Details of Drug Off-Target (DOT)

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

• DOT Name: DNA damage-regulated autophagy modulator protein 1 (DRAM1)
• Synonyms: Damage-regulated autophagy modulator
• Gene Name: DRAM1
• Related Disease:
  Acute myelogenous leukaemia
  Acute myocardial infarction
  Adult glioblastoma
  Advanced cancer
  Bone osteosarcoma
  Glioblastoma multiforme
  Hepatocellular carcinoma
  HIV infectious disease
  Mycobacterium infection
  Osteoporosis
  Osteosarcoma
  Systemic lupus erythematosus
  Breast cancer
  Breast carcinoma
  Carcinoma of liver and intrahepatic biliary tract
  High blood pressure
  Liver cancer
  Neoplasm
  Stroke
  Periodontal disease
  Periodontitis
• UniProt ID: DRAM1_HUMAN
• Pfam ID: PF10277
• Sequence:
  MLCFLRGMAFVPFLLVTWSSAAFIISYVVAVLSGHVNPFLPYISDTGTTPPESGIFGFMI
  NFSAFLGAATMYTRYKIVQKQNQTCYFSTPVFNLVSLVLGLVGCFGMGIVANFQELAVPV
  VHDGGALLAFVCGVVYTLLQSIISYKSCPQWNSLSTCHIRMVISAVSCAAVIPMIVCASL
  ISITKLEWNPREKDYVYHVVSAICEWTVAFGFIFYFLTFIQDFQSVTLRISTEINGDI
• Function: Lysosomal modulator of autophagy that plays a central role in p53/TP53-mediated apoptosis. Not involved in p73/TP73-mediated autophagy.

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[1]
Acute myocardial infarction	DISE3HTG	Strong	Altered Expression	[2]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[3]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Bone osteosarcoma	DIST1004	Strong	Altered Expression	[4]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[3]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[5]
HIV infectious disease	DISO97HC	Strong	Altered Expression	[6]
Mycobacterium infection	DISNSMUD	Strong	Biomarker	[7]
Osteoporosis	DISF2JE0	Strong	Altered Expression	[8]
Osteosarcoma	DISLQ7E2	Strong	Altered Expression	[4]
Systemic lupus erythematosus	DISI1SZ7	Strong	Genetic Variation	[9]
Breast cancer	DIS7DPX1	moderate	Genetic Variation	[10]
Breast carcinoma	DIS2UE88	moderate	Genetic Variation	[10]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	moderate	Altered Expression	[11]
High blood pressure	DISY2OHH	moderate	Genetic Variation	[12]
Liver cancer	DISDE4BI	moderate	Altered Expression	[11]
Neoplasm	DISZKGEW	moderate	Biomarker	[11]
Stroke	DISX6UHX	moderate	Biomarker	[13]
Periodontal disease	DISJQHVN	Limited	Biomarker	[14]
Periodontitis	DISI9JOI	Limited	Biomarker	[14]

2 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 DNA damage-regulated autophagy modulator protein 1 (DRAM1).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of DNA damage-regulated autophagy modulator protein 1 (DRAM1).	[36]

25 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 DNA damage-regulated autophagy modulator protein 1 (DRAM1).	[16]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of DNA damage-regulated autophagy modulator protein 1 (DRAM1).	[17]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of DNA damage-regulated autophagy modulator protein 1 (DRAM1).	[18]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of DNA damage-regulated autophagy modulator protein 1 (DRAM1).	[19]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of DNA damage-regulated autophagy modulator protein 1 (DRAM1).	[20]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of DNA damage-regulated autophagy modulator protein 1 (DRAM1).	[21]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of DNA damage-regulated autophagy modulator protein 1 (DRAM1).	[22]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of DNA damage-regulated autophagy modulator protein 1 (DRAM1).	[23]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of DNA damage-regulated autophagy modulator protein 1 (DRAM1).	[24]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of DNA damage-regulated autophagy modulator protein 1 (DRAM1).	[25]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of DNA damage-regulated autophagy modulator protein 1 (DRAM1).	[26]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of DNA damage-regulated autophagy modulator protein 1 (DRAM1).	[27]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of DNA damage-regulated autophagy modulator protein 1 (DRAM1).	[28]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of DNA damage-regulated autophagy modulator protein 1 (DRAM1).	[29]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of DNA damage-regulated autophagy modulator protein 1 (DRAM1).	[30]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of DNA damage-regulated autophagy modulator protein 1 (DRAM1).	[31]
Curcumin	DMQPH29	Phase 3	Curcumin increases the expression of DNA damage-regulated autophagy modulator protein 1 (DRAM1).	[32]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of DNA damage-regulated autophagy modulator protein 1 (DRAM1).	[16]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of DNA damage-regulated autophagy modulator protein 1 (DRAM1).	[33]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of DNA damage-regulated autophagy modulator protein 1 (DRAM1).	[34]
UNC0379	DMD1E4J	Preclinical	UNC0379 increases the expression of DNA damage-regulated autophagy modulator protein 1 (DRAM1).	[35]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of DNA damage-regulated autophagy modulator protein 1 (DRAM1).	[37]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of DNA damage-regulated autophagy modulator protein 1 (DRAM1).	[29]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of DNA damage-regulated autophagy modulator protein 1 (DRAM1).	[38]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE increases the expression of DNA damage-regulated autophagy modulator protein 1 (DRAM1).	[22]

References

• [1] miR-199a-5p Represses Protective Autophagy and Overcomes Chemoresistance by Directly Targeting DRAM1 in Acute Myeloid Leukemia.J Oncol. 2019 Sep 15;2019:5613417. doi: 10.1155/2019/5613417. eCollection 2019.
• [2] Increased expression of DRAM1 confers myocardial protection against ischemia via restoring autophagy flux.J Mol Cell Cardiol. 2018 Nov;124:70-82. doi: 10.1016/j.yjmcc.2018.08.018. Epub 2018 Aug 23.
• [3] DRAM1 regulates the migration and invasion of hepatoblastoma cells via autophagy-EMT pathway.Oncol Lett. 2018 Aug;16(2):2427-2433. doi: 10.3892/ol.2018.8937. Epub 2018 Jun 8.
• [4] Dual programmed cell death pathways induced by p53 transactivation overcome resistance to oncolytic adenovirus in human osteosarcoma cells.Mol Cancer Ther. 2013 Mar;12(3):314-25. doi: 10.1158/1535-7163.MCT-12-0869. Epub 2013 Jan 11.
• [5] Phosphorylated AKT inhibits the apoptosis induced by DRAM-mediated mitophagy in hepatocellular carcinoma by preventing the translocation of DRAM to mitochondria.Cell Death Dis. 2014 Feb 20;5(2):e1078. doi: 10.1038/cddis.2014.51.
• [6] DRAM triggers lysosomal membrane permeabilization and cell death in CD4(+) T cells infected with HIV.PLoS Pathog. 2013;9(5):e1003328. doi: 10.1371/journal.ppat.1003328. Epub 2013 May 2.
• [7] The DNA damage-regulated autophagy modulator DRAM1 links mycobacterial recognition via TLR-MYD88 to autophagic defense [corrected].Cell Host Microbe. 2014 Jun 11;15(6):753-67. doi: 10.1016/j.chom.2014.05.005.
• [8] Effect of autophagy gene DRAM on proliferation, cell cycle, apoptosis, and autophagy of osteoblast in osteoporosis rats.J Cell Physiol. 2019 Apr;234(4):5023-5032. doi: 10.1002/jcp.27304. Epub 2018 Sep 10.
• [9] Meta-analysis followed by replication identifies loci in or near CDKN1B, TET3, CD80, DRAM1, and ARID5B as associated with systemic lupus erythematosus in Asians.Am J Hum Genet. 2013 Jan 10;92(1):41-51. doi: 10.1016/j.ajhg.2012.11.018. Epub 2012 Dec 27.
• [10] Mutant p53 proteins counteract autophagic mechanism sensitizing cancer cells to mTOR inhibition.Mol Oncol. 2016 Aug;10(7):1008-29. doi: 10.1016/j.molonc.2016.04.001. Epub 2016 Apr 12.
• [11] Serum starvation induces DRAM expression in liver cancer cells via histone modifications within its promoter locus.PLoS One. 2012;7(12):e50502. doi: 10.1371/journal.pone.0050502. Epub 2012 Dec 12.
• [12] Hypertension and genetic variation in endothelial-specific genes.PLoS One. 2013 Apr 29;8(4):e62035. doi: 10.1371/journal.pone.0062035. Print 2013.
• [13] XingNaoJing, prescription of traditional Chinese medicine, prevents autophagy in experimental stroke by repressing p53-DRAM pathway.BMC Complement Altern Med. 2015 Oct 19;15:377. doi: 10.1186/s12906-015-0882-2.
• [14] Damage-regulated autophagy modulator 1 in oral inflammation and infection.Clin Oral Investig. 2018 Nov;22(8):2933-2941. doi: 10.1007/s00784-018-2381-6. Epub 2018 Feb 13.
• [15] 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.
• [16] 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.
• [17] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [18] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [19] RNA sequence analysis of inducible pluripotent stem cell-derived cardiomyocytes reveals altered expression of DNA damage and cell cycle genes in response to doxorubicin. Toxicol Appl Pharmacol. 2018 Oct 1;356:44-53.
• [20] Mechanism of cisplatin proximal tubule toxicity revealed by integrating transcriptomics, proteomics, metabolomics and biokinetics. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):117-27.
• [21] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [22] 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.
• [23] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [24] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [25] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [26] Functional gene expression profile underlying methotrexate-induced senescence in human colon cancer cells. Tumour Biol. 2011 Oct;32(5):965-76.
• [27] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [28] Apoptosis, cell cycle progression and gene expression in TP53-depleted HCT116 colon cancer cells in response to short-term 5-fluorouracil treatment. Int J Oncol. 2007 Dec;31(6):1491-500.
• [29] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [30] 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.
• [31] Up-regulation of endothelial nitric oxide synthase (eNOS), silent mating type information regulation 2 homologue 1 (SIRT1) and autophagy-related genes by repeated treatments with resveratrol in human umbilical vein endothelial cells. Br J Nutr. 2013 Dec;110(12):2150-5.
• [32] Curcumin suppresses growth of mesothelioma cells in vitro and in vivo, in part, by stimulating apoptosis. Mol Cell Biochem. 2011 Nov;357(1-2):83-94. doi: 10.1007/s11010-011-0878-2. Epub 2011 May 19.
• [33] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [34] 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.
• [35] Epigenetic siRNA and chemical screens identify SETD8 inhibition as a therapeutic strategy for p53 activation in high-risk neuroblastoma. Cancer Cell. 2017 Jan 9;31(1):50-63.
• [36] 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.
• [37] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [38] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.