Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5ZL00R)

• DOT Name: Cell cycle regulator of non-homologous end joining (CYREN)
• Synonyms: Cell cycle regulator of NHEJ; Modulator of retrovirus infection homolog
• Gene Name: CYREN
• Related Disease:
  Advanced cancer
  Cowden disease
  Prostate cancer
  Prostate carcinoma
  Metastatic malignant neoplasm
  Neoplasm
• UniProt ID: CYREN_HUMAN
• PDB ID: 6TYU
• Pfam ID: PF15325
• Sequence:
  METLQSETKTRVLPSWLTAQVATKNVAPMKAPKRMRMAAVPVAAARLPATRTVYCMNEAE
  IVDVALGILIESRKQEKACEQPALAGADNPEHSPPCSVSPHTSSGSSSEEEDSGKQALAP
  GLSPSQRPGGSSSACSRSPEEEEEEDVLKYVREIFFS
• Function: Cell-cycle-specific regulator of classical non-homologous end joining (NHEJ) of DNA double-strand break (DSB) repair, which can act both as an activator or inhibitor of NHEJ, depending on the cell cycle phase. Acts as a regulator of DNA repair pathway choice by specifically inhibiting classical NHEJ during the S and G2 phases, thereby promoting error-free repair by homologous recombination during cell cycle phases when sister chromatids are present. Preferentially protects single-stranded overhangs at break sites by inhibiting classical NHEJ, thereby creating a local environment that favors homologous recombination. Acts via interaction with XRCC5/Ku80 and XRCC6/Ku70. In contrast, acts as an activator of NHEJ during G1 phase of the cell cycle: promotes classical NHEJ in G1 phase cells via multivalent interactions that increase the affinity of DNA damage response proteins for DSB-associated chromatin. Also involved in immunoglobulin V(D)J recombination. May also act as an indirect regulator of proteasome.

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	Strong	Genetic Variation	[1]
Cowden disease	DISMYKCE	Strong	Biomarker	[2]
Prostate cancer	DISF190Y	Strong	Biomarker	[3]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[3]
Metastatic malignant neoplasm	DIS86UK6	Limited	Biomarker	[4]
Neoplasm	DISZKGEW	Limited	Biomarker	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Cell cycle regulator of non-homologous end joining (CYREN).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Cell cycle regulator of non-homologous end joining (CYREN).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cell cycle regulator of non-homologous end joining (CYREN).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Cell cycle regulator of non-homologous end joining (CYREN).	[8]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Cell cycle regulator of non-homologous end joining (CYREN).	[9]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Cell cycle regulator of non-homologous end joining (CYREN).	[11]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Cell cycle regulator of non-homologous end joining (CYREN).	[9]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Cell cycle regulator of non-homologous end joining (CYREN).	[13]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Cell cycle regulator of non-homologous end joining (CYREN).	[14]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Etoposide	DMNH3PG	Approved	Etoposide affects the localization of Cell cycle regulator of non-homologous end joining (CYREN).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Cell cycle regulator of non-homologous end joining (CYREN).	[12]

References

• [1] MRI-Targeted or Standard Biopsy for Prostate-Cancer Diagnosis.N Engl J Med. 2018 May 10;378(19):1767-1777. doi: 10.1056/NEJMoa1801993. Epub 2018 Mar 18.
• [2] Optimising the Diagnosis of Prostate Cancer in the Era of Multiparametric Magnetic Resonance Imaging: A Cost-effectiveness Analysis Based on the Prostate MR Imaging Study (PROMIS).Eur Urol. 2018 Jan;73(1):23-30. doi: 10.1016/j.eururo.2017.08.018. Epub 2017 Sep 19.
• [3] Prostate Magnetic Resonance Imaging, with or Without Magnetic Resonance Imaging-targeted Biopsy, and Systematic Biopsy for Detecting Prostate Cancer: A Cochrane Systematic Review and Meta-analysis.Eur Urol. 2020 Jan;77(1):78-94. doi: 10.1016/j.eururo.2019.06.023. Epub 2019 Jul 18.
• [4] Changes in Brain Metastasis During Radiosurgical Planning.Int J Radiat Oncol Biol Phys. 2018 Nov 15;102(4):727-733. doi: 10.1016/j.ijrobp.2018.06.021. Epub 2018 Jun 25.
• [5] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [6] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [7] 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.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] 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.
• [10] A human short open reading frame (sORF)-encoded polypeptide that stimulates DNA end joining. J Biol Chem. 2014 Apr 18;289(16):10950-10957. doi: 10.1074/jbc.C113.533968. Epub 2014 Mar 7.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] 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.
• [13] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [14] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.