Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTEV0AOD)

• DOT Name: Cohesin subunit SA-3 (STAG3)
• Synonyms: SCC3 homolog 3; Stromal antigen 3; Stromalin-3
• Gene Name: STAG3
• Related Disease:
  Alzheimer disease
  Colorectal neoplasm
  Epithelial ovarian cancer
  Female hypogonadism
  Ovarian cancer
  Ovarian neoplasm
  Premature ovarian failure 8
  Alcohol dependence
  Alcohol-induced disorders
  Alcohol-related disorders
  Major depressive disorder
  Male infertility
  Melanoma
  Neoplasm
  Spermatogenic failure 61
• UniProt ID: STAG3_HUMAN
• Pfam ID: PF21581 ; PF08514
• Sequence:
  MSSPLQRAVGDTKRALSASSSSSASLPFDDRDSNHTSEGNGDSLLADEDTDFEDSLNRNV
  KKRAAKRPPKTTPVAKHPKKGSRVVHRHSRKQSEPPANDLFNAVKAAKSDMQSLVDEWLD
  SYKQDQDAGFLELVNFFIQSCGCKGIVTPEMFKKMSNSEIIQHLTEQFNEDSGDYPLIAP
  GPSWKKFQGSFCEFVRTLVCQCQYSLLYDGFPMDDLISLLTGLSDSQVRAFRHTSTLAAM
  KLMTSLVKVALQLSVHQDNNQRQYEAERNKGPGQRAPERLESLLEKRKELQEHQEEIEGM
  MNALFRGVFVHRYRDVLPEIRAICIEEIGCWMQSYSTSFLTDSYLKYIGWTLHDKHREVR
  LKCVKALKGLYGNRDLTTRLELFTSRFKDRMVSMVMDREYDVAVEAVRLLILILKNMEGV
  LTDADCESVYPVVYASHRGLASAAGEFLYWKLFYPECEIRMMGGREQRQSPGAQRTFFQL
  LLSFFVESELHDHAAYLVDSLWDCAGARLKDWEGLTSLLLEKDQNLGDVQESTLIEILVS
  SARQASEGHPPVGRVTGRKGLTSKERKTQADDRVKLTEHLIPLLPQLLAKFSADAEKVTP
  LLQLLSCFDLHIYCTGRLEKHLELFLQQLQEVVVKHAEPAVLEAGAHALYLLCNPEFTFF
  SRADFARSQLVDLLTDRFQQELEELLQSSFLDEDEVYNLAATLKRLSAFYNTHDLTRWEL
  YEPCCQLLQKAVDTGEVPHQVILPALTLVYFSILWTLTHISKSDASQKQLSSLRDRMVAF
  CELCQSCLSDVDTEIQEQAFVLLSDLLLIFSPQMIVGGRDFLRPLVFFPEATLQSELASF
  LMDHVFIQPGDLGSGDSQEDHLQIERLHQRRRLLAGFCKLLLYGVLEMDAASDVFKHYNK
  FYNDYGDIIKETLTRARQIDRSHCSRILLLSLKQLYTELLQEHGPQGLNELPAFIEMRDL
  ARRFALSFGPQQLQNRDLVVMLHKEGIQFSLSELPPAGSSNQPPNLAFLELLSEFSPRLF
  HQDKQLLLSYLEKCLQHVSQAPGHPWGPVTTYCHSLSPVENTAETSPQVLPSSKRRRVEG
  PAKPNREDVSSSQEESLQLNSIPPTPTLTSTAVKSRQPLWGLKEMEEEDGSELDFAQGQP
  VAGTERSRFLGPQYFQTPHNPSGPGLGNQLMRLSLMEEDEEEELEIQDESNEERQDTDMQ
  ASSYSSTSERGLDLLDSTELDIEDF
• Function: Meiosis specific component of cohesin complex. The cohesin complex is required for the cohesion of sister chromatids after DNA replication. The cohesin complex apparently forms a large proteinaceous ring within which sister chromatids can be trapped. At anaphase, the complex is cleaved and dissociates from chromatin, allowing sister chromatids to segregate. The meiosis-specific cohesin complex probably replaces mitosis specific cohesin complex when it dissociates from chromatin during prophase I.
• Tissue Specificity: Testis specific.
• KEGG Pathway: Oocyte meiosis (hsa04114)
• 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
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[1]
Colorectal neoplasm	DISR1UCN	Strong	Genetic Variation	[2]
Epithelial ovarian cancer	DIS56MH2	Strong	Genetic Variation	[3]
Female hypogonadism	DISWASB4	Strong	Biomarker	[4]
Ovarian cancer	DISZJHAP	Strong	Genetic Variation	[3]
Ovarian neoplasm	DISEAFTY	Strong	Genetic Variation	[3]
Premature ovarian failure 8	DISCWHJZ	Strong	Autosomal recessive	[5]
Alcohol dependence	DIS4ZSCO	moderate	Genetic Variation	[6]
Alcohol-induced disorders	DIS3SFYT	moderate	Genetic Variation	[6]
Alcohol-related disorders	DIS3K4KK	moderate	Genetic Variation	[6]
Major depressive disorder	DIS4CL3X	moderate	Genetic Variation	[6]
Male infertility	DISY3YZZ	moderate	Genetic Variation	[7]
Melanoma	DIS1RRCY	Limited	Biomarker	[8]
Neoplasm	DISZKGEW	Limited	Biomarker	[8]
Spermatogenic failure 61	DISSMW2O	Limited	Autosomal recessive	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Cohesin subunit SA-3 (STAG3).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Cohesin subunit SA-3 (STAG3).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Cohesin subunit SA-3 (STAG3).	[12]

References

• [1] Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer's disease risk.Nat Genet. 2019 Mar;51(3):404-413. doi: 10.1038/s41588-018-0311-9. Epub 2019 Jan 7.
• [2] Chromatid cohesion defects may underlie chromosome instability in human colorectal cancers.Proc Natl Acad Sci U S A. 2008 Mar 4;105(9):3443-8. doi: 10.1073/pnas.0712384105. Epub 2008 Feb 25.
• [3] Sequencing of a 'mouse azoospermia' gene panel in azoospermic men: identification of RNF212 and STAG3 mutations as novel genetic causes of meiotic arrest.Hum Reprod. 2019 Jun 4;34(6):978-988. doi: 10.1093/humrep/dez042.
• [4] Two rare loss-of-function variants in the STAG3 gene leading to primary ovarian insufficiency.Eur J Med Genet. 2019 Mar;62(3):186-189. doi: 10.1016/j.ejmg.2018.07.008. Epub 2018 Jul 10.
• [5] Mutant cohesin in premature ovarian failure. N Engl J Med. 2014 Mar 6;370(10):943-949. doi: 10.1056/NEJMoa1309635.
• [6] Genetic Risk Variants Associated With Comorbid Alcohol Dependence and Major Depression.JAMA Psychiatry. 2017 Dec 1;74(12):1234-1241. doi: 10.1001/jamapsychiatry.2017.3275.
• [7] The association of stromal antigen 3 (STAG3) sequence variations with spermatogenic impairment in the male Korean population.Asian J Androl. 2020 Jan-Feb;22(1):106-111. doi: 10.4103/aja.aja_28_19.
• [8] Loss of cohesin complex components STAG2 or STAG3 confers resistance to BRAF inhibition in melanoma.Nat Med. 2016 Sep;22(9):1056-61. doi: 10.1038/nm.4155. Epub 2016 Aug 8.
• [9] STAG3 is a strong candidate gene for male infertility. Hum Mol Genet. 2014 Jul 1;23(13):3421-31. doi: 10.1093/hmg/ddu051. Epub 2014 Mar 7.
• [10] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [11] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [12] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.