Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCFH88S)

• DOT Name: Negative elongation factor B (NELFB)
• Synonyms: NELF-B; Cofactor of BRCA1
• Gene Name: NELFB
• Related Disease:
  B-cell neoplasm
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Prostate cancer
  Prostate carcinoma
  Prostate neoplasm
  Adenocarcinoma
  Gastric neoplasm
  Hepatocellular carcinoma
  Neoplasm
• UniProt ID: NELFB_HUMAN
• PDB ID: 6GML; 7PKS; 7YCX; 8JJ6
• Pfam ID: PF06209
• Sequence:
  MFAGLQDLGVANGEDLKETLTNCTEPLKAIEQFQTENGVLLPSLQSALPFLDLHGTPRLE
  FHQSVFDELRDKLLERVSAIASEGKAEERYKKLEDLLEKSFSLVKMPSLQPVVMCVMKHL
  PKVPEKKLKLVMADKELYRACAVEVKRQIWQDNQALFGDEVSPLLKQYILEKESALFSTE
  LSVLHNFFSPSPKTRRQGEVVQRLTRMVGKNVKLYDMVLQFLRTLFLRTRNVHYCTLRAE
  LLMSLHDLDVGEICTVDPCHKFTWCLDACIRERFVDSKRARELQGFLDGVKKGQEQVLGD
  LSMILCDPFAINTLALSTVRHLQELVGQETLPRDSPDLLLLLRLLALGQGAWDMIDSQVF
  KEPKMEVELITRFLPMLMSFLVDDYTFNVDQKLPAEEKAPVSYPNTLPESFTKFLQEQRM
  ACEVGLYYVLHITKQRNKNALLRLLPGLVETFGDLAFGDIFLHLLTGNLALLADEFALED
  FCSSLFDGFFLTASPRKENVHRHALRLLIHLHPRVAPSKLEALQKALEPTGQSGEAVKEL
  YSQLGEKLEQLDHRKPSPAQAAETPALELPLPSVPAPAPL
• Function: Essential component of the NELF complex, a complex that negatively regulates the elongation of transcription by RNA polymerase II. The NELF complex, which acts via an association with the DSIF complex and causes transcriptional pausing, is counteracted by the P-TEFb kinase complex. May be able to induce chromatin unfolding. Essential for early embryogenesis; plays an important role in maintaining the undifferentiated state of embryonic stem cells (ESCs) by preventing unscheduled expression of developmental genes. Plays a key role in establishing the responsiveness of stem cells to developmental cues; facilitates plasticity and cell fate commitment in ESCs by establishing the appropriate expression level of signaling molecules. Supports the transcription of genes involved in energy metabolism in cardiomyocytes; facilitates the association of transcription initiation factors with the promoters of the metabolism-related genes; (Microbial infection) The NELF complex is involved in HIV-1 latency possibly involving recruitment of PCF11 to paused RNA polymerase II. In vitro, binds weakly to the HIV-1 TAR RNA which is located in the long terminal repeat (LTR) of HIV-1.
• Tissue Specificity: Widely expressed. Expressed in heart, brain, lung, placenta, liver, skeletal muscle, kidney and pancreas.
• KEGG Pathway: Viral life cycle - HIV-1 (hsa03250)
• Reactome Pathway:
  Formation of the Early Elongation Complex (R-HSA-113418)
  Formation of HIV elongation complex in the absence of HIV Tat (R-HSA-167152)
  Formation of the HIV-1 Early Elongation Complex (R-HSA-167158)
  Formation of HIV-1 elongation complex containing HIV-1 Tat (R-HSA-167200)
  Pausing and recovery of Tat-mediated HIV elongation (R-HSA-167238)
  Abortive elongation of HIV-1 transcript in the absence of Tat (R-HSA-167242)
  Tat-mediated HIV elongation arrest and recovery (R-HSA-167243)
  Tat-mediated elongation of the HIV-1 transcript (R-HSA-167246)
  HIV elongation arrest and recovery (R-HSA-167287)
  Pausing and recovery of HIV elongation (R-HSA-167290)
  RNA Polymerase II Pre-transcription Events (R-HSA-674695)
  TP53 Regulates Transcription of DNA Repair Genes (R-HSA-6796648)
  RNA Polymerase II Transcription Elongation (R-HSA-75955)
  NTRK3 as a dependence receptor (R-HSA-9603505)
  Formation of RNA Pol II elongation complex (R-HSA-112382)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
B-cell neoplasm	DISVY326	Strong	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[3]
Prostate cancer	DISF190Y	Strong	Biomarker	[4]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[4]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[4]
Adenocarcinoma	DIS3IHTY	moderate	Altered Expression	[5]
Gastric neoplasm	DISOKN4Y	moderate	Altered Expression	[5]
Hepatocellular carcinoma	DIS0J828	moderate	Biomarker	[6]
Neoplasm	DISZKGEW	moderate	Altered Expression	[5]

3 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 Negative elongation factor B (NELFB).	[7]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the methylation of Negative elongation factor B (NELFB).	[10]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Negative elongation factor B (NELFB).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Negative elongation factor B (NELFB).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Negative elongation factor B (NELFB).	[9]

References

• [1] Hey1- and p53-dependent TrkC proapoptotic activity controls neuroblastoma growth.PLoS Biol. 2018 May 11;16(5):e2002912. doi: 10.1371/journal.pbio.2002912. eCollection 2018 May.
• [2] Gene-Specific Genetic Complementation between Brca1 and Cobra1 During Mouse Mammary Gland Development.Sci Rep. 2018 Feb 9;8(1):2731. doi: 10.1038/s41598-018-21044-2.
• [3] Concerted transcriptional regulation by BRCA1 and COBRA1 in breast cancer cells.Int J Biol Sci. 2007 Nov 26;3(7):486-92. doi: 10.7150/ijbs.3.486.
• [4] BRCA1 Interacting Protein COBRA1 Facilitates Adaptation to Castrate-Resistant Growth Conditions.Int J Mol Sci. 2018 Jul 20;19(7):2104. doi: 10.3390/ijms19072104.
• [5] Cofactor of BRCA1: a novel transcription factor regulator in upper gastrointestinal adenocarcinomas.Cancer Res. 2006 Feb 1;66(3):1346-53. doi: 10.1158/0008-5472.CAN-05-3593.
• [6] Knockdown of COBRA1 decreases the proliferation and migration of hepatocellular carcinoma cells.Oncol Rep. 2017 Mar;37(3):1896-1906. doi: 10.3892/or.2017.5390. Epub 2017 Jan 19.
• [7] 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.
• [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] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [10] Association of Arsenic Exposure with Whole Blood DNA Methylation: An Epigenome-Wide Study of Bangladeshi Adults. Environ Health Perspect. 2019 May;127(5):57011. doi: 10.1289/EHP3849. Epub 2019 May 28.
• [11] 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.