Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTASLBM1)

• DOT Name: 26S proteasome complex subunit SEM1 (SEM1)
• Synonyms: 26S proteasome complex subunit DSS1; Deleted in split hand/split foot protein 1; Split hand/foot deleted protein 1; Split hand/foot malformation type 1 protein
• Gene Name: SEM1
• Related Disease:
  Cervical cancer
  Cervical carcinoma
  Precancerous condition
  Advanced cancer
  Autism
  Breast cancer
  Breast carcinoma
  Chromosomal disorder
  Extragonadal germ cell tumor
  Extragonadal seminoma
  HIV infectious disease
  Osteoporosis
  Seminoma
  Squamous cell carcinoma
  Uveal Melanoma
  Gastric cancer
  Gastric neoplasm
  Stomach cancer
  Cutaneous squamous cell carcinoma
  Epithelial ovarian cancer
  Hereditary breast ovarian cancer syndrome
  Melanoma
  Neoplasm
  Ovarian cancer
  Ovarian neoplasm
  Prostate cancer
  Prostate carcinoma
  Skin cancer
  Split hand-foot malformation
• UniProt ID: SEM1_HUMAN
• PDB ID: 1IYJ ; 1MIU ; 1MJE ; 3T5X ; 5GJQ ; 5GJR ; 5L4K ; 5LN3 ; 5M32 ; 5T0C ; 5T0G ; 5T0H ; 5T0I ; 5T0J ; 5VFR ; 5VFT ; 5VGZ ; 5VHF ; 5VHH ; 5VHI ; 5VHS ; 6MSB ; 6MSD ; 6MSG ; 6MSH ; 6MSJ ; 6MSK ; 6WJD ; 6WJN ; 7QXN ; 7QXP ; 7QXU ; 7QXW ; 7QXX ; 7QY7 ; 7QYA ; 7QYB ; 7W37 ; 7W38 ; 7W39 ; 7W3A ; 7W3B ; 7W3C ; 7W3F ; 7W3G ; 7W3H ; 7W3I ; 7W3J ; 7W3K ; 7W3M ; 8CVT
• Pfam ID: PF05160
• Sequence:
  MSEKKQPVDLGLLEEDDEFEEFPAEDWAGLDEDEDAHVWEDNWDDDNVEDDFSNQLRAEL
  EKHGYKMETS
• Function: Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. Component of the TREX-2 complex (transcription and export complex 2), composed of at least ENY2, GANP, PCID2, SEM1, and either centrin CETN2 or CETN3. The TREX-2 complex functions in docking export-competent ribonucleoprotein particles (mRNPs) to the nuclear entrance of the nuclear pore complex (nuclear basket). TREX-2 participates in mRNA export and accurate chromatin positioning in the nucleus by tethering genes to the nuclear periphery. Binds and stabilizes BRCA2 and is thus involved in the control of R-loop-associated DNA damage and thus transcription-associated genomic instability. R-loop accumulation increases in SEM1-depleted cells.
• Tissue Specificity: Expressed in limb bud, craniofacial primordia and skin.
• KEGG Pathway:
  Proteasome (hsa03050)
  Homologous recombi.tion (hsa03440)
  Alzheimer disease (hsa05010)
  Parkinson disease (hsa05012)
  Amyotrophic lateral sclerosis (hsa05014)
  Huntington disease (hsa05016)
  Spinocerebellar ataxia (hsa05017)
  Prion disease (hsa05020)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Epstein-Barr virus infection (hsa05169)
• Reactome Pathway:
  Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha (R-HSA-1234176)
  ER-Phagosome pathway (R-HSA-1236974)
  Cross-presentation of soluble exogenous antigens (endosomes) (R-HSA-1236978)
  Autodegradation of Cdh1 by Cdh1 (R-HSA-174084)
  SCF-beta-TrCP mediated degradation of Emi1 (R-HSA-174113)
  APC/C (R-HSA-174154)
  APC/C (R-HSA-174178)
  Cdc20 (R-HSA-174184)
  Vpu mediated degradation of CD4 (R-HSA-180534)
  Vif-mediated degradation of APOBEC3G (R-HSA-180585)
  SCF(Skp2)-mediated degradation of p27/p21 (R-HSA-187577)
  Degradation of beta-catenin by the destruction complex (R-HSA-195253)
  Downstream TCR signaling (R-HSA-202424)
  Regulation of activated PAK-2p34 by proteasome mediated degradation (R-HSA-211733)
  Separation of Sister Chromatids (R-HSA-2467813)
  FCERI mediated NF-kB activation (R-HSA-2871837)
  Autodegradation of the E3 ubiquitin ligase COP1 (R-HSA-349425)
  Regulation of ornithine decarboxylase (ODC) (R-HSA-350562)
  ABC-family proteins mediated transport (R-HSA-382556)
  AUF1 (hnRNP D0) binds and destabilizes mRNA (R-HSA-450408)
  Asymmetric localization of PCP proteins (R-HSA-4608870)
  Degradation of AXIN (R-HSA-4641257)
  Degradation of DVL (R-HSA-4641258)
  Hedgehog ligand biogenesis (R-HSA-5358346)
  Hh mutants are degraded by ERAD (R-HSA-5362768)
  Dectin-1 mediated noncanonical NF-kB signaling (R-HSA-5607761)
  CLEC7A (Dectin-1) signaling (R-HSA-5607764)
  Degradation of GLI1 by the proteasome (R-HSA-5610780)
  Degradation of GLI2 by the proteasome (R-HSA-5610783)
  GLI3 is processed to GLI3R by the proteasome (R-HSA-5610785)
  Hedgehog 'on' state (R-HSA-5632684)
  Regulation of RAS by GAPs (R-HSA-5658442)
  TNFR2 non-canonical NF-kB pathway (R-HSA-5668541)
  NIK-->noncanonical NF-kB signaling (R-HSA-5676590)
  Defective CFTR causes cystic fibrosis (R-HSA-5678895)
  HDR through Homologous Recombination (HRR) (R-HSA-5685942)
  MAPK6/MAPK4 signaling (R-HSA-5687128)
  UCH proteinases (R-HSA-5689603)
  Ub-specific processing proteases (R-HSA-5689880)
  Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA) (R-HSA-5693554)
  Resolution of D-loop Structures through Holliday Junction Intermediates (R-HSA-5693568)
  Homologous DNA Pairing and Strand Exchange (R-HSA-5693579)
  Presynaptic phase of homologous DNA pairing and strand exchange (R-HSA-5693616)
  Assembly of the pre-replicative complex (R-HSA-68867)
  Orc1 removal from chromatin (R-HSA-68949)
  CDK-mediated phosphorylation and removal of Cdc6 (R-HSA-69017)
  G2/M Checkpoints (R-HSA-69481)
  Ubiquitin Mediated Degradation of Phosphorylated Cdc25A (R-HSA-69601)
  Ubiquitin-dependent degradation of Cyclin D (R-HSA-75815)
  The role of GTSE1 in G2/M progression after G2 checkpoint (R-HSA-8852276)
  FBXL7 down-regulates AURKA during mitotic entry and in early mitosis (R-HSA-8854050)
  RUNX1 regulates transcription of genes involved in differentiation of HSCs (R-HSA-8939236)
  Regulation of RUNX2 expression and activity (R-HSA-8939902)
  Regulation of RUNX3 expression and activity (R-HSA-8941858)
  Regulation of PTEN stability and activity (R-HSA-8948751)
  Neddylation (R-HSA-8951664)
  Regulation of expression of SLITs and ROBOs (R-HSA-9010553)
  Interleukin-1 signaling (R-HSA-9020702)
  Negative regulation of NOTCH4 signaling (R-HSA-9604323)
  Defective homologous recombination repair (HRR) due to BRCA1 loss of function (R-HSA-9701192)
  Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function (R-HSA-9704331)
  Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function (R-HSA-9704646)
  Impaired BRCA2 translocation to the nucleus (R-HSA-9709275)
  Impaired BRCA2 binding to RAD51 (R-HSA-9709570)
  KEAP1-NFE2L2 pathway (R-HSA-9755511)
  GSK3B and BTRC (R-HSA-9762114)
  Impaired BRCA2 binding to SEM1 (DSS1) (R-HSA-9763198)
  Somitogenesis (R-HSA-9824272)
  Antigen processing (R-HSA-983168)
  Activation of NF-kappaB in B cells (R-HSA-1169091)

Molecular Interaction Atlas (MIA) of This DOT

29 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cervical cancer	DISFSHPF	Definitive	Biomarker	[1]
Cervical carcinoma	DIST4S00	Definitive	Altered Expression	[1]
Precancerous condition	DISV06FL	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Autism	DISV4V1Z	Strong	Genetic Variation	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Chromosomal disorder	DISM5BB5	Strong	Biomarker	[5]
Extragonadal germ cell tumor	DISE6LY9	Strong	Biomarker	[2]
Extragonadal seminoma	DISU0O5L	Strong	Biomarker	[2]
HIV infectious disease	DISO97HC	Strong	Biomarker	[6]
Osteoporosis	DISF2JE0	Strong	Genetic Variation	[7]
Seminoma	DIS3J8LJ	Strong	Biomarker	[2]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[8]
Uveal Melanoma	DISA7ZGL	Strong	Biomarker	[9]
Gastric cancer	DISXGOUK	moderate	Genetic Variation	[10]
Gastric neoplasm	DISOKN4Y	moderate	Altered Expression	[10]
Stomach cancer	DISKIJSX	moderate	Genetic Variation	[10]
Cutaneous squamous cell carcinoma	DIS3LXUG	Limited	Genetic Variation	[11]
Epithelial ovarian cancer	DIS56MH2	Limited	Genetic Variation	[12]
Hereditary breast ovarian cancer syndrome	DISWDUGU	Limited	Genetic Variation	[12]
Melanoma	DIS1RRCY	Limited	Altered Expression	[8]
Neoplasm	DISZKGEW	Limited	Biomarker	[13]
Ovarian cancer	DISZJHAP	Limited	Genetic Variation	[12]
Ovarian neoplasm	DISEAFTY	Limited	Genetic Variation	[12]
Prostate cancer	DISF190Y	Limited	Biomarker	[14]
Prostate carcinoma	DISMJPLE	Limited	Biomarker	[14]
Skin cancer	DISTM18U	Limited	Biomarker	[11]
Split hand-foot malformation	DIS8PKGD	Limited	Genetic Variation	[15]

2 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 26S proteasome complex subunit SEM1 (SEM1).	[16]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of 26S proteasome complex subunit SEM1 (SEM1).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of 26S proteasome complex subunit SEM1 (SEM1).	[17]
Selenium	DM25CGV	Approved	Selenium decreases the expression of 26S proteasome complex subunit SEM1 (SEM1).	[18]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of 26S proteasome complex subunit SEM1 (SEM1).	[19]
Bicalutamide	DMZMSPF	Approved	Bicalutamide increases the expression of 26S proteasome complex subunit SEM1 (SEM1).	[21]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the expression of 26S proteasome complex subunit SEM1 (SEM1).	[22]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of 26S proteasome complex subunit SEM1 (SEM1).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of 26S proteasome complex subunit SEM1 (SEM1).	[24]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of 26S proteasome complex subunit SEM1 (SEM1).	[25]
AHPN	DM8G6O4	Investigative	AHPN decreases the expression of 26S proteasome complex subunit SEM1 (SEM1).	[26]

References

• [1] Identification of the deleted in split hand/split foot 1 protein as a novel biomarker for human cervical cancer.Carcinogenesis. 2013 Jan;34(1):68-78. doi: 10.1093/carcin/bgs279. Epub 2012 Sep 28.
• [2] Establishment and characterization of a new human extragonadal germ cell line, SEM-1, and its comparison with TCam-2 and JKT-1.Urology. 2013 Feb;81(2):464.e1-9. doi: 10.1016/j.urology.2012.09.029.
• [3] Sample size computation for association studies using case-parents design.J Genet. 2006 Dec;85(3):187-91. doi: 10.1007/BF02935329.
• [4] Breast cancers with high DSS1 expression that potentially maintains BRCA2 stability have poor prognosis in the relapse-free survival.BMC Cancer. 2013 Dec 1;13:562. doi: 10.1186/1471-2407-13-562.
• [5] Evidence for locus heterogeneity in human autosomal dominant split hand/split foot malformation.Am J Hum Genet. 1994 Jul;55(1):21-6.
• [6] Structural characterization of semen coagulum-derived SEM1(86-107) amyloid fibrils that enhance HIV-1 infection.Biochemistry. 2014 May 27;53(20):3267-77. doi: 10.1021/bi500427r. Epub 2014 May 12.
• [7] Functional characterization of the C7ORF76 genomic region, a prominent GWAS signal for osteoporosis in 7q21.3.Bone. 2019 Jun;123:39-47. doi: 10.1016/j.bone.2019.03.014. Epub 2019 Mar 14.
• [8] DSS1 promoter hypomethylation and overexpression predict poor prognosis in melanoma and squamous cell carcinoma patients.Hum Pathol. 2017 Feb;60:137-146. doi: 10.1016/j.humpath.2016.10.018. Epub 2016 Nov 4.
• [9] DNA Methylation and Uveal Melanoma.Chin Med J (Engl). 2018 Apr 5;131(7):845-851. doi: 10.4103/0366-6999.228229.
• [10] Juxtaposed genes in 7q21-22 amplicon contribute for two major gastric cancer sub-Types by mutual exclusive expression.Mol Carcinog. 2017 Apr;56(4):1239-1250. doi: 10.1002/mc.22586. Epub 2016 Nov 15.
• [11] Association of the DSS1 c.143G>A polymorphism with skin squamous cell carcinoma.J Invest Dermatol. 2010 Jun;130(6):1719-25. doi: 10.1038/jid.2010.21. Epub 2010 Mar 11.
• [12] Mutation analysis of the SHFM1 gene in breast/ovarian cancer families.J Cancer Res Clin Oncol. 2013 Mar;139(3):529-32. doi: 10.1007/s00432-013-1385-5. Epub 2013 Feb 1.
• [13] The -isoform of BCCIP promotes ADP release from the RAD51 presynaptic filament and enhances homologous DNA pairing.Nucleic Acids Res. 2017 Jan 25;45(2):711-725. doi: 10.1093/nar/gkw877. Epub 2016 Sep 30.
• [14] Steroidogenic factor 1 promotes aggressive growth of castration-resistant prostate cancer cells by stimulating steroid synthesis and cell proliferation.Endocrinology. 2014 Feb;155(2):358-69. doi: 10.1210/en.2013-1583. Epub 2013 Nov 21.
• [15] A 0.7Mb de novo duplication at 7q21.3 including the genes DLX5 and DLX6 in a patient with split-hand/split-foot malformation.Am J Med Genet A. 2012 Dec;158A(12):3201-6. doi: 10.1002/ajmg.a.35644. Epub 2012 Nov 20.
• [16] 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.
• [17] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [18] 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.
• [19] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [20] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [21] Differentially expressed genes in the prostate cancer cell line LNCaP after exposure to androgen and anti-androgen. Cancer Genet Cytogenet. 2006 Apr 15;166(2):130-8. doi: 10.1016/j.cancergencyto.2005.09.012.
• [22] Arsenic exposure in utero exacerbates skin cancer response in adulthood with contemporaneous distortion of tumor stem cell dynamics. Cancer Res. 2008 Oct 15;68(20):8278-85. doi: 10.1158/0008-5472.CAN-08-2099.
• [23] 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.
• [24] Comparison of transcriptome expression alterations by chronic exposure to low-dose bisphenol A in different subtypes of breast cancer cells. Toxicol Appl Pharmacol. 2019 Dec 15;385:114814. doi: 10.1016/j.taap.2019.114814. Epub 2019 Nov 9.
• [25] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [26] ST1926, a novel and orally active retinoid-related molecule inducing apoptosis in myeloid leukemia cells: modulation of intracellular calcium homeostasis. Blood. 2004 Jan 1;103(1):194-207.