Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTI8ABKF)

• DOT Name: ATPase family AAA domain-containing protein 5 (ATAD5)
• Synonyms: Chromosome fragility-associated gene 1 protein
• Gene Name: ATAD5
• Related Disease:
  Advanced cancer
  Beckwith-Wiedemann syndrome
  Bone osteosarcoma
  Breast carcinoma
  Epithelial ovarian cancer
  Fanconi anemia complementation group A
  Fanconi's anemia
  Hepatocellular carcinoma
  Malignant peripheral nerve sheath tumor
  Neoplasm
  Osteosarcoma
  Ovarian cancer
  Ovarian neoplasm
  Plexiform neurofibroma
  Triple negative breast cancer
  Neurofibromatosis
  Neurofibromatosis type 1
• UniProt ID: ATAD5_HUMAN
• Pfam ID: PF00004
• Sequence:
  MVGVLAMAAAAAPPPVKDCEIEPCKKRKKDDDTSTCKTITKYLSPLGKTRDRVFAPPKPS
  NILDYFRKTSPTNEKTQLGKECKIKSPESVPVDSNKDCTTPLEMFSNVEFKKKRKRVNLS
  HQLNNIKTENEAPIEISSDDSKEDYSLNNDFVESSTSVLRYKKQVEVLAENIQDTKSQPN
  TMTSLQNSKKVNPKQGTTKNDFKKLRKRKCRDVVDLSESLPLAEELNLLKKDGKDTKQME
  NTTSHANSRDNVTEAAQLNDSIITVSYEEFLKSHKENKVEEIPDSTMSICVPSETVDEIV
  KSGYISESENSEISQQVRFKTVTVLAQVHPIPPKKTGKIPRIFLKQKQFEMENSLSDPEN
  EQTVQKRKSNVVIQEEELELAVLEAGSSEAVKPKCTLEERQQFMKAFRQPASDALKNGVK
  KSSDKQKDLNEKCLYEVGRDDNSKKIMENSGIQMVSKNGNLQLHTDKGSFLKEKNKKLKK
  KNKKTLDTGAIPGKNREGNTQKKETTFFLKEKQYQNRMSLRQRKTEFFKSSTLFNNESLV
  YEDIANDDLLKVSSLCNNNKLSRKTSIPVKDIKLTQSKAESEASLLNVSTPKSTRRSGRI
  SSTPTTETIRGIDSDDVQDNSQLKASTQKAANLSEKHSLYTAELITVPFDSESPIRMKFT
  RISTPKKSKKKSNKRSEKSEATDGGFTSQIRKASNTSKNISKAKQLIEKAKALHISRSKV
  TEEIAIPLRRSSRHQTLPERKKLSETEDSVIIIDSSPTALKHPEKNQKKLQCLNDVLGKK
  LNTSTKNVPGKMKVAPLFLVRKAQKAADPVPSFDESSQDTSEKSQDCDVQCKAKRDFLMS
  GLPDLLKRQIAKKAAALDVYNAVSTSFQRVVHVQQKDDGCCLWHLKPPSCPLLTKFKELN
  TKVIDLSKCGIALGEFSTLNSKLKSGNSAAVFMRTRKEFTEEVRNLLLEEIRWSNPEFSL
  KKYFPLLLKKQIEHQVLSSECHSKQELEADVSHKETKRKLVEAENSKSKRKKPNEYSKNL
  EKTNRKSEELSKRNNSSGIKLDSSKDSGTEDMLWTEKYQPQTASELIGNELAIKKLHSWL
  KDWKRRAELEERQNLKGKRDEKHEDFSGGIDFKGSSDDEEESRLCNTVLITGPTGVGKTA
  AVYACAQELGFKIFEVNASSQRSGRQILSQLKEATQSHQVDKQGVNSQKPCFFNSYYIGK
  SPKKISSPKKVVTSPRKVPPPSPKSSGPKRALPPKTLANYFKVSPKPKNNEEIGMLLENN
  KGIKNSFEQKQITQTKSTNATNSNVKDVGAEEPSRKNATSLILFEEVDVIFDEDAGFLNA
  IKTFMATTKRPVILTTSDPTFSLMFDGCFEEIKFSTPSLLNVASYLQMICLTENFRTDVK
  DFVTLLTANTCDIRKSILYLQFWIRSGGGVLEERPLTLYRGNSRNVQLVCSEHGLDNKIY
  PKNTKKKRVDLPKCDSGCAETLFGLKNIFSPSEDLFSFLKHKITMKEEWHKFIQLLTEFQ
  MRNVDFLYSNLEFILPLPVDTIPETKNFCGPSVTVDASAATKSMNCLARKHSEREQPLKK
  SQKKKQKKTLVILDDSDLFDTDLDFPDQSISLSSVSSSSNAEESKTGDEESKARDKGNNP
  ETKKSIPCPPKTTAGKKCSALVSHCLNSLSEFMDNMSFLDALLTDVREQNKYGRNDFSWT
  NGKVTSGLCDEFSLESNDGWTSQSSGELKAAAEALSFTKCSSAISKALETLNSCKKLGRD
  PTNDLTFYVSQKRNNVYFSQSAANLDNAWKRISVIKSVFSSRSLLYVGNRQASIIEYLPT
  LRNICKTEKLKEQGKSKRRFLHYFEGIHLDIPKETVNTLAADFP
• Function: Has an important role in DNA replication and in maintaining genome integrity during replication stress. Involved in a RAD9A-related damage checkpoint, a pathway that is important in determining whether DNA damage is compatible with cell survival or whether it requires cell elimination by apoptosis. Modulates the RAD9A interaction with BCL2 and thereby induces DNA damage-induced apoptosis. Promotes PCNA deubiquitination by recruiting the ubiquitin-specific protease 1 (USP1) and WDR48 thereby down-regulating the error-prone damage bypass pathway. As component of the ATAD5 RFC-like complex, regulates the function of the DNA polymerase processivity factor PCNA by unloading the ring-shaped PCNA homotrimer from DNA after replication during the S phase of the cell cycle. This seems to be dependent on its ATPase activity. Plays important roles in restarting stalled replication forks under replication stress, by unloading the PCNA homotrimer from DNA and recruiting RAD51 possibly through an ATR-dependent manner. Ultimately this enables replication fork regression, breakage, and eventual fork restart. Both the PCNA unloading activity and the interaction with WDR48 are required to efficiently recruit RAD51 to stalled replication forks. Promotes the generation of MUS81-mediated single-stranded DNA-associated breaks in response to replication stress, which is an alternative pathway to restart stalled/regressed replication forks.

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[1]
Beckwith-Wiedemann syndrome	DISH15GR	Strong	Biomarker	[2]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[3]
Epithelial ovarian cancer	DIS56MH2	Strong	Genetic Variation	[4]
Fanconi anemia complementation group A	DIS8PZLI	Strong	Biomarker	[5]
Fanconi's anemia	DISGW6Q8	Strong	Biomarker	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[6]
Malignant peripheral nerve sheath tumor	DIS0JTN6	Strong	Biomarker	[7]
Neoplasm	DISZKGEW	Strong	Biomarker	[5]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[2]
Ovarian cancer	DISZJHAP	Strong	Genetic Variation	[4]
Ovarian neoplasm	DISEAFTY	Strong	Genetic Variation	[8]
Plexiform neurofibroma	DISW4XX7	Strong	Biomarker	[7]
Triple negative breast cancer	DISAMG6N	Strong	Genetic Variation	[4]
Neurofibromatosis	DIS5N2R6	moderate	Biomarker	[5]
Neurofibromatosis type 1	DIS53JH9	moderate	Biomarker	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of ATPase family AAA domain-containing protein 5 (ATAD5).	[9]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of ATPase family AAA domain-containing protein 5 (ATAD5).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of ATPase family AAA domain-containing protein 5 (ATAD5).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of ATPase family AAA domain-containing protein 5 (ATAD5).	[12]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of ATPase family AAA domain-containing protein 5 (ATAD5).	[13]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of ATPase family AAA domain-containing protein 5 (ATAD5).	[13]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of ATPase family AAA domain-containing protein 5 (ATAD5).	[14]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of ATPase family AAA domain-containing protein 5 (ATAD5).	[15]
PEITC	DMOMN31	Phase 2	PEITC decreases the expression of ATPase family AAA domain-containing protein 5 (ATAD5).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of ATPase family AAA domain-containing protein 5 (ATAD5).	[17]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of ATPase family AAA domain-containing protein 5 (ATAD5).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of ATPase family AAA domain-containing protein 5 (ATAD5).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of ATPase family AAA domain-containing protein 5 (ATAD5).	[22]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of ATPase family AAA domain-containing protein 5 (ATAD5).	[23]
Paraquat	DMR8O3X	Investigative	Paraquat decreases the expression of ATPase family AAA domain-containing protein 5 (ATAD5).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of ATPase family AAA domain-containing protein 5 (ATAD5).	[19]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of ATPase family AAA domain-containing protein 5 (ATAD5).	[21]

References

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• [4] Rare ATAD5 missense variants in breast and ovarian cancer patients.Cancer Lett. 2016 Jun 28;376(1):173-7. doi: 10.1016/j.canlet.2016.03.048. Epub 2016 Apr 1.
• [5] Elg1, a central player in genome stability.Mutat Res Rev Mutat Res. 2015 Jan-Mar;763:267-79. doi: 10.1016/j.mrrev.2014.11.007. Epub 2014 Nov 24.
• [6] Hepatitis B Virus X Protein Upregulates hELG1/ ATAD5 Expression through E2F1 in Hepatocellular Carcinoma.Int J Biol Sci. 2016 Jan 1;12(1):30-41. doi: 10.7150/ijbs.12310. eCollection 2016.
• [7] Identification of genes potentially involved in the increased risk of malignancy in NF1-microdeleted patients.Mol Med. 2011 Jan-Feb;17(1-2):79-87. doi: 10.2119/molmed.2010.00079. Epub 2010 Sep 10.
• [8] Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.Nat Genet. 2017 May;49(5):680-691. doi: 10.1038/ng.3826. Epub 2017 Mar 27.
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• [10] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [11] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [12] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [13] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [14] Cannabidiol enhances cytotoxicity of anti-cancer drugs in human head and neck squamous cell carcinoma. Sci Rep. 2020 Nov 26;10(1):20622. doi: 10.1038/s41598-020-77674-y.
• [15] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [16] Phenethyl isothiocyanate alters the gene expression and the levels of protein associated with cell cycle regulation in human glioblastoma GBM 8401 cells. Environ Toxicol. 2017 Jan;32(1):176-187.
• [17] 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.
• [18] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [19] 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.
• [20] 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.
• [21] 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.
• [22] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [23] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [24] CD34+ derived macrophage and dendritic cells display differential responses to paraquat. Toxicol In Vitro. 2021 Sep;75:105198. doi: 10.1016/j.tiv.2021.105198. Epub 2021 Jun 9.