Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWW9ME0)

• DOT Name: Tetratricopeptide repeat protein 5 (TTC5)
• Synonyms: TPR repeat protein 5; Stress-responsive activator of p300; Protein Strap
• Gene Name: TTC5
• Related Disease:
  Acute myelogenous leukaemia
  Neurodevelopmental disorder with cerebral atrophy and variable facial dysmorphism
  Autosomal recessive non-syndromic intellectual disability
• UniProt ID: TTC5_HUMAN
• PDB ID: 2XVS; 6T59; 7QWS; 8BPO
• Pfam ID: PF16669
• Sequence:
  MMADEEEEVKPILQKLQELVDQLYSFRDCYFETHSVEDAGRKQQDVQKEMEKTLQQMEEV
  VGSVQGKAQVLMLTGKALNVTPDYSPKAEELLSKAVKLEPELVEAWNQLGEVYWKKGDVA
  AAHTCFSGALTHCRNKVSLQNLSMVLRQLRTDTEDEHSHHVMDSVRQAKLAVQMDVHDGR
  SWYILGNSYLSLYFSTGQNPKISQQALSAYAQAEKVDRKASSNPDLHLNRATLHKYEESY
  GEALEGFSRAAALDPAWPEPRQREQQLLEFLDRLTSLLESKGKVKTKKLQSMLGSLRPAH
  LGPCSDGHYQSASGQKVTLELKPLSTLQPGVNSGAVILGKVVFSLTTEEKVPFTFGLVDS
  DGPCYAVMVYNIVQSWGVLIGDSVAIPEPNLRLHRIQHKGKDYSFSSVRVETPLLLVVNG
  KPQGSSSQAVATVASRPQCE
• Function: Cofactor involved in the regulation of various cellular mechanisms such as actin regulation, autophagy, chromatin regulation and DNA repair. In non-stress conditions, interacts with cofactor JMY in the cytoplasm which prevents JMY's actin nucleation activity and ability to activate the Arp2/3 complex. Acts as a negative regulator of nutrient stress-induced autophagy by preventing JMY's interaction with MAP1LC3B, thereby preventing autophagosome formation. Involves in tubulin autoregulation by promoting its degradation in response to excess soluble tubulin. To do so, associates with the active ribosome near the ribosome exit tunnel and with nascent tubulin polypeptides early during their translation, triggering tubulin mRNA-targeted degradation. Following DNA damage, phosphorylated by DNA damage responsive protein kinases ATM and CHEK2, leading to its nuclear accumulation and stability. Nuclear TTC5/STRAP promotes the assembly of a stress-responsive p53/TP53 coactivator complex, which includes the coactivators JMY and p300, thereby increasing p53/TP53-dependent transcription and apoptosis. Also recruits arginine methyltransferase PRMT5 to p53/TP53 when DNA is damaged, allowing PRMT5 to methylate p53/TP53. In DNA stress conditions, also prevents p53/TP53 degradation by E3 ubiquitin ligase MDM2. Upon heat-shock stress, forms a chromatin-associated complex with heat-shock factor 1 HSF1 and p300/EP300 to stimulate heat-shock-responsive transcription, thereby increasing cell survival. Mitochondrial TTC5/STRAP interacts with ATP synthase subunit beta ATP5F1B which decreased ATP synthase activity and lowers mitochondrial ATP production, thereby regulating cellular respiration and mitochondrial-dependent apoptosis. Mitochondrial TTC5/STRAP also regulates p53/TP53-mediated apoptosis.
• Reactome Pathway: Regulation of TP53 Activity through Methylation (R-HSA-6804760)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Definitive	Biomarker	[1]
Neurodevelopmental disorder with cerebral atrophy and variable facial dysmorphism	DISGE8Z3	Strong	Autosomal recessive	[2]
Autosomal recessive non-syndromic intellectual disability	DISJWRZZ	Supportive	Autosomal recessive	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Tetratricopeptide repeat protein 5 (TTC5).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Tetratricopeptide repeat protein 5 (TTC5).	[5]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Tetratricopeptide repeat protein 5 (TTC5).	[6]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Tetratricopeptide repeat protein 5 (TTC5).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Tetratricopeptide repeat protein 5 (TTC5).	[7]

References

• [1] TTC5 is required to prevent apoptosis of acute myeloid leukemia stem cells.Cell Death Dis. 2013 Apr 4;4(4):e573. doi: 10.1038/cddis.2013.107.
• [2] Genetics of intellectual disability in consanguineous families. Mol Psychiatry. 2019 Jul;24(7):1027-1039. doi: 10.1038/s41380-017-0012-2. Epub 2018 Jan 4.
• [3] Bi-allelic TTC5 variants cause delayed developmental milestones and intellectual disability. J Med Genet. 2021 Apr;58(4):237-246. doi: 10.1136/jmedgenet-2020-106849. Epub 2020 May 21.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] 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.
• [7] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [8] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.