Details of Drug Off-Target (DOT)

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

• DOT Name: RAD9, HUS1, RAD1-interacting nuclear orphan protein 1 (RHNO1)
• Synonyms: RAD9, RAD1, HUS1-interacting nuclear orphan protein
• Gene Name: RHNO1
• Related Disease:
  Breast cancer
  Breast carcinoma
• UniProt ID: RHNO1_HUMAN
• PDB ID: 6J8Y
• Pfam ID: PF15319
• Sequence:
  MPPRKKRRQPSQKAPLLFHQQPLEGPKHSCASTQLPITHTRQVPSKPIDHSTITSWVSPD
  FDTAAGSLFPAYQKHQNRARHSSRKPTTSKFPHLTFESPQSSSSETLGIPLIRECPSESE
  KDVSRRPLVPVLSPQSCGNMSVQALQSLPYVFIPPDIQTPESSSVKEELIPQDQKENSLL
  SCTLHTGTPNSPEPGPVLVKDTPEDKYGIKVTWRRRQHLLAYLRERGKLSRSQFLVKS
• Function: Involved in microhomology-mediated end-joining (MMEJ) DNA repair by promoting recruitment of polymerase theta (POLQ) to DNA damage sites during mitosis. MMEJ is an alternative non-homologous end-joining (NHEJ) machinery that takes place during mitosis to repair double-strand breaks in DNA that originate in S-phase. Accumulates in M-phase; following phosphorylation by PLK1, interacts with POLQ, enabling its recruitment to double-strand breaks for subsequent repair. Also involved in the DNA damage response (DDR) signaling in response to genotoxic stresses such as ionizing radiation (IR) during the S phase. Recruited to sites of DNA damage through interaction with the 9-1-1 cell-cycle checkpoint response complex and TOPBP1 in a ATR-dependent manner. Required for the progression of the G1 to S phase transition. Plays a role in the stimulation of CHEK1 phosphorylation.
• Tissue Specificity: Weakly expressed in testis, prostate, ovary, thymus and small intestine . Expressed strongly in breast cancer cells .
• Reactome Pathway:
  Processing of DNA double-strand break ends (R-HSA-5693607)
  Presynaptic phase of homologous DNA pairing and strand exchange (R-HSA-5693616)
  Regulation of TP53 Activity through Phosphorylation (R-HSA-6804756)
  G2/M DNA damage checkpoint (R-HSA-69473)
  Impaired BRCA2 binding to RAD51 (R-HSA-9709570)
  HDR through Single Strand Annealing (SSA) (R-HSA-5685938)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[1]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of RAD9, HUS1, RAD1-interacting nuclear orphan protein 1 (RHNO1).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of RAD9, HUS1, RAD1-interacting nuclear orphan protein 1 (RHNO1).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of RAD9, HUS1, RAD1-interacting nuclear orphan protein 1 (RHNO1).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of RAD9, HUS1, RAD1-interacting nuclear orphan protein 1 (RHNO1).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of RAD9, HUS1, RAD1-interacting nuclear orphan protein 1 (RHNO1).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of RAD9, HUS1, RAD1-interacting nuclear orphan protein 1 (RHNO1).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of RAD9, HUS1, RAD1-interacting nuclear orphan protein 1 (RHNO1).	[8]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of RAD9, HUS1, RAD1-interacting nuclear orphan protein 1 (RHNO1).	[9]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate decreases the expression of RAD9, HUS1, RAD1-interacting nuclear orphan protein 1 (RHNO1).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of RAD9, HUS1, RAD1-interacting nuclear orphan protein 1 (RHNO1).	[11]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of RAD9, HUS1, RAD1-interacting nuclear orphan protein 1 (RHNO1).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of RAD9, HUS1, RAD1-interacting nuclear orphan protein 1 (RHNO1).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of RAD9, HUS1, RAD1-interacting nuclear orphan protein 1 (RHNO1).	[14]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of RAD9, HUS1, RAD1-interacting nuclear orphan protein 1 (RHNO1).	[8]

References

• [1] Evaluation of the RHINO gene for breast cancer predisposition in Finnish breast cancer families.Breast Cancer Res Treat. 2014 Apr;144(2):437-41. doi: 10.1007/s10549-014-2884-z. Epub 2014 Feb 22.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] 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.
• [4] 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.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [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] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [10] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [11] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [12] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [13] 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.
• [14] 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.