

References

• [1] 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.
• [2] Rare ADAR and RNASEH2B variants and a type I interferon signature in glioma and prostate carcinoma risk and tumorigenesis.Acta Neuropathol. 2017 Dec;134(6):905-922. doi: 10.1007/s00401-017-1774-y. Epub 2017 Oct 13.
• [3] Epithelial RNase H2 Maintains Genome Integrity and Prevents Intestinal Tumorigenesis in Mice.Gastroenterology. 2019 Jan;156(1):145-159.e19. doi: 10.1053/j.gastro.2018.09.047. Epub 2018 Sep 28.
• [4] RNASEH2B Pathogenic Gene Variant in Uncomplicated Hereditary Spastic Paraplegia: Report of a New Patient.Neuropediatrics. 2018 Dec;49(6):419. doi: 10.1055/s-0038-1672174. Epub 2018 Sep 17.
• [5] CRISPR screens identify genomic ribonucleotides as a source of PARP-trapping lesions.Nature. 2018 Jul;559(7713):285-289. doi: 10.1038/s41586-018-0291-z. Epub 2018 Jul 4.
• [6] Genome-wide CRISPR screens reveal synthetic lethality of RNASEH2 deficiency and ATR inhibition.Oncogene. 2019 Apr;38(14):2451-2463. doi: 10.1038/s41388-018-0606-4. Epub 2018 Dec 7.
• [7] A genome-wide association study of rheumatoid arthritis without antibodies against citrullinated peptides.Ann Rheum Dis. 2015 Mar;74(3):e15. doi: 10.1136/annrheumdis-2013-204591. Epub 2014 Feb 14.
• [8] Aicardi-Goutires Syndrome. 2005 Jun 29 [updated 2016 Nov 22]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [9] Mutations in genes encoding ribonuclease H2 subunits cause Aicardi-Goutires syndrome and mimic congenital viral brain infection. Nat Genet. 2006 Aug;38(8):910-6. doi: 10.1038/ng1842. Epub 2006 Jul 16.
• [10] Advantages and pitfalls of an extended gene panel for investigating complex neurometabolic phenotypes.Brain. 2016 Nov 1;139(11):2844-2854. doi: 10.1093/brain/aww221.
• [11] 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.
• [12] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [13] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [14] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [15] 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.
• [16] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [17] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [18] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [19] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [20] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [21] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.
• [22] Adaptive changes in global gene expression profile of lung carcinoma A549 cells acutely exposed to distinct types of AhR ligands. Toxicol Lett. 2018 Aug;292:162-174.