Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2P6943)

• DOT Name: MBT domain-containing protein 1 (MBTD1)
• Gene Name: MBTD1
• Related Disease:
  Bone osteosarcoma
  Osteosarcoma
  Chromosomal disorder
  Neoplasm
  Prostate cancer
  Prostate carcinoma
  Brain cancer
• UniProt ID: MBTD1_HUMAN
• PDB ID: 3FEO; 4C5I; 6NFX
• Pfam ID: PF02820 ; PF21319
• Sequence:
  MFDGYDSCSEDTSSSSSSEESEEEVAPLPSNLPIIKNNGQVYTYPDGKSGMATCEMCGMV
  GVRDAFYSKTKRFCSVSCSRSYSSNSKKASILARLQGKPPTKKAKVLQKQPLVAKLAAYA
  QYQATLQNQAKTKAAVSMEGFSWGNYINSNSFIAAPVTCFKHAPMGTCWGDISENVRVEV
  PNTDCSLPTKVFWIAGIVKLAGYNALLRYEGFENDSGLDFWCNICGSDIHPVGWCAASGK
  PLVPPRTIQHKYTNWKAFLVKRLTGAKTLPPDFSQKVSESMQYPFKPCMRVEVVDKRHLC
  RTRVAVVESVIGGRLRLVYEESEDRTDDFWCHMHSPLIHHIGWSRSIGHRFKRSDITKKQ
  DGHFDTPPHLFAKVKEVDQSGEWFKEGMKLEAIDPLNLSTICVATIRKVLADGFLMIGID
  GSEAADGSDWFCYHATSPSIFPVGFCEINMIELTPPRGYTKLPFKWFDYLRETGSIAAPV
  KLFNKDVPNHGFRVGMKLEAVDLMEPRLICVATVTRIIHRLLRIHFDGWEEEYDQWVDCE
  SPDLYPVGWCQLTGYQLQPPASQSSRENQSASSKQKKKAKSQQYKGHKKMTTLQLKEELL
  DGEDYNFLQGASDQESNGSANFYIKQEP
• Function: Chromatin reader component of the NuA4 histone acetyltransferase complex, a multiprotein complex involved in transcriptional activation of select genes principally by acetylation of nucleosomal histones H4 and H2A. The NuA4 complex plays a direct role in repair of DNA double-strand breaks (DSBs) by promoting homologous recombination (HR). MBTD1 specifically recognizes and binds monomethylated and dimethylated 'Lys-20' on histone H4 (H4K20me1 and H4K20me2, respectively). In the NuA4 complex, MBTD1 promotes recruitment of the complex to H4K20me marks by competing with TP53BP1 for binding to H4K20me. Following recruitment to H4K20me at DNA breaks, the NuA4 complex catalyzes acetylation of 'Lys-15' on histone H2A (H2AK15), blocking the ubiquitination mark required for TP53BP1 localization at DNA breaks, thereby promoting homologous recombination (HR).

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bone osteosarcoma	DIST1004	Definitive	Altered Expression	[1]
Osteosarcoma	DISLQ7E2	Definitive	Altered Expression	[1]
Chromosomal disorder	DISM5BB5	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Prostate cancer	DISF190Y	Strong	Altered Expression	[3]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[3]
Brain cancer	DISBKFB7	Limited	Biomarker	[3]

3 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 MBT domain-containing protein 1 (MBTD1).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of MBT domain-containing protein 1 (MBTD1).	[13]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of MBT domain-containing protein 1 (MBTD1).	[14]

14 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 MBT domain-containing protein 1 (MBTD1).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of MBT domain-containing protein 1 (MBTD1).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of MBT domain-containing protein 1 (MBTD1).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of MBT domain-containing protein 1 (MBTD1).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of MBT domain-containing protein 1 (MBTD1).	[9]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of MBT domain-containing protein 1 (MBTD1).	[10]
Cytarabine	DMZD5QR	Approved	Cytarabine increases the expression of MBT domain-containing protein 1 (MBTD1).	[11]
Rofecoxib	DM3P5DA	Approved	Rofecoxib decreases the expression of MBT domain-containing protein 1 (MBTD1).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of MBT domain-containing protein 1 (MBTD1).	[15]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of MBT domain-containing protein 1 (MBTD1).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of MBT domain-containing protein 1 (MBTD1).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of MBT domain-containing protein 1 (MBTD1).	[18]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of MBT domain-containing protein 1 (MBTD1).	[19]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of MBT domain-containing protein 1 (MBTD1).	[20]

References

• [1] LncRNA TTN-AS1 regulates osteosarcoma cell apoptosis and drug resistance via the miR-134-5p/MBTD1 axis.Aging (Albany NY). 2019 Oct 10;11(19):8374-8385. doi: 10.18632/aging.102325. Epub 2019 Oct 10.
• [2] Identification of a novel, recurrent MBTD1-CXorf67 fusion in low-grade endometrial stromal sarcoma.Int J Cancer. 2014 Mar 1;134(5):1112-22. doi: 10.1002/ijc.28440. Epub 2013 Sep 4.
• [3] Overexpression of malignant brain tumor domain containing protein 1 predicts a poor prognosis of prostate cancer.Oncol Lett. 2019 May;17(5):4640-4646. doi: 10.3892/ol.2019.10109. Epub 2019 Mar 5.
• [4] 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.
• [5] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [6] 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.
• [7] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [8] 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.
• [9] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [10] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [11] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [12] Rofecoxib modulates multiple gene expression pathways in a clinical model of acute inflammatory pain. Pain. 2007 Mar;128(1-2):136-47.
• [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] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [15] 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.
• [16] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [17] Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A. Int J Mol Sci. 2022 Oct 1;23(19):11620. doi: 10.3390/ijms231911620.
• [18] 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.
• [19] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [20] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.