Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBOQ73Y)

• DOT Name: Tumor suppressor ARF (CDKN2A)
• Synonyms: Alternative reading frame; ARF; Cyclin-dependent kinase inhibitor 2A; p14ARF
• Gene Name: CDKN2A
• UniProt ID: ARF_HUMAN
• Pfam ID: PF07392
• Sequence:
  MVRRFLVTLRIRRACGPPRVRVFVVHIPRLTGEWAAPGAPAAVALVLMLLRSQRLGQQPL
  PRRPGHDDGQRPSGGAAAAPRRGAQLRRPRHSHPTRARRCPGGLPGHAGGAAPGRGAAGR
  ARCLGPSARGPG
• Function: Capable of inducing cell cycle arrest in G1 and G2 phases. Acts as a tumor suppressor. Binds to MDM2 and blocks its nucleocytoplasmic shuttling by sequestering it in the nucleolus. This inhibits the oncogenic action of MDM2 by blocking MDM2-induced degradation of p53 and enhancing p53-dependent transactivation and apoptosis. Also induces G2 arrest and apoptosis in a p53-independent manner by preventing the activation of cyclin B1/CDC2 complexes. Binds to BCL6 and down-regulates BCL6-induced transcriptional repression. Binds to E2F1 and MYC and blocks their transcriptional activator activity but has no effect on MYC transcriptional repression. Binds to TOP1/TOPOI and stimulates its activity. This complex binds to rRNA gene promoters and may play a role in rRNA transcription and/or maturation. Interacts with NPM1/B23 and promotes its polyubiquitination and degradation, thus inhibiting rRNA processing. Plays a role in inhibiting ribosome biogenesis, perhaps by binding to the nucleolar localization sequence of transcription termination factor TTF1, and thereby preventing nucleolar localization of TTF1. Interacts with COMMD1 and promotes its 'Lys63'-linked polyubiquitination. Interacts with UBE2I/UBC9 and enhances sumoylation of a number of its binding partners including MDM2 and E2F1. Binds to HUWE1 and represses its ubiquitin ligase activity. May play a role in controlling cell proliferation and apoptosis during mammary gland development; [Isoform smARF]: May be involved in regulation of autophagy and caspase-independent cell death; the short-lived mitochondrial isoform is stabilized by C1QBP.
• Reactome Pathway:
  Oxidative Stress Induced Senescence (R-HSA-2559580)
  Oncogene Induced Senescence (R-HSA-2559585)
  SUMOylation of DNA damage response and repair proteins (R-HSA-3108214)
  SUMOylation of transcription factors (R-HSA-3232118)
  Regulation of TP53 Degradation (R-HSA-6804757)
  Stabilization of p53 (R-HSA-69541)
  Regulation of RUNX3 expression and activity (R-HSA-8941858)
  Defective Intrinsic Pathway for Apoptosis Due to p14ARF Loss of Function (R-HSA-9645722)
  Evasion of Oncogene Induced Senescence Due to p14ARF Defects (R-HSA-9646303)
  Evasion of Oxidative Stress Induced Senescence Due to p14ARF Defects (R-HSA-9646304)
  Nuclear events mediated by NFE2L2 (R-HSA-9759194)
  Apoptotic factor-mediated response (R-HSA-111471)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Zidovudine	DM4KI7O	Approved	Tumor suppressor ARF (CDKN2A) increases the Cell death ADR of Zidovudine.	[1]

References

• [1] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.