Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTO73N00)

• DOT Name: Deubiquitinase MYSM1 (MYSM1)
• Synonyms: 2A-DUB; EC 3.4.19.-; Myb-like, SWIRM and MPN domain-containing protein 1
• Gene Name: MYSM1
• Related Disease:
  Bone marrow failure syndrome 4
  Castration-resistant prostate carcinoma
  Colorectal carcinoma
  Immunodeficiency
  Inborn error of immunity
  Inflammatory bowel disease
  Myelodysplastic syndrome
  Neoplasm
  Pancytopenia
  Prostate cancer
  Prostate carcinoma
  Prostate neoplasm
  Renal fibrosis
  Melanoma
• UniProt ID: MYSM1_HUMAN
• PDB ID: 2CU7; 2DCE
• EC Number: 3.4.19.-
• Pfam ID: PF01398 ; PF00249 ; PF04433
• Sequence:
  MAAEEADVDIEGDVVAAAGAQPGSGENTASVLQKDHYLDSSWRTENGLIPWTLDNTISEE
  NRAVIEKMLLEEEYYLSKKSQPEKVWLDQKEDDKKYMKSLQKTAKIMVHSPTKPASYSVK
  WTIEEKELFEQGLAKFGRRWTKISKLIGSRTVLQVKSYARQYFKNKVKCGLDKETPNQKT
  GHNLQVKNEDKGTKAWTPSCLRGRADPNLNAVKIEKLSDDEEVDITDEVDELSSQTPQKN
  SSSDLLLDFPNSKMHETNQGEFITSDSQEALFSKSSRGCLQNEKQDETLSSSEITLWTEK
  QSNGDKKSIELNDQKFNELIKNCNKHDGRGIIVDARQLPSPEPCEIQKNLNDNEMLFHSC
  QMVEESHEEEELKPPEQEIEIDRNIIQEEEKQAIPEFFEGRQAKTPERYLKIRNYILDQW
  EICKPKYLNKTSVRPGLKNCGDVNCIGRIHTYLELIGAINFGCEQAVYNRPQTVDKVRIR
  DRKDAVEAYQLAQRLQSMRTRRRRVRDPWGNWCDAKDLEGQTFEHLSAEELAKRREEEKG
  RPVKSLKVPRPTKSSFDPFQLIPCNFFSEEKQEPFQVKVASEALLIMDLHAHVSMAEVIG
  LLGGRYSEVDKVVEVCAAEPCNSLSTGLQCEMDPVSQTQASETLAVRGFSVIGWYHSHPA
  FDPNPSLRDIDTQAKYQSYFSRGGAKFIGMIVSPYNRNNPLPYSQITCLVISEEISPDGS
  YRLPYKFEVQQMLEEPQWGLVFEKTRWIIEKYRLSHSSVPMDKIFRRDSDLTCLQKLLEC
  MRKTLSKVTNCFMAEEFLTEIENLFLSNYKSNQENGVTEENCTKELLM
• Function: Metalloprotease with deubiquitinase activity that plays important regulator roles in hematopoietic stem cell function, blood cell production and immune response. Participates in the normal programming of B-cell responses to antigen after the maturation process. Within the cytoplasm, plays critical roles in the repression of innate immunity and autoimmunity. Removes 'Lys-63'-linked polyubiquitins from TRAF3 and TRAF6 complexes. Attenuates NOD2-mediated inflammation and tissue injury by promoting 'Lys-63'-linked deubiquitination of RIPK2 component. Suppresses the CGAS-STING1 signaling pathway by cleaving STING1 'Lys-63'-linked ubiquitin chains. In the nucleus, acts as a hematopoietic transcription regulator derepressing a range of genes essential for normal stem cell differentiation including EBF1 and PAX5 in B-cells, ID2 in NK-cell progenitor or FLT3 in dendritic cell precursors. Deubiquitinates monoubiquitinated histone H2A, a specific tag for epigenetic transcriptional repression, leading to dissociation of histone H1 from the nucleosome.
• Reactome Pathway: Metalloprotease DUBs (R-HSA-5689901)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bone marrow failure syndrome 4	DISZSAQO	Strong	Autosomal recessive	[1]
Castration-resistant prostate carcinoma	DISVGAE6	Strong	Biomarker	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[3]
Immunodeficiency	DIS093I0	Strong	Biomarker	[4]
Inborn error of immunity	DISNGCMN	Strong	Biomarker	[5]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[6]
Myelodysplastic syndrome	DISYHNUI	Strong	Genetic Variation	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[6]
Pancytopenia	DISVKEHV	Strong	Biomarker	[7]
Prostate cancer	DISF190Y	Strong	Biomarker	[2]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[2]
Prostate neoplasm	DISHDKGQ	Strong	Altered Expression	[2]
Renal fibrosis	DISMHI3I	Strong	Altered Expression	[8]
Melanoma	DIS1RRCY	Limited	Biomarker	[9]

6 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 Deubiquitinase MYSM1 (MYSM1).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Deubiquitinase MYSM1 (MYSM1).	[11]
Marinol	DM70IK5	Approved	Marinol increases the expression of Deubiquitinase MYSM1 (MYSM1).	[13]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Deubiquitinase MYSM1 (MYSM1).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Deubiquitinase MYSM1 (MYSM1).	[15]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Deubiquitinase MYSM1 (MYSM1).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Quercetin	DM3NC4M	Approved	Quercetin decreases the phosphorylation of Deubiquitinase MYSM1 (MYSM1).	[12]

References

• [1] MYSM1 is mutated in a family with transient transfusion-dependent anemia, mild thrombocytopenia, and low NK- and B-cell counts. Blood. 2013 Nov 28;122(23):3844-5. doi: 10.1182/blood-2013-09-527127.
• [2] MYSM1-AR complex-mediated repression of Akt/c-Raf/GSK-3 signaling impedes castration-resistant prostate cancer growth.Aging (Albany NY). 2019 Nov 24;11(22):10644-10663. doi: 10.18632/aging.102482. Epub 2019 Nov 24.
• [3] Correction: Expression of MYSM1 is associated with tumor progression in colorectal cancer.PLoS One. 2017 Oct 11;12(10):e0186530. doi: 10.1371/journal.pone.0186530. eCollection 2017.
• [4] Deubiquitinase MYSM1 Regulates Innate Immunity through Inactivation of TRAF3 and TRAF6 Complexes.Immunity. 2015 Oct 20;43(4):647-59. doi: 10.1016/j.immuni.2015.09.010.
• [5] Neutrophilic Panniculitis in a child with MYSM1 deficiency.Pediatr Dermatol. 2019 Mar;36(2):258-259. doi: 10.1111/pde.13757. Epub 2019 Feb 12.
• [6] Mysm1 epigenetically regulates the immunomodulatory function of adipose-derived stem cells in part by targeting miR-150.J Cell Mol Med. 2019 May;23(5):3737-3746. doi: 10.1111/jcmm.14281. Epub 2019 Mar 20.
• [7] Myb-like, SWIRM, and MPN domains 1 (MYSM1) deficiency: Genotoxic stress-associated bone marrow failure and developmental aberrations.J Allergy Clin Immunol. 2017 Oct;140(4):1112-1119. doi: 10.1016/j.jaci.2016.10.053. Epub 2017 Jan 21.
• [8] Novel reno-protective mechanism of Aspirin involves H2AK119 monoubiquitination and Set7 in preventing type 1 diabetic nephropathy.Pharmacol Rep. 2018 Jun;70(3):497-502. doi: 10.1016/j.pharep.2017.11.018. Epub 2017 Dec 2.
• [9] MYSM1/2A-DUB is an epigenetic regulator in human melanoma and contributes to tumor cell growth.Oncotarget. 2017 Jun 27;8(40):67287-67299. doi: 10.18632/oncotarget.18617. eCollection 2017 Sep 15.
• [10] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [11] 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.
• [12] 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.
• [13] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [14] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [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] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.