Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTG6CYJ0)

• DOT Name: TOG array regulator of axonemal microtubules protein 1 (TOGARAM1)
• Synonyms: Crescerin-1; Protein FAM179B
• Gene Name: TOGARAM1
• Related Disease:
  Advanced cancer
  Glioma
  Joubert syndrome 37
  Neoplasm
  Non-hodgkin lymphoma
  Ciliopathy
• UniProt ID: TGRM1_HUMAN
• Pfam ID: PF21040
• Sequence:
  MAAAPSALLLLPPFPVLSTYRLQSRSRPSAPETDDSRVGGIMRGEKNYYFRGAAGDHGSC
  PTTTSPLASALLMPSEAVSSSWSESGGGLSGGDEEDTRLLQLLRTARDPSEAFQALQAAL
  PRRGGRLGFPRRKEALYRALGRVLVEGGSDEKRLCLQLLSDVLRGQGEAGQLEEAFSLAL
  LPQLVVSLREENPALRKDALQILHICLKRSPGEVLRTLIQQGLESTDARLRASTALLLPI
  LLTTEDLLLGLDLTEVIISLARKLGDQETEEESETAFSALQQIGERLGQDRFQSYISRLP
  SALRRHYNRRLESQFGSQVPYYLELEASGFPEDPLPCAVTLSNSNLKFGIIPQELHSRLL
  DQEDYKNRTQAVEELKQVLGKFNPSSTPHSSLVGFISLLYNLLDDSNFKVVHGTLEVLHL
  LVIRLGEQVQQFLGPVIAASVKVLADNKLVIKQEYMKIFLKLMKEVGPQQVLCLLLEHLK
  HKHSRVREEVVNICICSLLTYPSEDFDLPKLSFDLAPALVDSKRRVRQAALEAFAVLASS
  MGSGKTSILFKAVDTVELQDNGDGVMNAVQARLARKTLPRLTEQGFVEYAVLMPSSAGGR
  SNHLAHGADTDWLLAGNRTQSAHCHCGDHVRDSMHIYGSYSPTICTRRVLSAGKGKNKLP
  WENEQPGIMGENQTSTSKDIEQFSTYDFIPSAKLKLSQGMPVNDDLCFSRKRVSRNLFQN
  SRDFNPDCLPLCAAGTTGTHQTNLSGKCAQLGFSQICGKTGSVGSDLQFLGTTSSHQEKV
  YASLNFGSKTQQTFGSQTECTSSNGQNPSPGAYILPSYPVSSPRTSPKHTSPLIISPKKS
  QDNSVNFSNSWPLKSFEGLSKPSPQKKLVSQKSSDPTGRNHGENSQEKPPVQLTPALVRS
  PSSRRGLNGTKPVPPIPRGISLLPDKADLSTVGHKKKEPDDIWKCEKDSLPIDLSELNFK
  DKDLDQEEMHSSLRSLRNSAAKKRAKLSGSTSDLESPDSAMKLDLTMDSPSLSSSPNINS
  YSESGVYSQESLTSSLSTTPQGKRIMSDIFPTFGSKPCPTRLSSAKKKISHIAEQSPSAG
  SSSNPQQISSFDFTTTKALSEDSVVVVGKGVFGSLSSAPATCSQSVISSVENGDTFSIKQ
  SIEPPSGIYGRSVQQNISSYLDVENEKDAKVSISKSTYNKMRQKRKEEKELFHNKDCEKK
  EKNSWERMRHTGTEKMASESETPTGAISQYKERMPSVTHSPEIMDLSELRPFSKPEIALT
  EALRLLADEDWEKKIEGLNFIRCLAAFHSEILNTKLHETNFAVVQEVKNLRSGVSRAAVV
  CLSDLFTYLKKSMDQELDTTVKVLLHKAGESNTFIREDVDKALRAMVNNVTPARAVVSLI
  NGGQRYYGRKMLFFMMCHPNFEKMLEKYVPSKDLPYIKDSVRNLQQKGLGEIPLDTPSAK
  GRRSHTGSVGNTRSSSVSRDAFNSAERAVTEVREVTRKSVPRNSLESAEYLKLITGLLNA
  KDFRDRINGIKQLLSDTENNQDLVVGNIVKIFDAFKSRLHDSNSKVNLVALETMHKMIPL
  LRDHLSPIINMLIPAIVDNNLNSKNPGIYAAATNVVQALSQHVDNYLLLQPFCTKAQFLN
  GKAKQDMTEKLADIVTELYQRKPHATEQKVLVVLWHLLGNMTNSGSLPGAGGNIRTATAK
  LSKALFAQMGQNLLNQAASQPPHIKKSLEELLDMTILNEL
• Function: Involved in ciliogenesis. It is required for appropriate acetylation and polyglutamylation of ciliary microtubules, and regulation of cilium length. Interacts with microtubules and promotes microtubule polymerization via its HEAT repeat domains, especially those in TOG region 2 and 4.

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[1]
Glioma	DIS5RPEH	Strong	Genetic Variation	[2]
Joubert syndrome 37	DIS5AGN8	Strong	Autosomal recessive	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Non-hodgkin lymphoma	DISS2Y8A	Strong	Genetic Variation	[1]
Ciliopathy	DIS10G4I	Limited	Autosomal recessive	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of TOG array regulator of axonemal microtubules protein 1 (TOGARAM1).	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of TOG array regulator of axonemal microtubules protein 1 (TOGARAM1).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of TOG array regulator of axonemal microtubules protein 1 (TOGARAM1).	[8]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of TOG array regulator of axonemal microtubules protein 1 (TOGARAM1).	[9]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of TOG array regulator of axonemal microtubules protein 1 (TOGARAM1).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of TOG array regulator of axonemal microtubules protein 1 (TOGARAM1).	[11]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of TOG array regulator of axonemal microtubules protein 1 (TOGARAM1).	[12]

References

• [1] A polymorphism at the microRNA binding site in the 3' untranslated region of C14orf101 is associated with non-Hodgkin lymphoma overall survival.Cancer Genet. 2014 Apr;207(4):141-6. doi: 10.1016/j.cancergen.2014.03.007. Epub 2014 Mar 22.
• [2] GOLGA7 rs11337, a Polymorphism at the MicroRNA Binding Site, Is Associated with Glioma Prognosis.Mol Ther Nucleic Acids. 2019 Dec 6;18:56-65. doi: 10.1016/j.omtn.2019.08.006. Epub 2019 Aug 14.
• [3] Dysfunction of the ciliary ARMC9/TOGARAM1 protein module causes Joubert syndrome. J Clin Invest. 2020 Aug 3;130(8):4423-4439. doi: 10.1172/JCI131656.
• [4] TOG-tubulin binding specificity promotes microtubule dynamics and mitotic spindle formation.J Cell Biol. 2017 Jun 5;216(6):1641-1657. doi: 10.1083/jcb.201610090. Epub 2017 May 16.
• [5] Biallelic mutations in the TOGARAM1 gene cause a novel primary ciliopathy. J Med Genet. 2021 Aug;58(8):526-533. doi: 10.1136/jmedgenet-2020-106833. Epub 2020 Aug 3.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [10] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [11] 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.
• [12] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.