Details of Drug Off-Target (DOT)

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

• DOT Name: H/ACA ribonucleoprotein complex non-core subunit NAF1 (NAF1)
• Synonyms: hNAF1
• Gene Name: NAF1
• Related Disease:
  Pulmonary fibrosis
  Acquired immune deficiency syndrome
  Breast cancer
  Breast carcinoma
  Carcinoma of esophagus
  Dyskeratosis congenita
  Esophageal cancer
  Glioma
  Haematological malignancy
  Hepatocellular carcinoma
  Matthew-Wood syndrome
  Neoplasm of esophagus
  Osteoarthritis
  Pancreatic cancer
  Rheumatoid arthritis
  Tuberculosis
  Type-1/2 diabetes
  Lung adenocarcinoma
  Neoplasm
  Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 7
• UniProt ID: NAF1_HUMAN
• PDB ID: 2EQN
• Pfam ID: PF04410
• Sequence:
  MEVVEAAAAQLETLKFNGTDFGVGEGPAAPSPGSAPVPGTQPPLQSFEGSPDAGQTVEVK
  PAGEQPLQPVLNAVAAGTPAPQPQPPAESPACGDCVTSPGAAEPARAPDSLETSDSDSDS
  DSETDSDSSSSSSSSSSSSSSSSSSCISLPPVLSDGDDDLQIEKENKNFPLKTKDELLLN
  ELPSVEELTIILPEDIELKPLGMVSSIIEQLVIIESMTNLPPVNEETVIFKSDRQAAGKI
  FEIFGPVAHPFYVLRFNSSDHIESKGIKIKETMYFAPSMKDFTQYIFTEKLKQDKGSDAS
  WKNDQEPPPEALDFSDDEKEKEAKQRKKSQIQGRKKLKSEFNEPGEDFTEVHQNWNAHSS
  ASEHAKGYRNREFTRGFSRARYPRSCHGRPPPQHFYNSEHMVSQETSGFPSQRQNNPIMP
  QYPFPLPVFDMHNFPLRPPPPPPPPPVNMGWATPNMAAHPLLNLPYSLPPPPPPPPLPPP
  PSSGDSNSHFGPYY
• Function: RNA-binding protein required for the maturation of box H/ACA snoRNPs complex and ribosome biogenesis. During assembly of the H/ACA snoRNPs complex, it associates with the complex and disappears during maturation of the complex and is replaced by NOLA1/GAR1 to yield mature H/ACA snoRNPs complex. Probably competes with NOLA1/GAR1 for binding with DKC1/NOLA4.

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Pulmonary fibrosis	DISQKVLA	Definitive	Genetic Variation	[1]
Acquired immune deficiency syndrome	DISL5UOX	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Carcinoma of esophagus	DISS6G4D	Strong	Genetic Variation	[4]
Dyskeratosis congenita	DISSXV0K	Strong	Genetic Variation	[5]
Esophageal cancer	DISGB2VN	Strong	Genetic Variation	[4]
Glioma	DIS5RPEH	Strong	Biomarker	[6]
Haematological malignancy	DISCDP7W	Strong	Genetic Variation	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[7]
Matthew-Wood syndrome	DISA7HR7	Strong	Genetic Variation	[8]
Neoplasm of esophagus	DISOLKAQ	Strong	Genetic Variation	[4]
Osteoarthritis	DIS05URM	Strong	Altered Expression	[9]
Pancreatic cancer	DISJC981	Strong	Genetic Variation	[8]
Rheumatoid arthritis	DISTSB4J	Strong	Altered Expression	[9]
Tuberculosis	DIS2YIMD	Strong	Genetic Variation	[10]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[11]
Lung adenocarcinoma	DISD51WR	Limited	Genetic Variation	[12]
Neoplasm	DISZKGEW	Limited	Altered Expression	[13]
Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 7	DISYTRD4	Limited	Autosomal dominant	[1]

8 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 H/ACA ribonucleoprotein complex non-core subunit NAF1 (NAF1).	[14]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of H/ACA ribonucleoprotein complex non-core subunit NAF1 (NAF1).	[15]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of H/ACA ribonucleoprotein complex non-core subunit NAF1 (NAF1).	[16]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of H/ACA ribonucleoprotein complex non-core subunit NAF1 (NAF1).	[17]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of H/ACA ribonucleoprotein complex non-core subunit NAF1 (NAF1).	[18]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of H/ACA ribonucleoprotein complex non-core subunit NAF1 (NAF1).	[19]
Rifampicin	DM5DSFZ	Approved	Rifampicin decreases the expression of H/ACA ribonucleoprotein complex non-core subunit NAF1 (NAF1).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of H/ACA ribonucleoprotein complex non-core subunit NAF1 (NAF1).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of H/ACA ribonucleoprotein complex non-core subunit NAF1 (NAF1).	[21]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of H/ACA ribonucleoprotein complex non-core subunit NAF1 (NAF1).	[22]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of H/ACA ribonucleoprotein complex non-core subunit NAF1 (NAF1).	[22]

References

• [1] Loss-of-function mutations in the RNA biogenesis factor NAF1 predispose to pulmonary fibrosis-emphysema. Sci Transl Med. 2016 Aug 10;8(351):351ra107. doi: 10.1126/scitranslmed.aaf7837.
• [2] Multiple splicing variants of Naf1/ABIN-1 transcripts and their alterations in hematopoietic tumors.Int J Mol Med. 2006 Nov;18(5):917-23.
• [3] The anti-apoptotic proteins NAF-1 and iASPP interact to drive apoptosis in cancer cells.Chem Sci. 2018 Nov 20;10(3):665-673. doi: 10.1039/c8sc03390k. eCollection 2019 Jan 21.
• [4] Association between genetic variants and esophageal cancer risk.Oncotarget. 2017 Jul 18;8(29):47167-47174. doi: 10.18632/oncotarget.17006.
• [5] Posttranscriptional modulation of TERC by PAPD5 inhibition rescues hematopoietic development in dyskeratosis congenita.Blood. 2019 Mar 21;133(12):1308-1312. doi: 10.1182/blood-2018-11-885368. Epub 2019 Feb 6.
• [6] Increased expression of NAF1 contributes to malignant phenotypes of glioma cells through promoting protein synthesis and associates with poor patient survival.Oncogenesis. 2019 Apr 1;8(4):25. doi: 10.1038/s41389-019-0134-2.
• [7] Binding of thiazolidinediones to the endoplasmic reticulum protein nutrient-deprivation autophagy factor-1.Bioorg Med Chem Lett. 2019 Apr 1;29(7):901-904. doi: 10.1016/j.bmcl.2019.01.041. Epub 2019 Feb 1.
• [8] Genetic determinants of telomere length and risk of pancreatic cancer: A PANDoRA study.Int J Cancer. 2019 Mar 15;144(6):1275-1283. doi: 10.1002/ijc.31928. Epub 2018 Nov 12.
• [9] Identification of Naf1/ABIN-1 among TNF-alpha-induced expressed genes in human synoviocytes using oligonucleotide microarrays.FEBS Lett. 2003 Sep 11;551(1-3):8-12. doi: 10.1016/s0014-5793(03)00823-8.
• [10] Association between common telomere length genetic variants and telomere length in an African population and impacts of HIV and TB.J Hum Genet. 2019 Oct;64(10):1033-1040. doi: 10.1038/s10038-019-0646-9. Epub 2019 Aug 6.
• [11] Interactions between mitoNEET and NAF-1 in cells.PLoS One. 2017 Apr 20;12(4):e0175796. doi: 10.1371/journal.pone.0175796. eCollection 2017.
• [12] Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes.Nat Genet. 2017 Jul;49(7):1126-1132. doi: 10.1038/ng.3892. Epub 2017 Jun 12.
• [13] NAF-1 and mitoNEET are central to human breast cancer proliferation by maintaining mitochondrial homeostasis and promoting tumor growth.Proc Natl Acad Sci U S A. 2013 Sep 3;110(36):14676-81. doi: 10.1073/pnas.1313198110. Epub 2013 Aug 19.
• [14] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [15] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [16] 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.
• [17] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [18] Pharmacogenomic identification of novel determinants of response to chemotherapy in colon cancer. Cancer Res. 2006 Mar 1;66(5):2765-77.
• [19] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [20] Integrated analysis of rifampicin-induced microRNA and gene expression changes in human hepatocytes. Drug Metab Pharmacokinet. 2014;29(4):333-40.
• [21] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [22] 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.
• [23] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.