Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9DK06P)

• DOT Name: Ribosome quality control complex subunit NEMF (NEMF)
• Synonyms: Antigen NY-CO-1; Nuclear export mediator factor; Serologically defined colon cancer antigen 1
• Gene Name: NEMF
• Related Disease:
  Autism spectrum disorder
  Colon cancer
  Colon carcinoma
  Intellectual developmental disorder with speech delay and axonal peripheral neuropathy
  Lung cancer
  Lung carcinoma
  Neoplasm
  Non-small-cell lung cancer
• UniProt ID: NEMF_HUMAN
• PDB ID: 3J92
• Pfam ID: PF11923 ; PF05670 ; PF05833
• Sequence:
  MKSRFSTIDLRAVLAELNASLLGMRVNNVYDVDNKTYLIRLQKPDFKATLLLESGIRIHT
  TEFEWPKNMMPSSFAMKCRKHLKSRRLVSAKQLGVDRIVDFQFGSDEAAYHLIIELYDRG
  NIVLTDYEYVILNILRFRTDEADDVKFAVRERYPLDHARAAEPLLTLERLTEIVASAPKG
  ELLKRVLNPLLPYGPALIEHCLLENGFSGNVKVDEKLETKDIEKVLVSLQKAEDYMKTTS
  NFSGKGYIIQKREIKPSLEADKPVEDILTYEEFHPFLFSQHSQCPYIEFESFDKAVDEFY
  SKIEGQKIDLKALQQEKQALKKLDNVRKDHENRLEALQQAQEIDKLKGELIEMNLQIVDR
  AIQVVRSALANQIDWTEIGLIVKEAQAQGDPVASAIKELKLQTNHVTMLLRNPYLLSEEE
  DDDVDGDVNVEKNETEPPKGKKKKQKNKQLQKPQKNKPLLVDVDLSLSAYANAKKYYDHK
  RYAAKKTQKTVEAAEKAFKSAEKKTKQTLKEVQTVTSIQKARKVYWFEKFLWFISSENYL
  IIGGRDQQQNEIIVKRYLTPGDIYVHADLHGATSCVIKNPTGEPIPPRTLTEAGTMALCY
  SAAWDARVITSAWWVYHHQVSKTAPTGEYLTTGSFMIRGKKNFLPPSYLMMGFSFLFKVD
  ESCVWRHQGERKVRVQDEDMETLASCTSELISEEMEQLDGGDTSSDEDKEEHETPVEVEL
  MTQVDQEDITLQSGRDELNEELIQEESSEDEGEYEEVRKDQDSVGEMKDEGEETLNYPDT
  TIDLSHLQPQRSIQKLASKEESSNSSDSKSQSRRHLSAKERREMKKKKLPSDSGDLEALE
  GKDKEKESTVHIETHQNTSKNVAAVQPMKRGQKSKMKKMKEKYKDQDEEDRELIMKLLGS
  AGSNKEEKGKKGKKGKTKDEPVKKQPQKPRGGQRVSDNIKKETPFLEVITHELQDFAVDD
  PHDDKEEQDLDQQGNEENLFDSLTGQPHPEDVLLFAIPICAPYTTMTNYKYKVKLTPGVQ
  KKGKAAKTALNSFMHSKEATAREKDLFRSVKDTDLSRNIPGKVKVSAPNLLNVKRK
• Function: Key component of the ribosome quality control complex (RQC), a ribosome-associated complex that mediates the extraction of incompletely synthesized nascent chains from stalled ribosomes as well as their ubiquitin-mediated proteasomal degradation. Thereby, frees 60S subunit ribosomes from the stalled translation complex and prevents the accumulation of nascent polypeptide chains that are potentially toxic for the cell. Within the RQC complex, NEMF specifically binds stalled 60S ribosomal subunits by recognizing an exposed, nascent chain-conjugated tRNA moiety and promotes the recruitment of LTN1 to stalled 60S subunits. Following binding to stalled 60S ribosomal subunits, NEMF mediates CAT tailing by recruiting alanine-charged tRNA to the A-site and directing the elongation of stalled nascent chains independently of mRNA or 40S subunits, leading to non-templated C-terminal alanine extensions (CAT tails). Mainly recruits alanine-charged tRNAs, but can also other amino acid-charged tRNAs. CAT tailing is required to promote ubiquitination of stalled nascent chains by different E3 ubiquitin-protein ligases. In the canonical RQC pathway (RQC-L), CAT tailing facilitates LTN1-dependent ubiquitination by exposing lysine residues that would otherwise remain buried in the ribosomal exit tunnel. In the alternative RQC pathway (RQC-C) CAT tailing creates an C-degron mainly composed of alanine that is recognized by the CRL2(KLHDC10) and RCHY1/PIRH2 E3 ligases, leading to ubiquitination and degradation of stalled nascent chains. NEMF may also indirectly play a role in nuclear export.
• Tissue Specificity: Expressed in brain, heart, liver, lung, spleen, and skeletal muscle. Also expressed at lower levels in stomach and testis.

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autism spectrum disorder	DISXK8NV	Definitive	Biomarker	[1]
Colon cancer	DISVC52G	Strong	Biomarker	[2]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[2]
Intellectual developmental disorder with speech delay and axonal peripheral neuropathy	DISPZZJY	Strong	Autosomal recessive	[3]
Lung cancer	DISCM4YA	Strong	Altered Expression	[4]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[5]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[5]

3 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 Ribosome quality control complex subunit NEMF (NEMF).	[6]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Ribosome quality control complex subunit NEMF (NEMF).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Ribosome quality control complex subunit NEMF (NEMF).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Ribosome quality control complex subunit NEMF (NEMF).	[7]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Ribosome quality control complex subunit NEMF (NEMF).	[8]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Ribosome quality control complex subunit NEMF (NEMF).	[11]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Ribosome quality control complex subunit NEMF (NEMF).	[12]

References

• [1] Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases. Nat Genet. 2017 Apr;49(4):515-526. doi: 10.1038/ng.3792. Epub 2017 Feb 13.
• [2] Characterization of human colon cancer antigens recognized by autologous antibodies.Int J Cancer. 1998 May 29;76(5):652-8. doi: 10.1002/(sici)1097-0215(19980529)76:5<652::aid-ijc7>3.0.co;2-p.
• [3] 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.
• [4] Drosophila caliban, a nuclear export mediator, can function as a tumor suppressor in human lung cancer cells.Oncogene. 2005 Dec 15;24(56):8229-39. doi: 10.1038/sj.onc.1208962.
• [5] The tumor suppressor Caliban regulates DNA damage-induced apoptosis through p53-dependent and -independent activity.Oncogene. 2013 Aug 15;32(33):3857-66. doi: 10.1038/onc.2012.395. Epub 2012 Sep 10.
• [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] 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.
• [9] 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.
• [10] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [11] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [12] Analysis of the prostate cancer cell line LNCaP transcriptome using a sequencing-by-synthesis approach. BMC Genomics. 2006 Sep 29;7:246. doi: 10.1186/1471-2164-7-246.