Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVQ5UWX)

• DOT Name: Charged multivesicular body protein 1a (CHMP1A)
• Synonyms: Chromatin-modifying protein 1a; CHMP1a; Vacuolar protein sorting-associated protein 46-1; Vps46-1; hVps46-1
• Gene Name: CHMP1A
• Related Disease:
  Advanced cancer
  Clear cell renal carcinoma
  Fanconi anemia complementation group A
  Fanconi's anemia
  Isolated congenital microcephaly
  Kidney neoplasm
  Pancreatic tumour
  Pontocerebellar hypoplasia
  Pontocerebellar hypoplasia type 8
  Renal cell carcinoma
  Neoplasm
• UniProt ID: CHM1A_HUMAN
• PDB ID: 2JQ9; 2YMB; 4A5X
• Pfam ID: PF03357
• Sequence:
  MDDTLFQLKFTAKQLEKLAKKAEKDSKAEQAKVKKALLQKNVECARVYAENAIRKKNEGV
  NWLRMASRVDAVASKVQTAVTMKGVTKNMAQVTKALDKALSTMDLQKVSSVMDRFEQQVQ
  NLDVHTSVMEDSMSSATTLTTPQEQVDSLIMQIAEENGLEVLDQLSQLPEGASAVGESSV
  RSQEDQLSRRLAALRN
• Function: Probable peripherally associated component of the endosomal sorting required for transport complex III (ESCRT-III) which is involved in multivesicular bodies (MVBs) formation and sorting of endosomal cargo proteins into MVBs. MVBs contain intraluminal vesicles (ILVs) that are generated by invagination and scission from the limiting membrane of the endosome and mostly are delivered to lysosomes enabling degradation of membrane proteins, such as stimulated growth factor receptors, lysosomal enzymes and lipids. The MVB pathway appears to require the sequential function of ESCRT-O, -I,-II and -III complexes. ESCRT-III proteins mostly dissociate from the invaginating membrane before the ILV is released. The ESCRT machinery also functions in topologically equivalent membrane fission events, such as the terminal stages of cytokinesis and the budding of enveloped viruses (HIV-1 and other lentiviruses). ESCRT-III proteins are believed to mediate the necessary vesicle extrusion and/or membrane fission activities, possibly in conjunction with the AAA ATPase VPS4. Involved in cytokinesis. Involved in recruiting VPS4A and/or VPS4B to the midbody of dividing cells. May also be involved in chromosome condensation. Targets the Polycomb group (PcG) protein BMI1/PCGF4 to regions of condensed chromatin. May play a role in stable cell cycle progression and in PcG gene silencing.
• Tissue Specificity: Expressed in placenta, cultured skin fibroblasts and in osteoblast cell line MG-63.
• KEGG Pathway:
  Endocytosis (hsa04144)
  Necroptosis (hsa04217)
• Reactome Pathway: HCMV Late Events (R-HSA-9610379)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[2]
Fanconi anemia complementation group A	DIS8PZLI	Strong	Genetic Variation	[3]
Fanconi's anemia	DISGW6Q8	Strong	Genetic Variation	[3]
Isolated congenital microcephaly	DISUXHZ6	Strong	Genetic Variation	[4]
Kidney neoplasm	DISBNZTN	Strong	Altered Expression	[2]
Pancreatic tumour	DIS3U0LK	Strong	Altered Expression	[1]
Pontocerebellar hypoplasia	DISRICMU	Strong	Genetic Variation	[4]
Pontocerebellar hypoplasia type 8	DISUI6L0	Strong	Autosomal recessive	[5]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Limited	Biomarker	[2]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Charged multivesicular body protein 1a (CHMP1A) decreases the response to substance of Arsenic trioxide.	[15]

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 Charged multivesicular body protein 1a (CHMP1A).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Charged multivesicular body protein 1a (CHMP1A).	[12]
Glyphosate	DM0AFY7	Investigative	Glyphosate affects the methylation of Charged multivesicular body protein 1a (CHMP1A).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Charged multivesicular body protein 1a (CHMP1A).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Charged multivesicular body protein 1a (CHMP1A).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Charged multivesicular body protein 1a (CHMP1A).	[9]
Selenium	DM25CGV	Approved	Selenium increases the expression of Charged multivesicular body protein 1a (CHMP1A).	[10]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of Charged multivesicular body protein 1a (CHMP1A).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Charged multivesicular body protein 1a (CHMP1A).	[13]

References

• [1] Chmp1A functions as a novel tumor suppressor gene in human embryonic kidney and ductal pancreatic tumor cells.Cell Cycle. 2008 Sep 15;7(18):2886-93. doi: 10.4161/cc.7.18.6677. Epub 2008 Sep 26.
• [2] Chmp1A acts as a tumor suppressor gene that inhibits proliferation of renal cell carcinoma.Cancer Lett. 2012 Jun 28;319(2):190-196. doi: 10.1016/j.canlet.2012.01.010. Epub 2012 Jan 17.
• [3] Construction of a high-resolution physical and transcription map of chromosome 16q24.3: a region of frequent loss of heterozygosity in sporadic breast cancer.Genomics. 1998 May 15;50(1):1-8. doi: 10.1006/geno.1998.5316.
• [4] The ESCRT-III Protein CHMP1A Mediates Secretion of Sonic Hedgehog on a Distinctive Subtype of Extracellular Vesicles.Cell Rep. 2018 Jul 24;24(4):973-986.e8. doi: 10.1016/j.celrep.2018.06.100.
• [5] CHMP1A encodes an essential regulator of BMI1-INK4A in cerebellar development. Nat Genet. 2012 Nov;44(11):1260-4. doi: 10.1038/ng.2425. Epub 2012 Sep 30.
• [6] 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.
• [7] 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.
• [8] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [9] 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.
• [10] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [11] DNA array analysis of the effects of aspirin on colon cancer cells: involvement of Rac1. Carcinogenesis. 2004 Jul;25(7):1293-8.
• [12] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [13] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [14] Association of Glyphosate Exposure with Blood DNA Methylation in a Cross-Sectional Study of Postmenopausal Women. Environ Health Perspect. 2022 Apr;130(4):47001. doi: 10.1289/EHP10174. Epub 2022 Apr 4.
• [15] The NRF2-mediated oxidative stress response pathway is associated with tumor cell resistance to arsenic trioxide across the NCI-60 panel. BMC Med Genomics. 2010 Aug 13;3:37. doi: 10.1186/1755-8794-3-37.