Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYOO05J)

• DOT Name: Non-homologous end-joining factor 1 (NHEJ1)
• Synonyms: Protein cernunnos; XRCC4-like factor
• Gene Name: NHEJ1
• Related Disease:
  Aplastic anemia
  Cernunnos-XLF deficiency
  Glioblastoma multiforme
  Pancytopenia
  Ataxia-telangiectasia
  Esophageal squamous cell carcinoma
  Hepatocellular carcinoma
  Immunodeficiency
  Isolated congenital microcephaly
  Nijmegen breakage syndrome
  Severe combined immunodeficiency
  Colorectal carcinoma
• UniProt ID: NHEJ1_HUMAN
• PDB ID: 2QM4; 2R9A; 3Q4F; 3RWR; 3SR2; 3W03; 6ERG; 6ERH; 7LSY; 7LT3; 7NFC; 7NFE; 7ZYG; 8BHV; 8BHY; 8BOT; 8EZA; 8EZB
• Pfam ID: PF09302
• Sequence:
  MEELEQGLLMQPWAWLQLAENSLLAKVFITKQGYALLVSDLQQVWHEQVDTSVVSQRAKE
  LNKRLTAPPAAFLCHLDNLLRPLLKDAAHPSEATFSCDCVADALILRVRSELSGLPFYWN
  FHCMLASPSLVSQHLIRPLMGMSLALQCQVRELATLLHMKDLEIQDYQESGATLIRDRLK
  TEPFEENSFLEQFMIEKLPEACSIGDGKPFVMNLQDLYMAVTTQEVQVGQKHQGAGDPHT
  SNSASLQGIDSQCVNQPEQLVSSAPTLSAPEKESTGTSGPLQRPQLSKVKRKKPRGLFS
• Function: DNA repair protein involved in DNA non-homologous end joining (NHEJ); required for double-strand break (DSB) repair and V(D)J recombination. Plays a key role in NHEJ by promoting the ligation of various mismatched and non-cohesive ends. Together with PAXX, collaborates with DNA polymerase lambda (POLL) to promote joining of non-cohesive DNA ends. May act in concert with XRCC5-XRCC6 (Ku) to stimulate XRCC4-mediated joining of blunt ends and several types of mismatched ends that are non-complementary or partially complementary. In some studies, has been shown to associate with XRCC4 to form alternating helical filaments that bridge DNA and act like a bandage, holding together the broken DNA until it is repaired. Alternatively, it has also been shown that rather than forming filaments, a single NHEJ1 dimer interacts through both head domains with XRCC4 to promote the close alignment of DNA ends. The XRCC4-NHEJ1/XLF subcomplex binds to the DNA fragments of a DSB in a highly diffusive manner and robustly bridges two independent DNA molecules, holding the broken DNA fragments in close proximity to one other. The mobility of the bridges ensures that the ends remain accessible for further processing by other repair factors. Binds DNA in a length-dependent manner.
• Tissue Specificity: Ubiquitously expressed.
• KEGG Pathway: Non-homologous end-joining (hsa03450)
• Reactome Pathway: Nonhomologous End-Joining (NHEJ) (R-HSA-5693571)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Aplastic anemia	DISJRSC0	Definitive	Genetic Variation	[1]
Cernunnos-XLF deficiency	DISQ70ZZ	Definitive	Autosomal recessive	[2]
Glioblastoma multiforme	DISK8246	Definitive	Biomarker	[3]
Pancytopenia	DISVKEHV	Definitive	Genetic Variation	[1]
Ataxia-telangiectasia	DISP3EVR	Strong	Genetic Variation	[4]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[6]
Immunodeficiency	DIS093I0	Strong	Genetic Variation	[7]
Isolated congenital microcephaly	DISUXHZ6	Strong	Genetic Variation	[8]
Nijmegen breakage syndrome	DIS98HVL	Strong	Genetic Variation	[9]
Severe combined immunodeficiency	DIS6MF4Q	Strong	Genetic Variation	[10]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[11]

6 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 Non-homologous end-joining factor 1 (NHEJ1).	[12]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Non-homologous end-joining factor 1 (NHEJ1).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Non-homologous end-joining factor 1 (NHEJ1).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Non-homologous end-joining factor 1 (NHEJ1).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Non-homologous end-joining factor 1 (NHEJ1).	[16]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride affects the expression of Non-homologous end-joining factor 1 (NHEJ1).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Non-homologous end-joining factor 1 (NHEJ1).	[17]

References

• [1] Mutations in XLF/NHEJ1/Cernunnos gene results in downregulation of telomerase genes expression and telomere shortening.Hum Mol Genet. 2017 May 15;26(10):1900-1914. doi: 10.1093/hmg/ddx098.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] Induction Of XLF And 53BP1 Expression Is Associated With Temozolomide Resistance In Glioblastoma Cells.Onco Targets Ther. 2019 Nov 25;12:10139-10151. doi: 10.2147/OTT.S221025. eCollection 2019.
• [4] DNA-PK and ATM phosphorylation sites in XLF/Cernunnos are not required for repair of DNA double strand breaks.DNA Repair (Amst). 2008 Oct 1;7(10):1680-92. doi: 10.1016/j.dnarep.2008.06.015. Epub 2008 Aug 3.
• [5] Inhibition of PC4 radiosensitizes non-small cell lung cancer by transcriptionally suppressing XLF.Cancer Med. 2018 Apr;7(4):1326-1337. doi: 10.1002/cam4.1332. Epub 2018 Mar 9.
• [6] XLF-mediated NHEJ activity in hepatocellular carcinoma therapy resistance.BMC Cancer. 2017 May 19;17(1):344. doi: 10.1186/s12885-017-3345-y.
• [7] Loss of NHEJ1 Protein Due to a Novel Splice Site Mutation in a Family Presenting with Combined Immunodeficiency, Microcephaly, and Growth Retardation and Literature Review.J Clin Immunol. 2017 Aug;37(6):575-581. doi: 10.1007/s10875-017-0423-5. Epub 2017 Jul 24.
• [8] XLF/Cernunnos: An important but puzzling participant in the nonhomologous end joining DNA repair pathway.DNA Repair (Amst). 2017 Oct;58:29-37. doi: 10.1016/j.dnarep.2017.08.003. Epub 2017 Aug 18.
• [9] Clinical variability and novel mutations in the NHEJ1 gene in patients with a Nijmegen breakage syndrome-like phenotype.Hum Mutat. 2010 Sep;31(9):1059-68. doi: 10.1002/humu.21315.
• [10] An immunocompetent patient with a nonsense mutation in NHEJ1 gene.BMC Med Genet. 2019 Mar 21;20(1):45. doi: 10.1186/s12881-019-0784-0.
• [11] Nonhomologous end joining key factor XLF enhances both 5-florouracil and oxaliplatin resistance in colorectal cancer.Onco Targets Ther. 2019 Mar 20;12:2095-2104. doi: 10.2147/OTT.S192923. eCollection 2019.
• [12] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [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] 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.
• [15] 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.
• [16] 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.
• [17] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [18] Nickel induces transcriptional down-regulation of DNA repair pathways in tumorigenic and non-tumorigenic lung cells. Carcinogenesis. 2017 Jun 1;38(6):627-637.