Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBDRH1J)

• DOT Name: Cyclin-T2 (CCNT2)
• Synonyms: CycT2
• Gene Name: CCNT2
• Related Disease:
  Acute myelogenous leukaemia
  Centronuclear myopathy
  Chronic kidney disease
  Neoplasm
• UniProt ID: CCNT2_HUMAN
• PDB ID: 2IVX
• Pfam ID: PF00134 ; PF21797
• Sequence:
  MASGRGASSRWFFTREQLENTPSRRCGVEADKELSCRQQAANLIQEMGQRLNVSQLTINT
  AIVYMHRFYMHHSFTKFNKNIISSTALFLAAKVEEQARKLEHVIKVAHACLHPLEPLLDT
  KCDAYLQQTQELVILETIMLQTLGFEITIEHPHTDVVKCTQLVRASKDLAQTSYFMATNS
  LHLTTFCLQYKPTVIACVCIHLACKWSNWEIPVSTDGKHWWEYVDPTVTLELLDELTHEF
  LQILEKTPNRLKKIRNWRANQAARKPKVDGQVSETPLLGSSLVQNSILVDSVTGVPTNPS
  FQKPSTSAFPAPVPLNSGNISVQDSHTSDNLSMLATGMPSTSYGLSSHQEWPQHQDSART
  EQLYSQKQETSLSGSQYNINFQQGPSISLHSGLHHRPDKISDHSSVKQEYTHKAGSSKHH
  GPISTTPGIIPQKMSLDKYREKRKLETLDLDVRDHYIAAQVEQQHKQGQSQAASSSSVTS
  PIKMKIPIANTEKYMADKKEKSGSLKLRIPIPPTDKSASKEELKMKIKVSSSERHSSSDE
  GSGKSKHSSPHISRDHKEKHKEHPSSRHHTSSHKHSHSHSGSSSGGSKHSADGIPPTVLR
  SPVGLSSDGISSSSSSSRKRLHVNDASHNHHSKMSKSSKSSGSSSSSSSSVKQYISSHNS
  VFNHPLPPPPPVTYQVGYGHLSTLVKLDKKPVETNGPDANHEYSTSSQHMDYKDTFDMLD
  SLLSAQGMNM
• Function: Regulatory subunit of the cyclin-dependent kinase pair (CDK9/cyclin T) complex, also called positive transcription elongation factor B (P-TEFB), which is proposed to facilitate the transition from abortive to production elongation by phosphorylating the CTD (carboxy-terminal domain) of the large subunit of RNA polymerase II (RNAP II). The activity of this complex is regulated by binding with 7SK snRNA. Plays a role during muscle differentiation; P-TEFB complex interacts with MYOD1; this tripartite complex promotes the transcriptional activity of MYOD1 through its CDK9-mediated phosphorylation and binds the chromatin of promoters and enhancers of muscle-specific genes; this event correlates with hyperphosphorylation of the CTD domain of RNA pol II. In addition, enhances MYOD1-dependent transcription through interaction with PKN1. Involved in early embryo development; (Microbial infection) Promotes transcriptional activation of early and late herpes simplex virus 1/HHV-1 promoters.
• Tissue Specificity: Ubiquitously expressed.
• KEGG Pathway:
  Viral life cycle - HIV-1 (hsa03250)
  Transcriptio.l misregulation in cancer (hsa05202)
• Reactome Pathway:
  Formation of HIV elongation complex in the absence of HIV Tat (R-HSA-167152)
  HIV elongation arrest and recovery (R-HSA-167287)
  Pausing and recovery of HIV elongation (R-HSA-167290)
  SMAD2/SMAD3 (R-HSA-2173796)
  RNA Polymerase II Pre-transcription Events (R-HSA-674695)
  TP53 Regulates Transcription of DNA Repair Genes (R-HSA-6796648)
  RNA polymerase II transcribes snRNA genes (R-HSA-6807505)
  RNA Polymerase II Transcription Elongation (R-HSA-75955)
  Formation of RNA Pol II elongation complex (R-HSA-112382)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[1]
Centronuclear myopathy	DISXBEJO	Strong	Altered Expression	[2]
Chronic kidney disease	DISW82R7	Strong	Altered Expression	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]

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 Cyclin-T2 (CCNT2).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Cyclin-T2 (CCNT2).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cyclin-T2 (CCNT2).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Cyclin-T2 (CCNT2).	[8]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Cyclin-T2 (CCNT2).	[9]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Cyclin-T2 (CCNT2).	[10]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Cyclin-T2 (CCNT2).	[9]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Cyclin-T2 (CCNT2).	[13]

2 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 affects the sumoylation of Cyclin-T2 (CCNT2).	[11]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Cyclin-T2 (CCNT2).	[12]

References

• [1] MicroRNA-192 regulates cell proliferation and cell cycle transition in acute myeloid leukemia via interaction with CCNT2.Int J Hematol. 2017 Aug;106(2):258-265. doi: 10.1007/s12185-017-2232-2. Epub 2017 Apr 13.
• [2] Cyclin T2a gene maps on human chromosome 2q21.J Histochem Cytochem. 2001 Jun;49(6):693-8. doi: 10.1177/002215540104900603.
• [3] The CDK9-cyclin T1 complex mediates saturated fatty acid-induced vascular calcification by inducing expression of the transcription factor CHOP.J Biol Chem. 2018 Nov 2;293(44):17008-17020. doi: 10.1074/jbc.RA118.004706. Epub 2018 Sep 12.
• [4] Downregulation of microRNA-142-3p and its tumor suppressor role in gastric cancer.Oncol Lett. 2018 May;15(5):8172-8180. doi: 10.3892/ol.2018.8330. Epub 2018 Mar 23.
• [5] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [6] 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.
• [7] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [10] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [11] 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.
• [12] 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.
• [13] MCM-2 is a therapeutic target of Trichostatin A in colon cancer cells. Toxicol Lett. 2013 Jul 31;221(1):23-30. doi: 10.1016/j.toxlet.2013.05.643. Epub 2013 Jun 13.