Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3GKXGI)

• DOT Name: SUMO-interacting motif-containing protein 1 (SIMC1)
• Synonyms: Platform element for inhibition of autolytic degradation
• Gene Name: SIMC1
• Related Disease: Alzheimer disease
• UniProt ID: SIMC1_HUMAN
• PDB ID: 7T5P
• Sequence:
  MAPASASGEDLRKLPTMAEVNGEQDFIDLTRETRPRTKDRSGLYVIDLTRAEGENRPIAT
  LDLTLEPVTPSQKEPTSLQTCASLSGKAVMEGHVDRSSQPTARRIINSDPVDLDLVEENT
  FVGPPPATSISGGSVYPTEPNCSSATFTGNLSFLASLQLSSDVSSLSPTSNNSRSSSSSS
  NQKAPLPCPQQDVSRPPQALPCPLRPLPCPPRASPCPPRASSCPPRALSCPSQTMQCQLP
  ALTHPPQEVPCPRQNIPGPPQDSLGLPQDVPGLPQSILHPQDVAYLQDMPRSPGDVPQSP
  SDVSPSPDAPQSPGGMPHLPGDVLHSPGDMPHSSGDVTHSPRDIPHLPGDRPDFTQNDVQ
  NRDMPMDISALSSPSCSPSPQSETPLEKVPWLSVMETPARKEISLSEPAKPGSAHVQSRT
  PQGGLYNRPCLHRLKYFLRPPVHHLFFQTLIPDKDTRENKGQKLEPIPHRRLRMVTNTIE
  ENFPLGTVQFLMDFVSPQHYPPREIVAHIIQKILLSGSETVDVLKEAYMLLMKIQQLHPA
  NAKTVEWDWKLLTYVMEEEGQTLPGRVLFLRYVVQTLEDDFQQTLRRQRQHLQQSIANMV
  LSCDKQPHNVRDVIKWLVKAVTEDGLTQPPNGNQTSSGTGILKASSSHPSSQPNLTKNTN
  QLIVCQLQRMLSIAVEVDRTPTCSSNKIAEMMFGFVLDIPERSQREMFFTTMESHLLRCK
  VLEIIFLHSCETPTRLPLSLAQALYFLNNSTSLLKCQSDKSQWQTWDELVEHLQFLLSSY
  QHVLREHLRSSVIDRKDLIIKRIKPKPQQGDDITVVDVEKQIEAFRSRLIQMLGEPLVPQ
  LQDKVHLLKLLLFYAADLNPDAEPFQKGWSGS
• Function: Plays a role in SMC5-SMC6 complex recruitment for viral restriction. Forms a complex with SLF2 and this complex is required to recruit SMC5-SMC6 complex to PML nuclear bodies and sites of viral replication; [Isoform 1]: Inhibits the protease activity of CAPN3; [Isoform 5]: Inhibits the protease activity of CAPN3.
• Tissue Specificity: .Skeletal muscle.

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[1]

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 SUMO-interacting motif-containing protein 1 (SIMC1).	[2]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of SUMO-interacting motif-containing protein 1 (SIMC1).	[6]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of SUMO-interacting motif-containing protein 1 (SIMC1).	[7]

4 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 SUMO-interacting motif-containing protein 1 (SIMC1).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of SUMO-interacting motif-containing protein 1 (SIMC1).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of SUMO-interacting motif-containing protein 1 (SIMC1).	[5]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of SUMO-interacting motif-containing protein 1 (SIMC1).	[8]

References

• [1] Genome-wide association of familial late-onset Alzheimer's disease replicates BIN1 and CLU and nominates CUGBP2 in interaction with APOE.PLoS Genet. 2011 Feb;7(2):e1001308. doi: 10.1371/journal.pgen.1001308. Epub 2011 Feb 17.
• [2] 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.
• [3] 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.
• [4] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [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] 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.
• [7] 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.
• [8] 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.