Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTEM0BTG)

• DOT Name: Exonuclease 3'-5' domain-containing protein 2 (EXD2)
• Synonyms: EC 3.1.11.1; 3'-5' exoribonuclease EXD2; EC 3.1.13.-; Exonuclease 3'-5' domain-like-containing protein 2
• Gene Name: EXD2
• Related Disease:
  Major depressive disorder
  Mood disorder
• UniProt ID: EXD2_HUMAN
• PDB ID: 6K17; 6K18; 6K19; 6K1A; 6K1B; 6K1C; 6K1D; 6K1E
• EC Number: 3.1.11.1; 3.1.13.-
• Pfam ID: PF01612
• Sequence:
  MSRQNLVALTVTTLLGVAVGGFVLWKGIQRRRRSKTSPVTQQPQQKVLGSRELPPPEDDQ
  LHSSAPRSSWKERILKAKVVTVSQEAEWDQIEPLLRSELEDFPVLGIDCEWVNLEGKASP
  LSLLQMASPSGLCVLVRLPKLICGGKTLPRTLLDILADGTILKVGVGCSEDASKLLQDYG
  LVVRGCLDLRYLAMRQRNNLLCNGLSLKSLAETVLNFPLDKSLLLRCSNWDAETLTEDQV
  IYAARDAQISVALFLHLLGYPFSRNSPGEKNDDHSSWRKVLEKCQGVVDIPFRSKGMSRL
  GEEVNGEATESQQKPRNKKSKMDGMVPGNHQGRDPRKHKRKPLGVGYSARKSPLYDNCFL
  HAPDGQPLCTCDRRKAQWYLDKGIGELVSEEPFVVKLRFEPAGRPESPGDYYLMVKENLC
  VVCGKRDSYIRKNVIPHEYRKHFPIEMKDHNSHDVLLLCTSCHAISNYYDNHLKQQLAKE
  FQAPIGSEEGLRLLEDPERRQVRSGARALLNAESLPTQRKEELLQALREFYNTDVVTEEM
  LQEAASLETRISNENYVPHGLKVVQCHSQGGLRSLMQLESRWRQHFLDSMQPKHLPQQWS
  VDHNHQKLLRKFGEDLPIQLS
• Function: Exonuclease that has both 3'-5' exoribonuclease and exodeoxyribonuclease activities, depending on the divalent metal cation used as cofactor. In presence of Mg(2+), only shows 3'-5' exoribonuclease activity, while it shows both exoribonuclease and exodeoxyribonuclease activities in presence of Mn(2+). Acts as an exoribonuclease in mitochondrion, possibly by regulating ATP production and mitochondrial translation. Also involved in the response to DNA damage. Acts as 3'-5' exodeoxyribonuclease for double-strand breaks resection and efficient homologous recombination. Plays a key role in controlling the initial steps of chromosomal break repair, it is recruited to chromatin in a damage-dependent manner and functionally interacts with the MRN complex to accelerate resection through its 3'-5' exonuclease activity, which efficiently processes double-stranded DNA substrates containing nicks. Also involved in response to replicative stress: recruited to stalled forks and is required to stabilize and restart stalled replication forks by restraining excessive fork regression, thereby suppressing their degradation.

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Major depressive disorder	DIS4CL3X	Strong	Genetic Variation	[1]
Mood disorder	DISLVMWO	Strong	Genetic Variation	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Exonuclease 3'-5' domain-containing protein 2 (EXD2).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Exonuclease 3'-5' domain-containing protein 2 (EXD2).	[3]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Exonuclease 3'-5' domain-containing protein 2 (EXD2).	[4]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Exonuclease 3'-5' domain-containing protein 2 (EXD2).	[5]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Exonuclease 3'-5' domain-containing protein 2 (EXD2).	[6]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Exonuclease 3'-5' domain-containing protein 2 (EXD2).	[7]

References

• [1] Meta-analysis of genome-wide association studies for neuroticism in 449,484 individuals identifies novel genetic loci and pathways.Nat Genet. 2018 Jul;50(7):920-927. doi: 10.1038/s41588-018-0151-7. Epub 2018 Jun 25.
• [2] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [3] 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.
• [4] 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.
• [5] 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.
• [6] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [7] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.