Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKU8KWH)

• DOT Name: THUMP domain-containing protein 1 (THUMPD1)
• Gene Name: THUMPD1
• Related Disease:
  Adult T-cell leukemia/lymphoma
  Breast cancer
  Breast carcinoma
  Endometrial cancer
  Endometrial carcinoma
  leukaemia
  Leukemia
  Neoplasm
  Neurodevelopmental disorder with speech delay and variable ocular anomalies
  Advanced cancer
  Colorectal carcinoma
• UniProt ID: THUM1_HUMAN
• PDB ID: 2DIR
• Pfam ID: PF02926
• Sequence:
  MAAPAQQTTQPGGGKRKGKAQYVLAKRARRCDAGGPRQLEPGLQGILITCNMNERKCVEE
  AYSLLNEYGDDMYGPEKFTDKDQQPSGSEGEDDDAEAALKKEVGDIKASTEMRLRRFQSV
  ESGANNVVFIRTLGIEPEKLVHHILQDMYKTKKKKTRVILRMLPISGTCKAFLEDMKKYA
  ETFLEPWFKAPNKGTFQIVYKSRNNSHVNREEVIRELAGIVCTLNSENKVDLTNPQYTVV
  VEIIKAVCCLSVVKDYMLFRKYNLQEVVKSPKDPSQLNSKQGNGKEAKLESADKSDQNNT
  AEGKNNQQVPENTEELGQTKPTSNPQVVNEGGAKPELASQATEGSKSNENDFS
• Function: Functions as a tRNA-binding adapter to mediate NAT10-dependent tRNA acetylation modifying cytidine to N4-acetylcytidine (ac4C).
• Reactome Pathway: rRNA modification in the nucleus and cytosol (R-HSA-6790901)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult T-cell leukemia/lymphoma	DIS882XU	Strong	Genetic Variation	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Endometrial cancer	DISW0LMR	Strong	Biomarker	[3]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[3]
leukaemia	DISS7D1V	Strong	Genetic Variation	[4]
Leukemia	DISNAKFL	Strong	Biomarker	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[5]
Neurodevelopmental disorder with speech delay and variable ocular anomalies	DIS7J3MD	Strong	Autosomal recessive	[6]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[7]
Colorectal carcinoma	DIS5PYL0	Limited	Genetic Variation	[7]

8 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 THUMP domain-containing protein 1 (THUMPD1).	[8]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of THUMP domain-containing protein 1 (THUMPD1).	[9]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of THUMP domain-containing protein 1 (THUMPD1).	[10]
Selenium	DM25CGV	Approved	Selenium decreases the expression of THUMP domain-containing protein 1 (THUMPD1).	[11]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of THUMP domain-containing protein 1 (THUMPD1).	[10]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of THUMP domain-containing protein 1 (THUMPD1).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of THUMP domain-containing protein 1 (THUMPD1).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of THUMP domain-containing protein 1 (THUMPD1).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of THUMP domain-containing protein 1 (THUMPD1).	[13]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of THUMP domain-containing protein 1 (THUMPD1).	[14]

References

• [1] T cell leukemia-associated human Notch/translocation-associated Notch homologue has I kappa B-like activity and physically interacts with nuclear factor-kappa B proteins in T cells.J Exp Med. 1996 May 1;183(5):2025-32. doi: 10.1084/jem.183.5.2025.
• [2] Cytosolic THUMPD1 promotes breast cancer cells invasion and metastasis via the AKT-GSK3-Snail pathway.Oncotarget. 2017 Feb 21;8(8):13357-13366. doi: 10.18632/oncotarget.14528.
• [3] Imbalanced expression of TAN-1 and human Notch4 in endometrial cancers.Int J Oncol. 2000 Dec;17(6):1131-9. doi: 10.3892/ijo.17.6.1131.
• [4] The human NOTCH1, 2, and 3 genes are located at chromosome positions 9q34, 1p13-p11, and 19p13.2-p13.1 in regions of neoplasia-associated translocation.Genomics. 1994 Nov 15;24(2):253-8. doi: 10.1006/geno.1994.1613.
• [5] Exclusive development of T cell neoplasms in mice transplanted with bone marrow expressing activated Notch alleles.J Exp Med. 1996 May 1;183(5):2283-91. doi: 10.1084/jem.183.5.2283.
• [6] THUMPD1 bi-allelic variants cause loss of tRNA acetylation and a syndromic neurodevelopmental disorder. Am J Hum Genet. 2022 Apr 7;109(4):587-600. doi: 10.1016/j.ajhg.2022.02.001. Epub 2022 Feb 22.
• [7] Searching for microsatellite mutations in coding regions in lung, breast, ovarian and colorectal cancers.Oncogene. 2001 Feb 22;20(8):1005-9. doi: 10.1038/sj.onc.1204211.
• [8] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [9] Cyclosporine A--induced oxidative stress in human renal mesangial cells: a role for ERK 1/2 MAPK signaling. Toxicol Sci. 2012 Mar;126(1):101-13.
• [10] The DNA methyltransferase inhibitors azacitidine, decitabine and zebularine exert differential effects on cancer gene expression in acute myeloid leukemia cells. Leukemia. 2009 Jun;23(6):1019-28.
• [11] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [12] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [13] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [14] 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.
• [15] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [16] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.