Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIU8V4U)

• DOT Name: SUN domain-containing protein 1 (SUN1)
• Synonyms: Protein unc-84 homolog A; Sad1/unc-84 protein-like 1
• Gene Name: SUN1
• Related Disease:
  Cockayne syndrome type 1
  Advanced cancer
  Atrial fibrillation
  Duchenne muscular dystrophy
  Emery-Dreifuss muscular dystrophy
  Hutchinson-Gilford progeria syndrome
  Lentivirus infection
  Lung adenocarcinoma
  Muscular dystrophy
  Myopathy
  Familial atrial fibrillation
  Breast cancer
  Breast carcinoma
  Malignant tumor of nasopharynx
  Nasopharyngeal carcinoma
• UniProt ID: SUN1_HUMAN
• PDB ID: 6R15; 6R16; 6R2I; 7E34; 7Z8Y; 8AU0; 8B46; 8B5X
• Pfam ID: PF18580 ; PF09387 ; PF07738
• Sequence:
  MDFSRLHMYSPPQCVPENTGYTYALSSSYSSDALDFETEHKLDPVFDSPRMSRRSLRLAT
  TACTLGDGEAVGADSGTSSAVSLKNRAARTTKQRRSTNKSAFSINHVSRQVTSSGVSHGG
  TVSLQDAVTRRPPVLDESWIREQTTVDHFWGLDDDGDLKGGNKAAIQGNGDVGAAAATAH
  NGFSCSNCSMLSERKDVLTAHPAAPGPVSRVYSRDRNQKCYFLLQILRRIGAVGQAVSRT
  AWSALWLAVVAPGKAASGVFWWLGIGWYQFVTLISWLNVFLLTRCLRNICKFLVLLIPLF
  LLLAGLSLRGQGNFFSFLPVLNWASMHRTQRVDDPQDVFKPTTSRLKQPLQGDSEAFPWH
  WMSGVEQQVASLSGQCHHHGENLRELTTLLQKLQARVDQMEGGAAGPSASVRDAVGQPPR
  ETDFMAFHQEHEVRMSHLEDILGKLREKSEAIQKELEQTKQKTISAVGEQLLPTVEHLQL
  ELDQLKSELSSWRHVKTGCETVDAVQERVDVQVREMVKLLFSEDQQGGSLEQLLQRFSSQ
  FVSKGDLQTMLRDLQLQILRNVTHHVSVTKQLPTSEAVVSAVSEAGASGITEAQARAIVN
  SALKLYSQDKTGMVDFALESGGGSILSTRCSETYETKTALMSLFGIPLWYFSQSPRVVIQ
  PDIYPGNCWAFKGSQGYLVVRLSMMIHPAAFTLEHIPKTLSPTGNISSAPKDFAVYGLEN
  EYQEEGQLLGQFTYDQDGESLQMFQALKRPDDTAFQIVELRIFSNWGHPEYTCLYRFRVH
  GEPVK
• Function: As a component of the LINC (LInker of Nucleoskeleton and Cytoskeleton) complex involved in the connection between the nuclear lamina and the cytoskeleton. The nucleocytoplasmic interactions established by the LINC complex play an important role in the transmission of mechanical forces across the nuclear envelope and in nuclear movement and positioning. Required for interkinetic nuclear migration (INM) and essential for nucleokinesis and centrosome-nucleus coupling during radial neuronal migration in the cerebral cortex and during glial migration. Involved in telomere attachment to nuclear envelope in the prophase of meiosis implicating a SUN1/2:KASH5 LINC complex in which SUN1 and SUN2 seem to act at least partial redundantly. Required for gametogenesis and involved in selective gene expression of coding and non-coding RNAs needed for gametogenesis. Helps to define the distribution of nuclear pore complexes (NPCs). Required for efficient localization of SYNE4 in the nuclear envelope. May be involved in nuclear remodeling during sperm head formation in spermatogenesis. May play a role in DNA repair by suppressing non-homologous end joining repair to facilitate the repair of DNA cross-links.
• KEGG Pathway: Cytoskeleton in muscle cells (hsa04820)
• Reactome Pathway: Meiotic synapsis (R-HSA-1221632)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cockayne syndrome type 1	DIS9JFVY	Definitive	Genetic Variation	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Atrial fibrillation	DIS15W6U	Strong	Genetic Variation	[3]
Duchenne muscular dystrophy	DISRQ3NV	Strong	Genetic Variation	[4]
Emery-Dreifuss muscular dystrophy	DISYTPR5	Strong	Genetic Variation	[4]
Hutchinson-Gilford progeria syndrome	DISY55BU	Strong	Biomarker	[5]
Lentivirus infection	DISX17PY	Strong	Altered Expression	[6]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[6]
Muscular dystrophy	DISJD6P7	Strong	Genetic Variation	[7]
Myopathy	DISOWG27	Strong	Biomarker	[8]
Familial atrial fibrillation	DISL4AGF	moderate	Biomarker	[3]
Breast cancer	DIS7DPX1	Limited	Altered Expression	[9]
Breast carcinoma	DIS2UE88	Limited	Altered Expression	[9]
Malignant tumor of nasopharynx	DISTGIGF	Limited	Biomarker	[10]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Biomarker	[10]

11 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of SUN domain-containing protein 1 (SUN1).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of SUN domain-containing protein 1 (SUN1).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of SUN domain-containing protein 1 (SUN1).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of SUN domain-containing protein 1 (SUN1).	[14]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of SUN domain-containing protein 1 (SUN1).	[15]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of SUN domain-containing protein 1 (SUN1).	[17]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of SUN domain-containing protein 1 (SUN1).	[18]
Rifampicin	DM5DSFZ	Approved	Rifampicin decreases the expression of SUN domain-containing protein 1 (SUN1).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of SUN domain-containing protein 1 (SUN1).	[21]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of SUN domain-containing protein 1 (SUN1).	[22]
AM251	DMTAWHL	Investigative	AM251 decreases the expression of SUN domain-containing protein 1 (SUN1).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Quercetin	DM3NC4M	Approved	Quercetin increases the phosphorylation of SUN domain-containing protein 1 (SUN1).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of SUN domain-containing protein 1 (SUN1).	[20]

References

• [1] SUN1 Regulates HIV-1 Nuclear Import in a Manner Dependent on the Interaction between the Viral Capsid and Cellular Cyclophilin A.J Virol. 2018 Jun 13;92(13):e00229-18. doi: 10.1128/JVI.00229-18. Print 2018 Jul 1.
• [2] Detection of SUN1 Splicing Variants at the mRNA and Protein Levels in Cancer.Methods Mol Biol. 2018;1840:307-319. doi: 10.1007/978-1-4939-8691-0_21.
• [3] Multi-ethnic genome-wide association study for atrial fibrillation.Nat Genet. 2018 Jun 11;50(9):1225-1233. doi: 10.1038/s41588-018-0133-9.
• [4] LINC complex alterations in DMD and EDMD/CMT fibroblasts.Eur J Cell Biol. 2012 Aug;91(8):614-28. doi: 10.1016/j.ejcb.2012.03.003. Epub 2012 May 1.
• [5] Dysregulated interactions between lamin A and SUN1 induce abnormalities in the nuclear envelope and endoplasmic reticulum in progeric laminopathies.J Cell Sci. 2014 Apr 15;127(Pt 8):1792-804. doi: 10.1242/jcs.139683. Epub 2014 Feb 12.
• [6] SUN1 silencing inhibits cell growth through G0/G1 phase arrest in lung adenocarcinoma.Onco Targets Ther. 2017 Jun 2;10:2825-2833. doi: 10.2147/OTT.S79727. eCollection 2017.
• [7] Contribution of SUN1 mutations to the pathomechanism in muscular dystrophies.Hum Mutat. 2014 Apr;35(4):452-61. doi: 10.1002/humu.22504. Epub 2014 Jan 13.
• [8] Muscular dystrophy-associated SUN1 and SUN2 variants disrupt nuclear-cytoskeletal connections and myonuclear organization.PLoS Genet. 2014 Sep 11;10(9):e1004605. doi: 10.1371/journal.pgen.1004605. eCollection 2014 Sep.
• [9] Differential expression and molecular interactions of chromosome region maintenance 1 and calreticulin exportins in breast cancer cells.J Steroid Biochem Mol Biol. 2019 Jan;185:7-16. doi: 10.1016/j.jsbmb.2018.07.003. Epub 2018 Jul 5.
• [10] Sulforaphane promotes apoptosis, and inhibits proliferation and self-renewal of nasopharyngeal cancer cells by targeting STAT signal through miRNA-124-3p.Biomed Pharmacother. 2018 Jul;103:473-481. doi: 10.1016/j.biopha.2018.03.121. Epub 2018 Apr 24.
• [11] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [16] 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.
• [17] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [18] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [19] Integrated analysis of rifampicin-induced microRNA and gene expression changes in human hepatocytes. Drug Metab Pharmacokinet. 2014;29(4):333-40.
• [20] 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.
• [21] 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.
• [22] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [23] Cannabinoid derivatives induce cell death in pancreatic MIA PaCa-2 cells via a receptor-independent mechanism. FEBS Lett. 2006 Mar 20;580(7):1733-9.