Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTU7TQCO)

• DOT Name: TELO2-interacting protein 2 (TTI2)
• Gene Name: TTI2
• Related Disease:
  Severe intellectual disability-short stature-behavioral abnormalities-facial dysmorphism syndrome
  Intellectual disability
• UniProt ID: TTI2_HUMAN
• PDB ID: 7OLE
• Pfam ID: PF10521
• Sequence:
  MELDSALEAPSQEDSNLSEELSHSAFGQAFSKILHCLARPEARRGNVKDAVLKDLGDLIE
  ATEFDRLFEGTGARLRGMPETLGQVAKALEKYAAPSKEEEGGGDGHSEAAEKAAQVGLLF
  LKLLGKVETAKNSLVGPAWQTGLHHLAGPVYIFAITHSLEQPWTTPRSREVAREVLTSLL
  QVTECGSVAGFLHGENEDEKGRLSVILGLLKPDLYKESWKNNPAIKHVFSWTLQQVTRPW
  LSQHLERVLPASLVISDDYQTENKILGVHCLHHIVLNVPAADLLQYNRAQVLYHAISNHL
  YTPEHHLIQAVLLCLLDLFPILEKTLHWKGDGARPTTHCDEVLRLILTHMEPEHRLLLRR
  TYARNLPAFVNRLGILTVRHLKRLERVIIGYLEVYDGPEEEARLKILETLKLLMQHTWPR
  VSCRLVVLLKALLKLICDVARDPNLTPESVKSALLQEATDCLILLDRCSQGRVKGLLAKI
  PQSCEDRKVVNYIRKVQQVSEGAPYNGT
• Function: Regulator of the DNA damage response (DDR). Part of the TTT complex that is required to stabilize protein levels of the phosphatidylinositol 3-kinase-related protein kinase (PIKK) family proteins. The TTT complex is involved in the cellular resistance to DNA damage stresses, like ionizing radiation (IR), ultraviolet (UV) and mitomycin C (MMC). Together with the TTT complex and HSP90 may participate in the proper folding of newly synthesized PIKKs.

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Severe intellectual disability-short stature-behavioral abnormalities-facial dysmorphism syndrome	DISTOVDL	Strong	Autosomal recessive	[1]
Intellectual disability	DISMBNXP	Limited	Genetic Variation	[2]

3 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 TELO2-interacting protein 2 (TTI2).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of TELO2-interacting protein 2 (TTI2).	[4]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of TELO2-interacting protein 2 (TTI2).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of TELO2-interacting protein 2 (TTI2).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of TELO2-interacting protein 2 (TTI2).	[6]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of TELO2-interacting protein 2 (TTI2).	[5]

References

• [1] Homozygosity mapping in consanguineous families reveals extreme heterogeneity of non-syndromic autosomal recessive mental retardation and identifies 8 novel gene loci. Hum Genet. 2007 Mar;121(1):43-8. doi: 10.1007/s00439-006-0292-0. Epub 2006 Nov 21.
• [2] Novel Compound Heterozygous Mutations in TTI2 Cause Syndromic Intellectual Disability in a Chinese Family.Front Genet. 2019 Oct 29;10:1060. doi: 10.3389/fgene.2019.01060. eCollection 2019.
• [3] 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.
• [4] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [5] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [6] 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.
• [7] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.