Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTHFFT6G)

• DOT Name: SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 1 (SMARCD1)
• Synonyms: 60 kDa BRG-1/Brm-associated factor subunit A; BRG1-associated factor 60A; BAF60A; SWI/SNF complex 60 kDa subunit
• Gene Name: SMARCD1
• Related Disease:
  Acquired aplastic anemia
  Autism, susceptibility to, 15
  Coffin-Siris syndrome 11
  Epithelial ovarian cancer
  Intellectual disability
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Neoplasm
  Non-small-cell lung cancer
  Ovarian serous adenocarcinoma
  Triple-A syndrome
  Head-neck squamous cell carcinoma
  Coffin-Siris syndrome
  Hyperlipidemia
  Hyperlipoproteinemia
• UniProt ID: SMRD1_HUMAN
• PDB ID: 6LTH; 6LTJ; 7VDV; 7Y8R
• Pfam ID: PF02201
• Sequence:
  MAARAGFQSVAPSGGAGASGGAGAAAALGPGGTPGPPVRMGPAPGQGLYRSPMPGAAYPR
  PGMLPGSRMTPQGPSMGPPGYGGNPSVRPGLAQSGMDQSRKRPAPQQIQQVQQQAVQNRN
  HNAKKKKMADKILPQRIRELVPESQAYMDLLAFERKLDQTIMRKRLDIQEALKRPIKQKR
  KLRIFISNTFNPAKSDAEDGEGTVASWELRVEGRLLEDSALSKYDATKQKRKFSSFFKSL
  VIELDKDLYGPDNHLVEWHRTATTQETDGFQVKRPGDVNVRCTVLLMLDYQPPQFKLDPR
  LARLLGIHTQTRPVIIQALWQYIKTHKLQDPHEREFVICDKYLQQIFESQRMKFSEIPQR
  LHALLMPPEPIIINHVISVDPNDQKKTACYDIDVEVDDTLKTQMNSFLLSTASQQEIATL
  DNKIHETIETINQLKTQREFMLSFARDPQGFINDWLQSQCRDLKTMTDVVGNPEEERRAE
  FYFQPWAQEAVCRYFYSKVQQRRQELEQALGIRNT
• Function: Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology). Component of SWI/SNF chromatin remodeling complexes that carry out key enzymatic activities, changing chromatin structure by altering DNA-histone contacts within a nucleosome in an ATP-dependent manner. Belongs to the neural progenitors-specific chromatin remodeling complex (npBAF complex) and the neuron-specific chromatin remodeling complex (nBAF complex). During neural development a switch from a stem/progenitor to a postmitotic chromatin remodeling mechanism occurs as neurons exit the cell cycle and become committed to their adult state. The transition from proliferating neural stem/progenitor cells to postmitotic neurons requires a switch in subunit composition of the npBAF and nBAF complexes. As neural progenitors exit mitosis and differentiate into neurons, npBAF complexes which contain ACTL6A/BAF53A and PHF10/BAF45A, are exchanged for homologous alternative ACTL6B/BAF53B and DPF1/BAF45B or DPF3/BAF45C subunits in neuron-specific complexes (nBAF). The npBAF complex is essential for the self-renewal/proliferative capacity of the multipotent neural stem cells. The nBAF complex along with CREST plays a role regulating the activity of genes essential for dendrite growth. Has a strong influence on vitamin D-mediated transcriptional activity from an enhancer vitamin D receptor element (VDRE). May be a link between mammalian SWI-SNF-like chromatin remodeling complexes and the vitamin D receptor (VDR) heterodimer. Mediates critical interactions between nuclear receptors and the BRG1/SMARCA4 chromatin-remodeling complex for transactivation. Interacts with AKIRIN2.
• Tissue Specificity: Expressed in all tissues tested, including brain, heart, kidney, liver, lung, muscle, pancreas and placenta.
• KEGG Pathway:
  ATP-dependent chromatin remodeling (hsa03082)
  Thermogenesis (hsa04714)
  Hepatocellular carcinoma (hsa05225)
• Reactome Pathway:
  RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known (R-HSA-8939243)
  RMTs methylate histone arginines (R-HSA-3214858)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acquired aplastic anemia	DISCMKMX	Strong	Biomarker	[1]
Autism, susceptibility to, 15	DISYCG6A	Strong	Autosomal dominant	[2]
Coffin-Siris syndrome 11	DISFBB1D	Strong	Autosomal dominant	[2]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[3]
Intellectual disability	DISMBNXP	Strong	Biomarker	[2]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[4]
Lung cancer	DISCM4YA	Strong	Biomarker	[4]
Lung carcinoma	DISTR26C	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Altered Expression	[5]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[4]
Ovarian serous adenocarcinoma	DISSU72Z	Strong	Biomarker	[6]
Triple-A syndrome	DISCOH2J	Strong	Biomarker	[7]
Head-neck squamous cell carcinoma	DISF7P24	moderate	Altered Expression	[5]
Coffin-Siris syndrome	DIS8L03H	Supportive	Autosomal dominant	[2]
Hyperlipidemia	DIS61J3S	Limited	Biomarker	[8]
Hyperlipoproteinemia	DISVBLBO	Limited	Biomarker	[8]

4 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 SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 1 (SMARCD1).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 1 (SMARCD1).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 1 (SMARCD1).	[11]
DTI-015	DMXZRW0	Approved	DTI-015 increases the expression of SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 1 (SMARCD1).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 1 (SMARCD1).	[13]

References

• [1] SWI/SNF subunit expression heterogeneity in human aplastic anemia stem/progenitors.Exp Hematol. 2018 Jun;62:39-44.e2. doi: 10.1016/j.exphem.2018.03.005. Epub 2018 Mar 27.
• [2] A Syndromic Neurodevelopmental Disorder Caused by Mutations in SMARCD1, a Core SWI/SNF Subunit Needed for Context-Dependent Neuronal Gene Regulation in Flies. Am J Hum Genet. 2019 Apr 4;104(4):596-610. doi: 10.1016/j.ajhg.2019.02.001. Epub 2019 Mar 14.
• [3] DLEU1 contributes to ovarian carcinoma tumourigenesis and development by interacting with miR-490-3p and altering CDK1 expression.J Cell Mol Med. 2017 Nov;21(11):3055-3065. doi: 10.1111/jcmm.13217. Epub 2017 Jun 9.
• [4] MicroRNA-7 Compromises p53 Protein-dependent Apoptosis by Controlling the Expression of the Chromatin Remodeling Factor SMARCD1.J Biol Chem. 2016 Jan 22;291(4):1877-1889. doi: 10.1074/jbc.M115.667568. Epub 2015 Nov 5.
• [5] SMARCD1 is a transcriptional target of specific non-hotspot mutant p53 forms.J Cell Physiol. 2020 May;235(5):4559-4570. doi: 10.1002/jcp.29332. Epub 2019 Oct 21.
• [6] miR-223 potentially targets SWI/SNF complex protein SMARCD1 in atypical proliferative serous tumor and high-grade ovarian serous carcinoma.Hum Pathol. 2017 Dec;70:98-104. doi: 10.1016/j.humpath.2017.10.008. Epub 2017 Oct 24.
• [7] Five SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin (SMARC) genes are dispersed in the human genome.Genomics. 1998 Jul 1;51(1):140-3. doi: 10.1006/geno.1998.5343.
• [8] Hyperlipidaemia impairs the circadian clock and physiological homeostasis of vascular smooth muscle cells via the suppression of Smarcd1.J Pathol. 2014 Jun;233(2):159-69. doi: 10.1002/path.4338. Epub 2014 Mar 28.
• [9] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [10] 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.
• [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] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [13] 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.