Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2LFW7A)

• DOT Name: 5' exonuclease Apollo (DCLRE1B)
• Synonyms: EC 3.1.-.-; Beta-lactamase DCLRE1B; EC 3.5.2.6; DNA cross-link repair 1B protein; SNM1 homolog B; SNMIB; hSNM1B
• Gene Name: DCLRE1B
• Related Disease:
  Autonomic neuropathy
  Breast cancer
  Breast carcinoma
  Chromosomal disorder
  Colorectal carcinoma
  Dyskeratosis congenita, X-linked
  Fanconi anemia complementation group A
  Fanconi's anemia
  HIV infectious disease
  Hoyeraal-Hreidarsson syndrome
  Amyloidosis
  Polyneuropathy
  Dyskeratosis congenita, autosomal recessive 8
  Lung cancer
  Ocular hypertension
  Open-angle glaucoma
• UniProt ID: DCR1B_HUMAN
• PDB ID: 3BUA; 5AHO; 7A1F; 7B2X; 7B9B
• EC Number: 3.1.-.-; 3.5.2.6
• Pfam ID: PF07522
• Sequence:
  MNGVLIPHTPIAVDFWSLRRAGTARLFFLSHMHSDHTVGLSSTWARPLYCSPITAHLLHR
  HLQVSKQWIQALEVGESHVLPLDEIGQETMTVTLLDANHCPGSVMFLFEGYFGTILYTGD
  FRYTPSMLKEPALTLGKQIHTLYLDNTNCNPALVLPSRQEAAHQIVQLIRKHPQHNIKIG
  LYSLGKESLLEQLALEFQTWVVLSPRRLELVQLLGLADVFTVEEKAGRIHAVDHMEICHS
  NMLRWNQTHPTIAILPTSRKIHSSHPDIHVIPYSDHSSYSELRAFVAALKPCQVVPIVSR
  RPCGGFQDSLSPRISVPLIPDSVQQYMSSSSRKPSLLWLLERRLKRPRTQGVVFESPEES
  ADQSQADRDSKKAKKEKLSPWPADLEKQPSHHPLRIKKQLFPDLYSKEWNKAVPFCESQK
  RVTMLTAPLGFSVHLRSTDEEFISQKTREEIGLGSPLVPMGDDDGGPEATGNQSAWMGHG
  SPLSHSSKGTPLLATEFRGLALKYLLTPVNFFQAGYSSRRFDQQVEKYHKPC
• Function: 5'-3' exonuclease that plays a central role in telomere maintenance and protection during S-phase. Participates in the protection of telomeres against non-homologous end-joining (NHEJ)-mediated repair, thereby ensuring that telomeres do not fuse. Plays a key role in telomeric loop (T loop) formation by being recruited by TERF2 at the leading end telomeres and by processing leading-end telomeres immediately after their replication via its exonuclease activity: generates 3' single-stranded overhang at the leading end telomeres avoiding blunt leading-end telomeres that are vulnerable to end-joining reactions and expose the telomere end in a manner that activates the DNA repair pathways. Together with TERF2, required to protect telomeres from replicative damage during replication by controlling the amount of DNA topoisomerase (TOP1, TOP2A and TOP2B) needed for telomere replication during fork passage and prevent aberrant telomere topology. Also involved in response to DNA damage: plays a role in response to DNA interstrand cross-links (ICLs) by facilitating double-strand break formation. In case of spindle stress, involved in prophase checkpoint. Possesses beta-lactamase activity, catalyzing the hydrolysis of penicillin G and nitrocefin. Exhibits no activity towards other beta-lactam antibiotic classes including cephalosporins (cefotaxime) and carbapenems (imipenem).
• Reactome Pathway: Fanconi Anemia Pathway (R-HSA-6783310)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autonomic neuropathy	DISI3WJ0	Strong	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[2]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[2]
Chromosomal disorder	DISM5BB5	Strong	Biomarker	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[4]
Dyskeratosis congenita, X-linked	DISJ3Y69	Strong	Genetic Variation	[5]
Fanconi anemia complementation group A	DIS8PZLI	Strong	Biomarker	[6]
Fanconi's anemia	DISGW6Q8	Strong	Biomarker	[6]
HIV infectious disease	DISO97HC	Strong	Biomarker	[7]
Hoyeraal-Hreidarsson syndrome	DISAUR8F	Strong	Biomarker	[5]
Amyloidosis	DISHTAI2	moderate	Biomarker	[1]
Polyneuropathy	DISB9G3W	Disputed	Biomarker	[1]
Dyskeratosis congenita, autosomal recessive 8	DISQTA7T	Limited	Autosomal recessive	[8]
Lung cancer	DISCM4YA	Limited	Genetic Variation	[9]
Ocular hypertension	DISC2BT9	Limited	Biomarker	[10]
Open-angle glaucoma	DISSZEE8	Limited	Biomarker	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of 5' exonuclease Apollo (DCLRE1B).	[11]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of 5' exonuclease Apollo (DCLRE1B).	[12]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of 5' exonuclease Apollo (DCLRE1B).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of 5' exonuclease Apollo (DCLRE1B).	[14]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of 5' exonuclease Apollo (DCLRE1B).	[15]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of 5' exonuclease Apollo (DCLRE1B).	[17]
Rifampicin	DM5DSFZ	Approved	Rifampicin decreases the expression of 5' exonuclease Apollo (DCLRE1B).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of 5' exonuclease Apollo (DCLRE1B).	[19]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of 5' exonuclease Apollo (DCLRE1B).	[20]
Arecoline	DMFJZK3	Phase 1	Arecoline decreases the expression of 5' exonuclease Apollo (DCLRE1B).	[21]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of 5' exonuclease Apollo (DCLRE1B).	[22]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of 5' exonuclease Apollo (DCLRE1B).	[23]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of 5' exonuclease Apollo (DCLRE1B).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of 5' exonuclease Apollo (DCLRE1B).	[16]

References

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• [2] The hSNM1B/Apollo variant rs11552449 is associated with cellular sensitivity towards mitomycin C and ionizing radiation.DNA Repair (Amst). 2018 Dec;72:93-98. doi: 10.1016/j.dnarep.2018.09.004. Epub 2018 Sep 12.
• [3] Snm1B/Apollo functions in the Fanconi anemia pathway in response to DNA interstrand crosslinks.Hum Mol Genet. 2011 Jul 1;20(13):2549-59. doi: 10.1093/hmg/ddr153. Epub 2011 Apr 8.
• [4] Mlh1 deficiency in normal mouse colon mucosa associates with chromosomally unstable colon cancer.Carcinogenesis. 2018 May 28;39(6):788-797. doi: 10.1093/carcin/bgy056.
• [5] Function of Apollo (SNM1B) at telomere highlighted by a splice variant identified in a patient with Hoyeraal-Hreidarsson syndrome. Proc Natl Acad Sci U S A. 2010 Jun 1;107(22):10097-102. doi: 10.1073/pnas.0914918107. Epub 2010 May 17.
• [6] The SNM1B/APOLLO DNA nuclease functions in resolution of replication stress and maintenance of common fragile site stability.Hum Mol Genet. 2013 Dec 15;22(24):4901-13. doi: 10.1093/hmg/ddt340. Epub 2013 Jul 17.
• [7] Role and evolution of viral tropism in patients with advanced HIV disease receiving intensified initial regimen in the ANRS 130 APOLLO trial.J Antimicrob Chemother. 2013 Mar;68(3):690-6. doi: 10.1093/jac/dks455. Epub 2012 Nov 14.
• [8] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [9] Telomere structure and maintenance gene variants and risk of five cancer types.Int J Cancer. 2016 Dec 15;139(12):2655-2670. doi: 10.1002/ijc.30288. Epub 2016 Sep 8.
• [10] Latanoprostene Bunod Ophthalmic Solution 0.024%: A Review in Open-Angle Glaucoma and Ocular Hypertension.Drugs. 2018 May;78(7):773-780. doi: 10.1007/s40265-018-0914-6.
• [11] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [12] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [13] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [14] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [15] 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.
• [16] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [17] Cannabidiol-induced transcriptomic changes and cellular senescence in human Sertoli cells. Toxicol Sci. 2023 Feb 17;191(2):227-238. doi: 10.1093/toxsci/kfac131.
• [18] Integrated analysis of rifampicin-induced microRNA and gene expression changes in human hepatocytes. Drug Metab Pharmacokinet. 2014;29(4):333-40.
• [19] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [20] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [21] Characterization of arecoline-induced effects on cytotoxicity in normal human gingival fibroblasts by global gene expression profiling. Toxicol Sci. 2007 Nov;100(1):66-74.
• [22] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [23] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [24] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.