Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5ABVYX)

• DOT Name: BRCA1-associated ATM activator 1 (BRAT1)
• Synonyms: BRCA1-associated protein required for ATM activation protein 1
• Gene Name: BRAT1
• Related Disease:
  Neonatal-onset encephalopathy with rigidity and seizures
  Neurodevelopmental disorder with cerebellar atrophy and with or without seizures
  Absence epilepsy
  Cerebellar ataxia
  Epilepsy
  Epileptic encephalopathy
  Infantile epileptic-dyskinetic encephalopathy
  Inherited retinal dystrophy
  Intellectual disability
  Isolated congenital microcephaly
  Advanced cancer
• UniProt ID: BRAT1_HUMAN
• PDB ID: 4IFI
• Pfam ID: PF02985
• Sequence:
  MDPECAQLLPALCAVLVDPRQPVADDTCLEKLLDWFKTVTEGESSVVLLQEHPCLVELLS
  HVLKVQDLSSGVLSFSLRLAGTFAAQENCFQYLQQGELLPGLFGEPGPLGRATWAVPTVR
  SGWIQGLRSLAQHPSALRFLADHGAVDTIFSLQGDSSLFVASAASQLLVHVLALSMRGGA
  EGQPCLPGGDWPACAQKIMDHVEESLCSAATPKVTQALNVLTTTFGRCQSPWTEALWVRL
  SPRVACLLERDPIPAAHSFVDLLLCVARSPVFSSSDGSLWETVARALSCLGPTHMGPLAL
  GILKLEHCPQALRTQAFQVLLQPLACVLKATVQAPGPPGLLDGTADDATTVDTLLASKSS
  CAGLLCRTLAHLEELQPLPQRPSPWPQASLLGATVTVLRLCDGSAAPASSVGGHLCGTLA
  GCVRVQRAALDFLGTLSQGTGPQELVTQALAVLLECLESPGSSPTVLKKAFQATLRWLLS
  SPKTPGCSDLGPLIPQFLRELFPVLQKRLCHPCWEVRDSALEFLTQLSRHWGGQADFRCA
  LLASEVPQLALQLLQDPESYVRASAVTAMGQLSSQGLHAPTSPEHAEARQSLFLELLHIL
  SVDSEGFPRRAVMQVFTEWLRDGHADAAQDTEQFVATVLQAASRDLDWEVRAQGLELALV
  FLGQTLGPPRTHCPYAVALPEVAPAQPLTEALRALCHVGLFDFAFCALFDCDRPVAQKSC
  DLLLFLRDKIASYSSLREARGSPNTASAEATLPRWRAGEQAQPPGDQEPEAVLAMLRSLD
  LEGLRSTLAESSDHVEKSPQSLLQDMLATGGFLQGDEADCY
• Function: Involved in DNA damage response; activates kinases ATM, SMC1A and PRKDC by modulating their phosphorylation status following ionizing radiation (IR) stress. Plays a role in regulating mitochondrial function and cell proliferation. Required for protein stability of MTOR and MTOR-related proteins, and cell cycle progress by growth factors.
• Tissue Specificity: Ubiquitously expressed.

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neonatal-onset encephalopathy with rigidity and seizures	DIS8U111	Definitive	Autosomal recessive	[1]
Neurodevelopmental disorder with cerebellar atrophy and with or without seizures	DISZC8X8	Definitive	Autosomal recessive	[1]
Absence epilepsy	DISJPOUD	Strong	Genetic Variation	[2]
Cerebellar ataxia	DIS9IRAV	Strong	Genetic Variation	[3]
Epilepsy	DISBB28L	Strong	Biomarker	[4]
Epileptic encephalopathy	DISZOCA3	Strong	Genetic Variation	[5]
Infantile epileptic-dyskinetic encephalopathy	DISD2ZNC	Strong	Genetic Variation	[5]
Inherited retinal dystrophy	DISGGL77	Strong	Genetic Variation	[3]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[3]
Isolated congenital microcephaly	DISUXHZ6	Strong	Genetic Variation	[2]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[6]

5 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 BRCA1-associated ATM activator 1 (BRAT1).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of BRCA1-associated ATM activator 1 (BRAT1).	[13]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of BRCA1-associated ATM activator 1 (BRAT1).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of BRCA1-associated ATM activator 1 (BRAT1).	[15]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of BRCA1-associated ATM activator 1 (BRAT1).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of BRCA1-associated ATM activator 1 (BRAT1).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of BRCA1-associated ATM activator 1 (BRAT1).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of BRCA1-associated ATM activator 1 (BRAT1).	[10]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of BRCA1-associated ATM activator 1 (BRAT1).	[11]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of BRCA1-associated ATM activator 1 (BRAT1).	[12]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] BRAT1-related disease--identification of a patient without early lethality.Am J Med Genet A. 2016 Mar;170(3):699-702. doi: 10.1002/ajmg.a.37434. Epub 2015 Oct 22.
• [3] Inner retinal dystrophy in a patient with biallelic sequence variants in BRAT1.Ophthalmic Genet. 2017 Dec;38(6):559-561. doi: 10.1080/13816810.2017.1290118. Epub 2017 Mar 2.
• [4] Early-Onset Severe Encephalopathy with Epilepsy: The BRAT1 Gene Should Be Added to the List of Causes.Neuropediatrics. 2015 Dec;46(6):392-400. doi: 10.1055/s-0035-1564791. Epub 2015 Nov 4.
• [5] Compound heterozygous BRAT1 mutations cause familial Ohtahara syndrome with hypertonia and microcephaly.J Hum Genet. 2014 Dec;59(12):687-90. doi: 10.1038/jhg.2014.91. Epub 2014 Oct 16.
• [6] BRAT1 deficiency causes increased glucose metabolism and mitochondrial malfunction.BMC Cancer. 2014 Jul 29;14:548. doi: 10.1186/1471-2407-14-548.
• [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] 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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [11] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] 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.
• [14] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [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.
• [16] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.