Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTS94JFM)

• DOT Name: PHD finger-like domain-containing protein 5A (PHF5A)
• Synonyms: PHD finger-like domain protein 5A; Splicing factor 3B-associated 14 kDa protein; SF3b14b
• Gene Name: PHF5A
• Related Disease:
  Atypical teratoid/rhabdoid tumour
  Brain neoplasm
  Breast cancer
  Breast carcinoma
  Colon cancer
  Colon carcinoma
  Congenital alveolar dysplasia
  Hepatocellular carcinoma
  Lung adenocarcinoma
  Medulloblastoma
  Neoplasm
  Non-small-cell lung cancer
  Primitive neuroectodermal tumor
  Schizophrenia
  Sporotrichosis
  Advanced cancer
  Asthma
  Glioblastoma multiforme
  Lung cancer
  Lung carcinoma
  Malignant rhabdoid tumour
• UniProt ID: PHF5A_HUMAN
• PDB ID: 5IFE ; 5O9Z ; 5SYB ; 5Z56 ; 5Z57 ; 5Z58 ; 5ZYA ; 6AH0 ; 6AHD ; 6EN4 ; 6FF4 ; 6FF7 ; 6QX9 ; 6Y50 ; 6Y5Q ; 7ABG ; 7ABH ; 7ABI ; 7B0I ; 7B91 ; 7B92 ; 7B9C ; 7DVQ ; 7EVN ; 7EVO ; 7OMF ; 7ONB ; 7OPI ; 7Q3L ; 7Q4O ; 7Q4P ; 7QTT ; 7VPX ; 8CH6 ; 8HK1
• Pfam ID: PF03660
• Sequence:
  MAKHHPDLIFCRKQAGVAIGRLCEKCDGKCVICDSYVRPCTLVRICDECNYGSYQGRCVI
  CGGPGVSDAYYCKECTIQEKDRDGCPKIVNLGSSKTDLFYERKKYGFKKR
• Function: Component of the 17S U2 SnRNP complex of the spliceosome, a large ribonucleoprotein complex that removes introns from transcribed pre-mRNAs. The 17S U2 SnRNP complex (1) directly participates in early spliceosome assembly and (2) mediates recognition of the intron branch site during pre-mRNA splicing by promoting the selection of the pre-mRNA branch-site adenosine, the nucleophile for the first step of splicing. Within the 17S U2 SnRNP complex, PHF5A is part of the SF3B subcomplex, which is required for 'A' complex assembly formed by the stable binding of U2 snRNP to the branchpoint sequence in pre-mRNA. Sequence independent binding of SF3A and SF3B subcomplexes upstream of the branch site is essential, it may anchor U2 snRNP to the pre-mRNA. Also acts as a component of the minor spliceosome, which is involved in the splicing of U12-type introns in pre-mRNAs. Also involved in elongation by RNA polymerase II as part of the PAF1 complex (PAF1C). PAF1C is required for maintenance of embryonic stem cell (ESC) self-renewal and cellular reprogramming of stem cells. Maintains pluripotency by recruiting and stabilizing PAF1C on pluripotency genes loci, and by regulating the expression of the pluripotency genes. Regulates the deposition of elongation-associated histone modifications, including dimethylated histone H3 'Lys-79' (H3K79me2) and trimethylated histone H3 'Lys-36' (H3K36me3), on PAF1C targets, self-renewal and pluripotency genes. Regulates RNA polymerase II promoter-proximal pause release of the PAF1C targets and self-renewal genes, and the levels of elongating ('Ser-2' phosphorylated) RNA polymerase II in their gene bodies. Regulates muscle specification in adult stem cells by stabilizing PAF1C in chromatin to promote myogenic differentiation. Acts as a transcriptional regulator by binding to the GJA1/Cx43 promoter and enhancing its up-regulation by ESR1/ER-alpha.
• KEGG Pathway: Spliceosome (hsa03040)
• Reactome Pathway: mRNA Splicing - Major Pathway (R-HSA-72163)

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Atypical teratoid/rhabdoid tumour	DIS1FA0D	Strong	Biomarker	[1]
Brain neoplasm	DISY3EKS	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Colon cancer	DISVC52G	Strong	Altered Expression	[4]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[4]
Congenital alveolar dysplasia	DIS1IYUN	Strong	Genetic Variation	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[6]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[3]
Medulloblastoma	DISZD2ZL	Strong	Biomarker	[1]
Neoplasm	DISZKGEW	Strong	Altered Expression	[7]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[3]
Primitive neuroectodermal tumor	DISFHXHA	Strong	Biomarker	[1]
Schizophrenia	DISSRV2N	Strong	Altered Expression	[8]
Sporotrichosis	DISZA6J9	Strong	Biomarker	[9]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[4]
Asthma	DISW9QNS	Limited	Genetic Variation	[10]
Glioblastoma multiforme	DISK8246	Limited	Biomarker	[3]
Lung cancer	DISCM4YA	Limited	Biomarker	[3]
Lung carcinoma	DISTR26C	Limited	Biomarker	[3]
Malignant rhabdoid tumour	DIS46HZU	Limited	Altered Expression	[11]

11 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 PHD finger-like domain-containing protein 5A (PHF5A).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of PHD finger-like domain-containing protein 5A (PHF5A).	[13]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of PHD finger-like domain-containing protein 5A (PHF5A).	[14]
Marinol	DM70IK5	Approved	Marinol decreases the expression of PHD finger-like domain-containing protein 5A (PHF5A).	[15]
Folic acid	DMEMBJC	Approved	Folic acid increases the expression of PHD finger-like domain-containing protein 5A (PHF5A).	[16]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of PHD finger-like domain-containing protein 5A (PHF5A).	[17]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of PHD finger-like domain-containing protein 5A (PHF5A).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of PHD finger-like domain-containing protein 5A (PHF5A).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of PHD finger-like domain-containing protein 5A (PHF5A).	[20]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of PHD finger-like domain-containing protein 5A (PHF5A).	[21]
Aminohippuric acid	DMUN54G	Investigative	Aminohippuric acid affects the expression of PHD finger-like domain-containing protein 5A (PHF5A).	[22]

References

• [1] Integrated genomics has identified a new AT/RT-like yet INI1-positive brain tumor subtype among primary pediatric embryonal tumors.BMC Med Genomics. 2015 Jun 25;8:32. doi: 10.1186/s12920-015-0103-3.
• [2] Genome-wide RNAi screens in human brain tumor isolates reveal a novel viability requirement for PHF5A.Genes Dev. 2013 May 1;27(9):1032-45. doi: 10.1101/gad.212548.112.
• [3] PHD finger protein 5A promoted lung adenocarcinoma progression via alternative splicing.Cancer Med. 2019 May;8(5):2429-2441. doi: 10.1002/cam4.2115. Epub 2019 Apr 1.
• [4] Acetylation of PHF5A Modulates Stress Responses and Colorectal Carcinogenesis through Alternative Splicing-Mediated Upregulation of KDM3A.Mol Cell. 2019 Jun 20;74(6):1250-1263.e6. doi: 10.1016/j.molcel.2019.04.009. Epub 2019 May 1.
• [5] Correlation of expression levels of caspase-3 and Bcl-2 in alveolar lavage fluid in neonatal respiratory distress syndrome and prognosis.Exp Ther Med. 2018 Mar;15(3):2891-2895. doi: 10.3892/etm.2018.5755. Epub 2018 Jan 16.
• [6] Knockdown of PHF5A Inhibits Migration and Invasion of HCC Cells via Downregulating NF-B Signaling.Biomed Res Int. 2019 Jan 15;2019:1621854. doi: 10.1155/2019/1621854. eCollection 2019.
• [7] BRAF Mutation in Colorectal Rhabdoid and Poorly Differentiated Medullary Carcinomas.Cancers (Basel). 2019 Aug 26;11(9):1252. doi: 10.3390/cancers11091252.
• [8] RNA editing of the 5-HT(2C) receptor is reduced in schizophrenia.Mol Psychiatry. 2001 Jul;6(4):373-9. doi: 10.1038/sj.mp.4000920.
• [9] Zoonotic sporotrichosis with greater severity in Rio de Janeiro, Brazil: 118 hospitalizations and 11 deaths in the last 2 decades in a reference institution.Med Mycol. 2020 Jan 1;58(1):141-143. doi: 10.1093/mmy/myz024.
• [10] Genetic Architectures of Childhood- and Adult-Onset Asthma Are Partly Distinct.Am J Hum Genet. 2019 Apr 4;104(4):665-684. doi: 10.1016/j.ajhg.2019.02.022. Epub 2019 Mar 28.
• [11] SMARCB1/INI1 protein expression in round cell soft tissue sarcomas associated with chromosomal translocations involving EWS: a special reference to SMARCB1/INI1 negative variant extraskeletal myxoid chondrosarcoma.Am J Surg Pathol. 2008 Aug;32(8):1168-74. doi: 10.1097/PAS.0b013e318161781a.
• [12] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [13] 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.
• [14] Proteomics-based identification of differentially abundant proteins from human keratinocytes exposed to arsenic trioxide. J Proteomics Bioinform. 2014 Jul;7(7):166-178.
• [15] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [16] Folic acid induces cell type-specific changes in the transcriptome of breast cancer cell lines: a proof-of-concept study. J Nutr Sci. 2016 Apr 26;5:e17. doi: 10.1017/jns.2016.8. eCollection 2016.
• [17] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [18] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [19] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [20] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [21] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [22] Identification of molecular signatures predicting the carcinogenicity of polycyclic aromatic hydrocarbons (PAHs). Toxicol Lett. 2012 Jul 7;212(1):18-28. doi: 10.1016/j.toxlet.2012.04.013. Epub 2012 May 1.