Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYUR3AH)

• DOT Name: Aprataxin and PNK-like factor (APLF)
• Synonyms: EC 3.1.-.-; Apurinic-apyrimidinic endonuclease APLF; PNK and APTX-like FHA domain-containing protein; XRCC1-interacting protein 1
• Gene Name: APLF
• Related Disease:
  Aplastic anemia
  Melanoma
  Acute myelogenous leukaemia
  Bladder cancer
  Urinary bladder cancer
  Urinary bladder neoplasm
  Werner syndrome
• UniProt ID: APLF_HUMAN
• PDB ID: 2KQB; 2KQC; 2KQD; 2KQE; 2KUO; 5E50; 5W7W; 5W7X; 5W7Y; 6ERF; 6TYT; 6TYW; 6TYZ; 6YN1
• EC Number: 3.1.-.-
• Pfam ID: PF17913 ; PF10283
• Sequence:
  MSGGFELQPRDGGPRVALAPGETVIGRGPLLGITDKRVSRRHAILEVAGGQLRIKPIHTN
  PCFYQSSEKSQLLPLKPNLWCYLNPGDSFSLLVDKYIFRILSIPSEVEMQCTLRNSQVLD
  EDNILNETPKSPVINLPHETTGASQLEGSTEIAKTQMTPTNSVSFLGENRDCNKQQPILA
  ERKRILPTWMLAEHLSDQNLSVPAISGGNVIQGSGKEEICKDKSQLNTTQQGRRQLISSG
  SSENTSAEQDTGEECKNTDQEESTISSKEMPQSFSAITLSNTEMNNIKTNAQRNKLPIEE
  LGKVSKHKIATKRTPHKEDEAMSCSENCSSAQGDSLQDESQGSHSESSSNPSNPETLHAK
  ATDSVLQGSEGNKVKRTSCMYGANCYRKNPVHFQHFSHPGDSDYGGVQIVGQDETDDRPE
  CPYGPSCYRKNPQHKIEYRHNTLPVRNVLDEDNDNVGQPNEYDLNDSFLDDEEEDYEPTD
  EDSDWEPGKEDEEKEDVEELLKEAKRFMKRK
• Function: Histone chaperone involved in single-strand and double-strand DNA break repair. Recruited to sites of DNA damage through interaction with branched poly-ADP-ribose chains, a polymeric post-translational modification synthesized transiently at sites of chromosomal damage to accelerate DNA strand break repair reactions. Following recruitment to DNA damage sites, acts as a histone chaperone that mediates histone eviction during DNA repair and promotes recruitment of histone variant MACROH2A1. Also has a nuclease activity: displays apurinic-apyrimidinic (AP) endonuclease and 3'-5' exonuclease activities in vitro. Also able to introduce nicks at hydroxyuracil and other types of pyrimidine base damage. Together with PARP3, promotes the retention of the LIG4-XRCC4 complex on chromatin and accelerate DNA ligation during non-homologous end-joining (NHEJ). Also acts as a negative regulator of cell pluripotency by promoting histone exchange. Required for the embryo implantation during the epithelial to mesenchymal transition in females.

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Aplastic anemia	DISJRSC0	Definitive	Biomarker	[1]
Melanoma	DIS1RRCY	Strong	Biomarker	[2]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[3]
Bladder cancer	DISUHNM0	moderate	Biomarker	[4]
Urinary bladder cancer	DISDV4T7	moderate	Biomarker	[4]
Urinary bladder neoplasm	DIS7HACE	moderate	Biomarker	[4]
Werner syndrome	DISZY45W	moderate	Biomarker	[5]

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 Aprataxin and PNK-like factor (APLF).	[6]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Aprataxin and PNK-like factor (APLF).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Aprataxin and PNK-like factor (APLF).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Aprataxin and PNK-like factor (APLF).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Aprataxin and PNK-like factor (APLF).	[9]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Aprataxin and PNK-like factor (APLF).	[10]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the expression of Aprataxin and PNK-like factor (APLF).	[10]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Aprataxin and PNK-like factor (APLF).	[12]
Malathion	DMXZ84M	Approved	Malathion decreases the expression of Aprataxin and PNK-like factor (APLF).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Aprataxin and PNK-like factor (APLF).	[14]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Aprataxin and PNK-like factor (APLF).	[15]

References

• [1] Corticosteroid Therapy for Indeterminate Pediatric Acute Liver Failure and Aplastic Anemia with Acute Hepatitis.J Pediatr. 2019 May;208:23-29. doi: 10.1016/j.jpeds.2018.12.042. Epub 2019 Feb 13.
• [2] Isolation of x-ray-inducible transcripts from radioresistant human melanoma cells.Proc Natl Acad Sci U S A. 1993 Aug 1;90(15):7200-4. doi: 10.1073/pnas.90.15.7200.
• [3] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [4] Rewiring E2F1 with classical NHEJ via APLF suppression promotes bladder cancer invasiveness.J Exp Clin Cancer Res. 2019 Jul 8;38(1):292. doi: 10.1186/s13046-019-1286-9.
• [5] Ligand binding characteristics of the Ku80 von Willebrand domain.DNA Repair (Amst). 2020 Jan;85:102739. doi: 10.1016/j.dnarep.2019.102739. Epub 2019 Oct 24.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [10] Arsenite and cadmium promote the development of mammary tumors. Carcinogenesis. 2020 Jul 14;41(7):1005-1014. doi: 10.1093/carcin/bgz176.
• [11] 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.
• [12] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [13] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [14] 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.
• [15] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.