Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6JAVXE)

• DOT Name: Meiotic recombination protein REC8 homolog (REC8)
• Synonyms: Cohesin Rec8p
• Gene Name: REC8
• Related Disease:
  Azoospermia
  Congenital heart disease
  Gastric neoplasm
  Melanoma
  Oligospermia
  Prostate cancer
  Prostate neoplasm
  Tetralogy of fallot
  Ventricular septal defect
  Neoplasm
  Thyroid cancer
  Thyroid gland carcinoma
  Thyroid tumor
  Intellectual disability
• UniProt ID: REC8_HUMAN
• Pfam ID: PF04824 ; PF04825
• Sequence:
  MFYYPNVLQRHTGCFATIWLAATRGSRLVKREYLRVNVVKTCEEILNYVLVRVQPPQPGL
  PRPRFSLYLSAQLQIGVIRVYSQQCQYLVEDIQHILERLHRAQLQIRIDMETELPSLLLP
  NHLAMMETLEDAPDPFFGMMSVDPRLPSPFDIPQIRHLLEAAIPERVEEIPPEVPTEPRE
  PERIPVTVLPPEAITILEAEPIRMLEIEGERELPEVSRRELDLLIAEEEEAILLEIPRLP
  PPAPAEVEGIGEALGPEELRLTGWEPGALLMEVTPPEELRLPAPPSPERRPPVPPPPRRR
  RRRRLLFWDKETQISPEKFQEQLQTRAHCWECPMVQPPERTIRGPAELFRTPTLSGWLPP
  ELLGLWTHCAQPPPKALRRELPEEAAAEEERRKIEVPSEIEVPREALEPSVPLMVSLEIS
  LEAAEEEKSRISLIPPEERWAWPEVEAPEAPALPVVPELPEVPMEMPLVLPPELELLSLE
  AVHRAVALELQANREPDFSSLVSPLSPRRMAARVFYLLLVLSAQQILHVKQEKPYGRLLI
  QPGPRFH
• Function: Required during meiosis for separation of sister chromatids and homologous chromosomes. Proteolytic cleavage of REC8 on chromosome arms by separin during anaphase I allows for homologous chromosome separation in meiosis I and cleavage of REC8 on centromeres during anaphase II allows for sister chromatid separation in meiosis II.
• Tissue Specificity: Expressed in testis and thymus. Expressed in the B-cell lines WI-L2-NS and Namalwa (at protein level).
• KEGG Pathway: Oocyte meiosis (hsa04114)
• Reactome Pathway: Meiotic synapsis (R-HSA-1221632)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Azoospermia	DIS94181	Strong	Genetic Variation	[1]
Congenital heart disease	DISQBA23	Strong	Genetic Variation	[2]
Gastric neoplasm	DISOKN4Y	Strong	Altered Expression	[3]
Melanoma	DIS1RRCY	Strong	Biomarker	[4]
Oligospermia	DIS6YJF3	Strong	Genetic Variation	[5]
Prostate cancer	DISF190Y	Strong	Biomarker	[6]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[6]
Tetralogy of fallot	DISMHFNW	Strong	Genetic Variation	[2]
Ventricular septal defect	DISICO41	Strong	Genetic Variation	[2]
Neoplasm	DISZKGEW	moderate	Altered Expression	[3]
Thyroid cancer	DIS3VLDH	moderate	Altered Expression	[7]
Thyroid gland carcinoma	DISMNGZ0	moderate	Altered Expression	[7]
Thyroid tumor	DISLVKMD	moderate	Altered Expression	[7]
Intellectual disability	DISMBNXP	Limited	Genetic Variation	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Meiotic recombination protein REC8 homolog (REC8).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Meiotic recombination protein REC8 homolog (REC8).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Meiotic recombination protein REC8 homolog (REC8).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Meiotic recombination protein REC8 homolog (REC8).	[11]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Meiotic recombination protein REC8 homolog (REC8).	[12]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Meiotic recombination protein REC8 homolog (REC8).	[13]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Meiotic recombination protein REC8 homolog (REC8).	[14]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Meiotic recombination protein REC8 homolog (REC8).	[15]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Meiotic recombination protein REC8 homolog (REC8).	[16]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Meiotic recombination protein REC8 homolog (REC8).	[17]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Meiotic recombination protein REC8 homolog (REC8).	[18]

References

• [1] Sequence analysis of 37 candidate genes for male infertility: challenges in variant assessment and validating genes.Andrology. 2020 Mar;8(2):434-441. doi: 10.1111/andr.12704. Epub 2019 Nov 22.
• [2] San Luis Valley recombinant chromosome 8 and tetralogy of Fallot: a review of chromosome 8 anomalies and congenital heart disease.Am J Med Genet. 1991 Sep 15;40(4):471-6. doi: 10.1002/ajmg.1320400420.
• [3] REC8 functions as a tumor suppressor and is epigenetically downregulated in gastric cancer, especially in EBV-positive subtype.Oncogene. 2017 Jan 12;36(2):182-193. doi: 10.1038/onc.2016.187. Epub 2016 May 23.
• [4] Silencing of Peroxiredoxin 2 and aberrant methylation of 33 CpG islands in putative promoter regions in human malignant melanomas.Cancer Res. 2006 Jun 15;66(12):6080-6. doi: 10.1158/0008-5472.CAN-06-0157.
• [5] Analysis of the meiotic recombination gene REC8 for sequence variations in a population with severe male factor infertility.Syst Biol Reprod Med. 2008 May-Jun;54(3):163-5. doi: 10.1080/19396360802061317.
• [6] Identification of genes potentially involved in the acquisition of androgen-independent and metastatic tumor growth in an autochthonous genetically engineered mouse prostate cancer model.Prostate. 2007 Jan 1;67(1):83-106. doi: 10.1002/pros.20505.
• [7] REC8 is a novel tumor suppressor gene epigenetically robustly targeted by the PI3K pathway in thyroid cancer.Oncotarget. 2015 Nov 17;6(36):39211-24. doi: 10.18632/oncotarget.5391.
• [8] Pre- and postnatal findings in a patient with a novel rec(8)dup(8q)inv(8)(p23.2q22.3) associated with San Luis Valley syndrome.Am J Med Genet A. 2013 Sep;161A(9):2369-75. doi: 10.1002/ajmg.a.36103. Epub 2013 Jul 25.
• [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] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [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] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [14] 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.
• [15] Characterization of DOK1, a candidate tumor suppressor gene, in epithelial ovarian cancer. Mol Oncol. 2011 Oct;5(5):438-53. doi: 10.1016/j.molonc.2011.07.003. Epub 2011 Jul 26.
• [16] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [17] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [18] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [19] 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.