Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBWODM9)

• DOT Name: Tonsoku-like protein (TONSL)
• Synonyms: Inhibitor of kappa B-related protein; I-kappa-B-related protein; IkappaBR; NF-kappa-B inhibitor-like protein 2; Nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor-like 2
• Gene Name: TONSL
• Related Disease:
  Cervical cancer
  Cervical carcinoma
  Hepatocellular carcinoma
  Neoplasm
  Polycystic ovarian syndrome
  Spondyloepimetaphyseal dysplasia, sponastrime type
  Spondyloepimetaphyseal dysplasia, Strudwick type
  Pneumococcal infection
• UniProt ID: TONSL_HUMAN
• PDB ID: 5JA4
• Pfam ID: PF12796 ; PF13516 ; PF13181
• Sequence:
  MSLERELRQLSKAKAKAQRAGQRREEAALCHQLGELLAGHGRYAEALEQHWQELQLRERA
  DDPLGCAVAHRKIGERLAEMEDYPAALQHQHQYLELAHSLRNHTELQRAWATIGRTHLDI
  YDHCQSRDALLQAQAAFEKSLAIVDEELEGTLAQGELNEMRTRLYLNLGLTFESLQQTAL
  CNDYFRKSIFLAEQNHLYEDLFRARYNLGTIHWRAGQHSQAMRCLEGARECAHTMRKRFM
  ESECCVVIAQVLQDLGDFLAAKRALKKAYRLGSQKPVQRAAICQNLQHVLAVVRLQQQLE
  EAEGRDPQGAMVICEQLGDLFSKAGDFPRAAEAYQKQLRFAELLDRPGAERAIIHVSLAT
  TLGDMKDHHGAVRHYEEELRLRSGNVLEEAKTWLNIALSREEAGDAYELLAPCFQKALSC
  AQQAQRPQLQRQVLQHLHTVQLRLQPQEAPETETRLRELSVAEDEDEEEEAEEAAATAES
  EALEAGEVELSEGEDDTDGLTPQLEEDEELQGHLGRRKGSKWNRRNDMGETLLHRACIEG
  QLRRVQDLVRQGHPLNPRDYCGWTPLHEACNYGHLEIVRFLLDHGAAVDDPGGQGCEGIT
  PLHDALNCGHFEVAELLLERGASVTLRTRKGLSPLETLQQWVKLYRRDLDLETRQKARAM
  EMLLQAAASGQDPHSSQAFHTPSSLLFDPETSPPLSPCPEPPSNSTRLPEASQAHVRVSP
  GQAAPAMARPRRSRHGPASSSSSSEGEDSAGPARPSQKRPRCSATAQRVAAWTPGPASNR
  EAATASTSRAAYQAAIRGVGSAQSRLGPGPPRGHSKALAPQAALIPEEECLAGDWLELDM
  PLTRSRRPRPRGTGDNRRPSSTSGSDSEESRPRARAKQVRLTCMQSCSAPVNAGPSSLAS
  EPPGSPSTPRVSEPSGDSSAAGQPLGPAPPPPIRVRVQVQDHLFLIPVPHSSDTHSVAWL
  AEQAAQRYYQTCGLLPRLTLRKEGALLAPQDLIPDVLQSNDEVLAEVTSWDLPPLTDRYR
  RACQSLGQGEHQQVLQAVELQGLGLSFSACSLALDQAQLTPLLRALKLHTALRELRLAGN
  RLGDKCVAELVAALGTMPSLALLDLSSNHLGPEGLRQLAMGLPGQATLQSLEELDLSMNP
  LGDGCGQSLASLLHACPLLSTLRLQACGFGPSFFLSHQTALGSAFQDAEHLKTLSLSYNA
  LGAPALARTLQSLPAGTLLHLELSSVAAGKGDSDLMEPVFRYLAKEGCALAHLTLSANHL
  GDKAVRDLCRCLSLCPSLISLDLSANPEISCASLEELLSTLQKRPQGLSFLGLSGCAVQG
  PLGLGLWDKIAAQLRELQLCSRRLCAEDRDALRQLQPSRPGPGECTLDHGSKLFFRRL
• Function: Component of the MMS22L-TONSL complex, a complex that promotes homologous recombination-mediated repair of double-strand breaks (DSBs) at stalled or collapsed replication forks. The MMS22L-TONSL complex is required to maintain genome integrity during DNA replication. It mediates the assembly of RAD51 filaments on single-stranded DNA (ssDNA): the MMS22L-TONSL complex is recruited to DSBs following histone replacement by histone chaperones and eviction of the replication protein A complex (RPA/RP-A) from DSBs. Following recruitment to DSBs, the TONSL-MMS22L complex promotes recruitment of RAD51 filaments and subsequent homologous recombination. Within the complex, TONSL acts as a histone reader, which recognizes and binds newly synthesized histones following their replacement by histone chaperones. Specifically binds histone H4 lacking methylation at 'Lys-20' (H4K20me0) and histone H3.1.
• Tissue Specificity: Expressed in heart, skeletal muscle and tracheal epithelial cells.

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cervical cancer	DISFSHPF	Strong	Biomarker	[1]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Biomarker	[3]
Spondyloepimetaphyseal dysplasia, sponastrime type	DISO1D8J	Strong	Autosomal recessive	[4]
Spondyloepimetaphyseal dysplasia, Strudwick type	DISNRAF6	Strong	Genetic Variation	[5]
Pneumococcal infection	DIS6SXQD	Limited	Genetic Variation	[6]

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 Tonsoku-like protein (TONSL).	[7]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Tonsoku-like protein (TONSL).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Tonsoku-like protein (TONSL).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Tonsoku-like protein (TONSL).	[8]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Tonsoku-like protein (TONSL).	[10]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Tonsoku-like protein (TONSL).	[11]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Tonsoku-like protein (TONSL).	[11]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Tonsoku-like protein (TONSL).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Tonsoku-like protein (TONSL).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Tonsoku-like protein (TONSL).	[14]

References

• [1] Overexpression of TONSL might be an independent unfavorable prognostic indicator in hepatocellular carcinoma.Pathol Res Pract. 2019 May;215(5):939-945. doi: 10.1016/j.prp.2019.01.044. Epub 2019 Jan 30.
• [2] A novel long non-coding RNA TONSL-AS1 regulates progression of gastric cancer via activating TONSL.Exp Cell Res. 2019 Sep 1;382(1):111453. doi: 10.1016/j.yexcr.2019.05.034. Epub 2019 May 31.
• [3] Progesterone resistance in PCOS endometrium: a microarray analysis in clomiphene citrate-treated and artificial menstrual cycles.J Clin Endocrinol Metab. 2011 Jun;96(6):1737-46. doi: 10.1210/jc.2010-2600. Epub 2011 Mar 16.
• [4] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [5] Bi-allelic Variants in TONSL Cause SPONASTRIME Dysplasia and a Spectrum of Skeletal Dysplasia Phenotypes.Am J Hum Genet. 2019 Mar 7;104(3):422-438. doi: 10.1016/j.ajhg.2019.01.007. Epub 2019 Feb 14.
• [6] Common NFKBIL2 polymorphisms and susceptibility to pneumococcal disease: a genetic association study.Crit Care. 2010;14(6):R227. doi: 10.1186/cc9377. Epub 2010 Dec 20.
• [7] 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.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] 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.
• [10] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [11] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [14] 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.
• [15] 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.