Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTP8V0HC)

• DOT Name: SMC5-SMC6 complex localization factor protein 2 (SLF2)
• Synonyms: Smc5/6 localization factor 1
• Gene Name: SLF2
• Related Disease:
  Autism spectrum disorder
  Mitochondrial DNA depletion syndrome 7 (hepatocerebral type)
  Atelis syndrome 1
• UniProt ID: SLF2_HUMAN
• PDB ID: 7T5P
• Pfam ID: PF14816
• Sequence:
  MTRRCMPARPGFPSSPAPGSSPPRCHLRPGSTAHAAAGKRTESPGDRKQSIIDFFKPASK
  QDRHMLDSPQKSNIKYGGSRLSITGTEQFERKLSSPKESKPKRVPPEKSPIIEAFMKGVK
  EHHEDHGIHESRRPCLSLASKYLAKGTNIYVPSSYHLPKEMKSLKKKHRSPERRKSLFIH
  ENNEKNDRDRGKTNADSKKQTTVAEADIFNNSSRSLSSRSSLSRHHPEESPLGAKFQLSL
  ASYCRERELKRLRKEQMEQRINSENSFSEASSLSLKSSIERKYKPRQEQRKQNDIIPGKN
  NLSNVENGHLSRKRSSSDSWEPTSAGSKQNKFPEKRKRNSVDSDLKSTRESMIPKARESF
  LEKRPDGPHQKEKFIKHIALKTPGDVLRLEDISKEPSDETDGSSAGLAPSNSGNSGHHST
  RNSDQIQVAGTKETKMQKPHLPLSQEKSAIKKASNLQKNKTASSTTKEKETKLPLLSRVP
  SAGSSLVPLNAKNCALPVSKKDKERSSSKECSGHSTESTKHKEHKAKTNKADSNVSSGKI
  SGGPLRSEYGTPTKSPPAALEVVPCIPSPAAPSDKAPSEGESSGNSNAGSSALKRKLRGD
  FDSDEESLGYNLDSDEEEETLKSLEEIMALNFNQTPAATGKPPALSKGLRSQSSDYTGHV
  HPGTYTNTLERLVKEMEDTQRLDELQKQLQEDIRQGRGIKSPIRIGEEDSTDDEDGLLEE
  HKEFLKKFSVTIDAIPDHHPGEEIFNFLNSGKIFNQYTLDLRDSGFIGQSAVEKLILKSG
  KTDQIFLTTQGFLTSAYHYVQCPVPVLKWLFRMMSVHTDCIVSVQILSTLMEITIRNDTF
  SDSPVWPWIPSLSDVAAVFFNMGIDFRSLFPLENLQPDFNEDYLVSETQTTSRGKESEDS
  SYKPIFSTLPETNILNVVKFLGLCTSIHPEGYQDREIMLLILMLFKMSLEKQLKQIPLVD
  FQSLLINLMKNIRDWNTKVPELCLGINELSSHPHNLLWLVQLVPNWTSRGRQLRQCLSLV
  IISKLLDEKHEDVPNASNLQVSVLHRYLVQMKPSDLLKKMVLKKKAEQPDGIIDDSLHLE
  LEKQAYYLTYILLHLVGEVSCSHSFSSGQRKHFVLLCGALEKHVKCDIREDARLFYRTKV
  KDLVARIHGKWQEIIQNCRPTQGQLHDFWVPDS
• Function: Plays a role in the DNA damage response (DDR) pathway by regulating postreplication repair of UV-damaged DNA and genomic stability maintenance. The SLF1-SLF2 complex acts to link RAD18 with the SMC5-SMC6 complex at replication-coupled interstrand cross-links (ICL) and DNA double-strand breaks (DSBs) sites on chromatin during DNA repair in response to stalled replication forks. Promotes the recruitment of the SMC5-SMC6 complex to DNA lesions. Plays a role in SMC5-SMC6 complex recruitment for viral restriction. Forms a complex with SIMC1 and this complex is required to recruit SMC5-SMC6 complex to PML nuclear bodies and sites of viral replication.
• Tissue Specificity: Widely expressed . Expressed at higher level in skeletal muscle and at slightly lower level in brain, liver and heart, than in lung, kidney, spleen and thymus .

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[1]
Mitochondrial DNA depletion syndrome 7 (hepatocerebral type)	DISWVOY7	Strong	Genetic Variation	[2]
Atelis syndrome 1	DIS5E882	Moderate	Autosomal recessive	[3]

10 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 SMC5-SMC6 complex localization factor protein 2 (SLF2).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of SMC5-SMC6 complex localization factor protein 2 (SLF2).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of SMC5-SMC6 complex localization factor protein 2 (SLF2).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of SMC5-SMC6 complex localization factor protein 2 (SLF2).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of SMC5-SMC6 complex localization factor protein 2 (SLF2).	[8]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of SMC5-SMC6 complex localization factor protein 2 (SLF2).	[9]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of SMC5-SMC6 complex localization factor protein 2 (SLF2).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of SMC5-SMC6 complex localization factor protein 2 (SLF2).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of SMC5-SMC6 complex localization factor protein 2 (SLF2).	[13]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of SMC5-SMC6 complex localization factor protein 2 (SLF2).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of SMC5-SMC6 complex localization factor protein 2 (SLF2).	[12]

References

• [1] Abnormal fronto-parietal white matter organisation in the superior longitudinal fasciculus branches in autism spectrum disorders.Eur J Neurosci. 2018 Mar;47(6):652-661. doi: 10.1111/ejn.13655. Epub 2017 Sep 1.
• [2] cDNA cloning, expression profile and genomic structure of a novel human transcript on chromosome 10q24, and its analyses as a candidate gene for infantile onset spinocerebellar ataxia.Gene. 2002 Oct 16;299(1-2):111-5. doi: 10.1016/s0378-1119(02)01019-3.
• [3] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] 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.
• [9] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [10] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [11] 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.
• [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] 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.
• [14] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.