Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTS4UBI8)

• DOT Name: ATP-dependent RNA helicase TDRD9 (TDRD9)
• Synonyms: EC 3.6.4.13; Tudor domain-containing protein 9
• Gene Name: TDRD9
• Related Disease:
  Advanced cancer
  Alzheimer disease
  Arteriosclerosis
  Atherosclerosis
  Azoospermia
  Carcinoma
  Cerebral palsy
  Lung adenocarcinoma
  Pheochromocytoma
  Spermatogenic failure 30
  Von hippel-lindau disease
  Breast cancer
  Breast carcinoma
  Obsolete male infertility with azoospermia or oligozoospermia due to single gene mutation
  Age-related macular degeneration
  Diabetic macular edema
  High blood pressure
  Neoplasm
  Retinal vein occlusion
• UniProt ID: TDRD9_HUMAN
• EC Number: 3.6.4.13
• Pfam ID: PF00270 ; PF21010 ; PF00271 ; PF00567
• Sequence:
  MLRKLTIEQINDWFTIGKTVTNVELLGAPPAFPAGAAREEVQRQDVAPGAGPAAQAPALA
  QAPARPAAAFERSLSQRSSEVEYINKYRQLEAQELDVCRSVQPTSGPGPRPSLAKLSSVT
  CIPGTTYKYPDLPISRYKEEVVSLIESNSVVIIHGATGSGKSTQLPQYILDHYVQRSAYC
  SIVVTQPRKIGASSIARWISKERAWTLGGVVGYQVGLEKIATEDTRLIYMTTGVLLQKIV
  SAKSLMEFTHIIIDEVHERTEEMDFLLLVVRKLLRTNSRFVKVVLMSATISCKEFADYFA
  VPVQNKMNPAYIFEVEGKPHSVEEYYLNDLEHIHHSKLSPHLLEEPVITKDIYEVAVSLI
  QMFDDLDMKESGNKAWSGAQFVLERSSVLVFLPGLGEINYMHELLTSLVHKRLQVYPLHS
  SVALEEQNNVFLSPVPGYRKIILSTNIAESSVTVPDVKYVIDFCLTRTLVCDEDTNYQSL
  RLSWASKTSCNQRKGRAGRVSRGYCYRLVHKDFWDNSIPDHVVPEMLRCPLGSTILKVKL
  LDMGEPRALLATALSPPGLSDIERTILLLKEVGALAVSGQREDENPHDGELTFLGRVLAQ
  LPVNQQLGKLIVLGHVFGCLDECLIIAAALSLKNFFAMPFRQHLDGYRNKVNFSGSSKSD
  CIALVEAFKTWKACRQTGELRYPKDELNWGRLNYIQIKRIREVAELYEELKTRISQFNMH
  VDSRRPVMDQEYIYKQRFILQVVLAGAFYPNYFTFGQPDEEMAVRELAGKDPKTTVVLKH
  IPPYGFLYYKQLQSLFRQCGQVKSIVFDGAKAFVEFSRNPTERFKTLPAVYMAIKMSQLK
  VSLELSVHSAEEIEGKVQGMNVSKLRNTRVNVDFQKQTVDPMQVSFNTSDRSQTVTDLLL
  TIDVTEVVEVGHFWGYRIDENNSEILKKLTAEINQLTLVPLPTHPHPDLVCLAPFADFDK
  QRYFRAQVLYVSGNSAEVFFVDYGNKSHVDLHLLMEIPCQFLELPFQALEFKICKMRPSA
  KSLVCGKHWSDGASQWFASLVSGCTLLVKVFSVVHSVLHVDVYQYSGVQDAINIRDVLIQ
  QGYAELTEESYESKQSHEVLKGLFSKSVENMTDGSVPFPMKDDEKYLIRILLESFSTNKL
  GTPNCKAELHGPFNPYELKCHSLTRISKFRCVWIEKESINSVIISDAPEDLHQRMLVAAS
  LSINATGSTMLLRETSLMPHIPGLPALLSMLFAPVIELRIDQNGKYYTGVLCGLGWNPAT
  GASILPEHDMELAFDVQFSVEDVVEVNILRAAINKLVCDGPNGCKCLGPERVAQLQDIAR
  QKLLGLFCQSKPREKIVPKWHEKPYEWNQVDPKLVMEQADRESSRGKNTFLYQLHKLVVL
  GT
• Function: ATP-binding RNA helicase required during spermatogenesis. Required to repress transposable elements and prevent their mobilization, which is essential for the germline integrity. Acts via the piRNA metabolic process, which mediates the repression of transposable elements during meiosis by forming complexes composed of piRNAs and Piwi proteins and governs the methylation and subsequent repression of transposons. Acts downstream of piRNA biogenesis: exclusively required for transposon silencing in the nucleus, suggesting that it acts as a nuclear effector in the nucleus together with PIWIL4.
• Reactome Pathway: PIWI-interacting RNA (piRNA) biogenesis (R-HSA-5601884)

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[2]
Arteriosclerosis	DISK5QGC	Strong	Genetic Variation	[3]
Atherosclerosis	DISMN9J3	Strong	Genetic Variation	[3]
Azoospermia	DIS94181	Strong	Altered Expression	[4]
Carcinoma	DISH9F1N	Strong	Biomarker	[5]
Cerebral palsy	DIS82ODL	Strong	Biomarker	[6]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[5]
Pheochromocytoma	DIS56IFV	Strong	Biomarker	[7]
Spermatogenic failure 30	DISJOB3P	Strong	Autosomal recessive	[8]
Von hippel-lindau disease	DIS6ZFQQ	Strong	Biomarker	[7]
Breast cancer	DIS7DPX1	moderate	Genetic Variation	[9]
Breast carcinoma	DIS2UE88	moderate	Genetic Variation	[9]
Obsolete male infertility with azoospermia or oligozoospermia due to single gene mutation	DIS56JR8	Supportive	Autosomal dominant	[10]
Age-related macular degeneration	DIS0XS2C	Limited	Biomarker	[11]
Diabetic macular edema	DIS162FN	Limited	Genetic Variation	[11]
High blood pressure	DISY2OHH	Limited	Biomarker	[12]
Neoplasm	DISZKGEW	Limited	Biomarker	[13]
Retinal vein occlusion	DISSVWOE	Limited	Genetic Variation	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of ATP-dependent RNA helicase TDRD9 (TDRD9).	[14]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of ATP-dependent RNA helicase TDRD9 (TDRD9).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of ATP-dependent RNA helicase TDRD9 (TDRD9).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of ATP-dependent RNA helicase TDRD9 (TDRD9).	[16]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of ATP-dependent RNA helicase TDRD9 (TDRD9).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of ATP-dependent RNA helicase TDRD9 (TDRD9).	[18]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of ATP-dependent RNA helicase TDRD9 (TDRD9).	[17]

References

• [1] Development and Psychometric Evaluation of the Cancer Health Literacy Scale in Newly Diagnosed Cancer Patients.Cancer Nurs. 2020 Sep/Oct;43(5):E291-E303. doi: 10.1097/NCC.0000000000000711.
• [2] Intranasal delivery of a novel acetylcholinesterase inhibitor HLS-3 for treatment of Alzheimer's disease.Life Sci. 2018 Aug 15;207:428-435. doi: 10.1016/j.lfs.2018.06.032. Epub 2018 Jun 30.
• [3] Healthy Lifestyle During the Midlife Is Prospectively Associated With Less Subclinical Carotid Atherosclerosis: The Study of Women's Health Across the Nation.J Am Heart Assoc. 2018 Dec 4;7(23):e010405. doi: 10.1161/JAHA.118.010405.
• [4] Deficient expression of genes involved in the endogenous defense system against transposons in cryptorchid boys with impaired mini-puberty.Sex Dev. 2011;5(6):287-93. doi: 10.1159/000335188. Epub 2012 Jan 5.
• [5] Expression of TDRD9 in a subset of lung carcinomas by CpG island hypomethylation protects from DNA damage.Oncotarget. 2017 Nov 27;9(11):9618-9631. doi: 10.18632/oncotarget.22709. eCollection 2018 Feb 9.
• [6] Percutaneous Hamstring Lengthening Surgery is as Effective as Open Lengthening in Children With Cerebral Palsy.J Pediatr Orthop. 2019 Aug;39(7):366-371. doi: 10.1097/BPO.0000000000000924.
• [7] Clustering of features of von Hippel-Lindau syndrome: evidence for a complex genetic locus.Lancet. 1991 May 4;337(8749):1052-4. doi: 10.1016/0140-6736(91)91705-y.
• [8] The TDRD9-MIWI2 complex is essential for piRNA-mediated retrotransposon silencing in the mouse male germline. Dev Cell. 2009 Dec;17(6):775-87. doi: 10.1016/j.devcel.2009.10.012.
• [9] Validation of the European Health Literacy Survey Questionnaire in Women With Breast Cancer.Cancer Nurs. 2018 Mar/Apr;41(2):E40-E48. doi: 10.1097/NCC.0000000000000475.
• [10] Mutation in TDRD9 causes non-obstructive azoospermia in infertile men. J Med Genet. 2017 Sep;54(9):633-639. doi: 10.1136/jmedgenet-2017-104514. Epub 2017 May 23.
• [11] Low health literacy levels in patients with chronic retinal disease.BMC Ophthalmol. 2019 Aug 8;19(1):174. doi: 10.1186/s12886-019-1191-1.
• [12] The role of lifestyle behaviour on the risk of hypertension in the SUN cohort: The hypertension preventive score.Prev Med. 2019 Jun;123:171-178. doi: 10.1016/j.ypmed.2019.03.026. Epub 2019 Mar 19.
• [13] Central nervous system lesions in von Hippel-Lindau syndrome.J Neurol Neurosurg Psychiatry. 1992 Oct;55(10):898-901. doi: 10.1136/jnnp.55.10.898.
• [14] 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.
• [15] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [16] Genistein disrupts glucocorticoid receptor signaling in human uterine endometrial Ishikawa cells. Environ Health Perspect. 2015 Jan;123(1):80-7. doi: 10.1289/ehp.1408437. Epub 2014 Aug 19.
• [17] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [18] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [19] 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.