Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQ7WN9J)

• DOT Name: Ankyrin repeat and LEM domain-containing protein 1 (ANKLE1)
• Synonyms: EC 3.1.-.-; Ankyrin repeat domain-containing protein 41; LEM-domain containing protein 3
• Gene Name: ANKLE1
• Related Disease:
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Colorectal carcinoma
  Ovarian cancer
  Ovarian neoplasm
• UniProt ID: ANKL1_HUMAN
• EC Number: 3.1.-.-
• Pfam ID: PF12796
• Sequence:
  MCSEARLARRLRDALREEEPWAVEELLRCGADPNLVLEDGAAAVHLAAGARHPRGLRCLG
  ALLRQGGDPNARSVEALTPLHVAAAWGCRRGLELLLSQGADPALRDQDGLRPLDLALQQG
  HLECARVLQDLDTRTRTRTRIGAETQEPEPAPGTPGLSGPTDETLDSIALQKQPCRGDNR
  DIGLEADPGPPSLPVPLETVDKHGSSASPPGHWDYSSDASFVTAVEVSGAEDPASDTPPW
  AGSLPPTRQGLLHVVHANQRVPRSQGTEAELNARLQALTLTPPNAAGFQSSPSSMPLLDR
  SPAHSPPRTPTPGASDCHCLWEHQTSIDSDMATLWLTEDEASSTGGREPVGPCRHLPVST
  VSDLELLKGLRALGENPHPITPFTRQLYHQQLEEAQIAPGPEFSGHSLELAAALRTGCIP
  DVQADEDALAQQFEQPDPARRWREGVVKSSFTYLLLDPRETQDLPARAFSLTPAERLQTF
  IRAIFYVGKGTRARPYVHLWEALGHHGRSRKQPHQACPKVRQILDIWASGCGVVSLHCFQ
  HVVAVEAYTREACIVEALGIQTLTNQKQGHCYGVVAGWPPARRRRLGVHLLHRALLVFLA
  EGERQLHPQDIQARG
• Function: Endonuclease that probably plays a role in the DNA damage response and DNA repair.
• Tissue Specificity: Expression is predominant in adult bone marrow.

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Definitive	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[3]
Ovarian cancer	DISZJHAP	Limited	Genetic Variation	[4]
Ovarian neoplasm	DISEAFTY	Limited	Genetic Variation	[4]

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 Ankyrin repeat and LEM domain-containing protein 1 (ANKLE1).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Ankyrin repeat and LEM domain-containing protein 1 (ANKLE1).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Ankyrin repeat and LEM domain-containing protein 1 (ANKLE1).	[6]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Ankyrin repeat and LEM domain-containing protein 1 (ANKLE1).	[8]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Ankyrin repeat and LEM domain-containing protein 1 (ANKLE1).	[9]

References

• [1] Identification of breast cancer associated variants that modulate transcription factor binding.PLoS Genet. 2017 Sep 28;13(9):e1006761. doi: 10.1371/journal.pgen.1006761. eCollection 2017 Sep.
• [2] LEM-3 is a midbody-tethered DNA nuclease that resolves chromatin bridges during late mitosis.Nat Commun. 2018 Feb 20;9(1):728. doi: 10.1038/s41467-018-03135-w.
• [3] ANKLE1 N(6) -Methyladenosine-related variant is associated with colorectal cancer risk by maintaining the genomic stability.Int J Cancer. 2020 Jun 15;146(12):3281-3293. doi: 10.1002/ijc.32677. Epub 2019 Nov 6.
• [4] Common variants at 19p13 are associated with susceptibility to ovarian cancer.Nat Genet. 2010 Oct;42(10):880-4. doi: 10.1038/ng.666. Epub 2010 Sep 19.
• [5] 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.
• [6] 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.
• [7] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [8] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [9] 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.