Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTF6236I)

• DOT Name: Structure-specific endonuclease subunit SLX4 (SLX4)
• Synonyms: BTB/POZ domain-containing protein 12
• Gene Name: SLX4
• Related Disease:
  Fanconi anemia complementation group P
  Acute monocytic leukemia
  Acute myelogenous leukaemia
  Chromosomal disorder
  Myelodysplastic syndrome
  Neoplasm
  Pancytopenia
  Xeroderma pigmentosum
  Bloom syndrome
  Fanconi's anemia
  Breast cancer
  Breast carcinoma
  Fanconi anemia complementation group A
  Hereditary breast carcinoma
  Familial ovarian cancer
• UniProt ID: SLX4_HUMAN
• PDB ID: 4M7C; 4UYI; 4ZOU; 7BU5; 7TUJ
• Pfam ID: PF00651 ; PF09494
• Sequence:
  MKLSVNEAQLGFYLGSLSHLSACPGIDPRSSEDQPESLKTGQMMDESDEDFKELCASFFQ
  RVKKHGIKEVSGERKTQKAASNGTQIRSKLKRTKQTATKTKTLQGPAEKKPPSGSQAPRT
  KKQRVTKWQASEPAHSVNGEGGVLASAPDPPVLRETAQNTQTGNQQEPSPNLSREKTREN
  VPNSDSQPPPSCLTTAVPSPSKPRTAQLVLQRMQQFKRADPERLRHASEECSLEAAREEN
  VPKDPQEEMMAGNVYGLGPPAPESDAAVALTLQQEFARVGASAHDDSLEEKGLFFCQICQ
  KNLSAMNVTRREQHVNRCLDEAEKTLRPSVPQIPECPICGKPFLTLKSRTSHLKQCAVKM
  EVGPQLLLQAVRLQTAQPEGSSSPPMFSFSDHSRGLKRRGPTSKKEPRKRRKVDEAPSED
  LLVAMALSRSEMEPGAAVPALRLESAFSERIRPEAENKSRKKKPPVSPPLLLVQDSETTG
  RQIEDRVALLLSEEVELSSTPPLPASRILKEGWERAGQCPPPPERKQSFLWEGSALTGAW
  AMEDFYTARLVPPLVPQRPAQGLMQEPVPPLVPPEHSELSERRSPALHGTPTAGCGSRGP
  SPSASQREHQALQDLVDLAREGLSASPWPGSGGLAGSEGTAGLDVVPGGLPLTGFVVPSQ
  DKHPDRGGRTLLSLGLLVADFGAMVNNPHLSDVQFQTDSGEVLYAHKFVLYARCPLLIQY
  VNNEGFSAVEDGVLTQRVLLGDVSTEAARTFLHYLYTADTGLPPGLSSELSSLAHRFGVS
  ELVHLCEQVPIATDSEGKPWEEKEAENCESRAENFQELLRSMWADEEEEAETLLKSKDHE
  EDQENVNEAEMEEIYEFAATQRKLLQEERAAGAGEDADWLEGGSPVSGQLLAGVQVQKQW
  DKVEEMEPLEPGRDEAATTWEKMGQCALPPPQGQHSGARGAEAPEQEAPEEALGHSSCSS
  PSRDCQAERKEGSLPHSDDAGDYEQLFSSTQGEISEPSQITSEPEEQSGAVRERGLEVSH
  RLAPWQASPPHPCRFLLGPPQGGSPRGSHHTSGSSLSTPRSRGGTSQVGSPTLLSPAVPS
  KQKRDRSILTLSKEPGHQKGKERRSVLECRNKGVLMFPEKSPSIDLTQSNPDHSSSRSQK
  SSSKLNEEDEVILLLDSDEELELEQTKMKSISSDPLEEKKALEISPRSCELFSIIDVDAD
  QEPSQSPPRSEAVLQQEDEGALPENRGSLGRRGAPWLFCDRESSPSEASTTDTSWLVPAT
  PLASRSRDCSSQTQISSLRSGLAVQAVTQHTPRASVGNREGNEVAQKFSVIRPQTPPPQT
  PSSCLTPVSPGTSDGRRQGHRSPSRPHPGGHPHSSPLAPHPISGDRAHFSRRFLKHSPPG
  PSFLNQTPAGEVVEVGDSDDEQEVASHQANRSPPLDSDPPIPIDDCCWHMEPLSPIPIDH
  WNLERTGPLSTSSPSRRMNEAADSRDCRSPGLLDTTPIRGSCTTQRKLQEKSSGAGSLGN
  SRPSFLNSALWDVWDGEEQRPPETPPPAQMPSAGGAQKPEGLETPKGANRKKNLPPKVPI
  TPMPQYSIMETPVLKKELDRFGVRPLPKRQMVLKLKEIFQYTHQTLDSDSEDESQSSQPL
  LQAPHCQTLASQTYKPSRAGVHAQQEATTGPGAHRPKGPAKTKGPRHQRKHHESITPPSR
  SPTKEAPPGLNDDAQIPASQESVATSVDGSDSSLSSQSSSSCEFGAAFESAGEEEGEGEV
  SASQAAVQAADTDEALRCYIRSKPALYQKVLLYQPFELRELQAELRQNGLRVSSRRLLDF
  LDTHCITFTTAATRREKLQGRRRQPRGKKKVERN
• Function: Regulatory subunit that interacts with and increases the activity of different structure-specific endonucleases. Has several distinct roles in protecting genome stability by resolving diverse forms of deleterious DNA structures originating from replication and recombination intermediates and from DNA damage. Component of the SLX1-SLX4 structure-specific endonuclease that resolves DNA secondary structures generated during DNA repair and recombination. Has endonuclease activity towards branched DNA substrates, introducing single-strand cuts in duplex DNA close to junctions with ss-DNA. Has a preference for 5'-flap structures, and promotes symmetrical cleavage of static and migrating Holliday junctions (HJs). Resolves HJs by generating two pairs of ligatable, nicked duplex products. Interacts with the structure-specific ERCC4-ERCC1 endonuclease and promotes the cleavage of bubble structures. Interacts with the structure-specific MUS81-EME1 endonuclease and promotes the cleavage of 3'-flap and replication fork-like structures. SLX4 is required for recovery from alkylation-induced DNA damage and is involved in the resolution of DNA double-strand breaks.
• KEGG Pathway: Fanconi anemia pathway (hsa03460)
• Reactome Pathway:
  Fanconi Anemia Pathway (R-HSA-6783310)
  Resolution of D-loop Structures through Holliday Junction Intermediates (R-HSA-5693568)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Fanconi anemia complementation group P	DISB1IL9	Definitive	Autosomal recessive	[1]
Acute monocytic leukemia	DIS28NEL	Strong	Biomarker	[2]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[2]
Chromosomal disorder	DISM5BB5	Strong	Genetic Variation	[3]
Myelodysplastic syndrome	DISYHNUI	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Pancytopenia	DISVKEHV	Strong	Biomarker	[2]
Xeroderma pigmentosum	DISQ9H19	Strong	Genetic Variation	[3]
Bloom syndrome	DISKXQ7J	moderate	Biomarker	[5]
Fanconi's anemia	DISGW6Q8	Supportive	Autosomal recessive	[6]
Breast cancer	DIS7DPX1	Limited	Biomarker	[7]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[7]
Fanconi anemia complementation group A	DIS8PZLI	Limited	Biomarker	[8]
Hereditary breast carcinoma	DISAEZT5	Refuted	Autosomal dominant	[1]
Familial ovarian cancer	DISGLR2C	No Known	Autosomal dominant	[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 Structure-specific endonuclease subunit SLX4 (SLX4).	[9]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Structure-specific endonuclease subunit SLX4 (SLX4).	[16]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Structure-specific endonuclease subunit SLX4 (SLX4).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Structure-specific endonuclease subunit SLX4 (SLX4).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Structure-specific endonuclease subunit SLX4 (SLX4).	[11]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Structure-specific endonuclease subunit SLX4 (SLX4).	[12]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Structure-specific endonuclease subunit SLX4 (SLX4).	[13]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Structure-specific endonuclease subunit SLX4 (SLX4).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Structure-specific endonuclease subunit SLX4 (SLX4).	[15]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Structure-specific endonuclease subunit SLX4 (SLX4).	[18]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Structure-specific endonuclease subunit SLX4 (SLX4).	[19]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Germline Genetic Predisposition to Hematologic Malignancy.J Clin Oncol. 2017 Mar 20;35(9):1018-1028. doi: 10.1200/JCO.2016.70.8644. Epub 2017 Feb 13.
• [3] Physical interaction between SLX4 (FANCP) and XPF (FANCQ) proteins and biological consequences of interaction-defective missense mutations.DNA Repair (Amst). 2015 Nov;35:48-54. doi: 10.1016/j.dnarep.2015.09.022. Epub 2015 Sep 30.
• [4] The SLX4 complex is a SUMO E3 ligase that impacts on replication stress outcome and genome stability.Mol Cell. 2015 Jan 8;57(1):123-37. doi: 10.1016/j.molcel.2014.11.014. Epub 2014 Dec 18.
• [5] Aberrant chromosome morphology in human cells defective for Holliday junction resolution.Nature. 2011 Mar 31;471(7340):642-6. doi: 10.1038/nature09790. Epub 2011 Mar 13.
• [6] Fanconi Anemia. 2002 Feb 14 [updated 2021 Jun 3]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [7] A low-frequency haplotype spanning SLX4/FANCP constitutes a new risk locus for early-onset breast cancer (<60 years) and is associated with reduced DNA repair capacity.Int J Cancer. 2018 Feb 15;142(4):757-768. doi: 10.1002/ijc.31105. Epub 2017 Oct 30.
• [8] Upregulated LINE-1 Activity in the Fanconi Anemia Cancer Susceptibility Syndrome Leads to Spontaneous Pro-inflammatory Cytokine Production.EBioMedicine. 2016 Jun;8:184-194. doi: 10.1016/j.ebiom.2016.05.005. Epub 2016 May 6.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [16] 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.
• [17] 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.
• [18] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [19] Cellular reactions to long-term volatile organic compound (VOC) exposures. Sci Rep. 2016 Dec 1;6:37842. doi: 10.1038/srep37842.