Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3B204T)

• DOT Name: Activating signal cointegrator 1 complex subunit 2 (ASCC2)
• Synonyms: ASC-1 complex subunit p100; Trip4 complex subunit p100
• Gene Name: ASCC2
• Related Disease:
  OPTN-related open angle glaucoma
  Adult T-cell leukemia/lymphoma
  Advanced cancer
  Alzheimer disease
  B-cell lymphoma
  Bipolar disorder
  Bone disease
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Colitis
  Colon cancer
  Hepatitis C virus infection
  Lung cancer
  Lung carcinoma
  Multiple sclerosis
  Myelitis
  Neoplasm
  Neuromyelitis optica
  Non-insulin dependent diabetes
  Plasma cell myeloma
  Pneumonia
  Pneumonitis
  T-cell leukaemia
  Attention deficit hyperactivity disorder
  Optic neuritis
  Type-1 diabetes
  Adult lymphoma
  Anxiety
  Anxiety disorder
  Lymphoma
  Pediatric lymphoma
  Phenylketonuria
  Primary cutaneous T-cell lymphoma
  Type-1/2 diabetes
• UniProt ID: ASCC2_HUMAN
• PDB ID: 2DI0; 6YXQ
• Pfam ID: PF02845
• Sequence:
  MPALPLDQLQITHKDPKTGKLRTSPALHPEQKADRYFVLYKPPPKDNIPALVEEYLERAT
  FVANDLDWLLALPHDKFWCQVIFDETLQKCLDSYLRYVPRKFDEGVASAPEVVDMQKRLH
  RSVFLTFLRMSTHKESKDHFISPSAFGEILYNNFLFDIPKILDLCVLFGKGNSPLLQKMI
  GNIFTQQPSYYSDLDETLPTILQVFSNILQHCGLQGDGANTTPQKLEERGRLTPSDMPLL
  ELKDIVLYLCDTCTTLWAFLDIFPLACQTFQKHDFCYRLASFYEAAIPEMESAIKKRRLE
  DSKLLGDLWQRLSHSRKKLMEIFHIILNQICLLPILESSCDNIQGFIEEFLQIFSSLLQE
  KRFLRDYDALFPVAEDISLLQQASSVLDETRTAYILQAVESAWEGVDRRKATDAKDPSVI
  EEPNGEPNGVTVTAEAVSQASSHPENSEEEECMGAAAAVGPAMCGVELDSLISQVKDLLP
  DLGEGFILACLEYYHYDPEQVINNILEERLAPTLSQLDRNLDREMKPDPTPLLTSRHNVF
  QNDEFDVFSRDSVDLSRVHKGKSTRKEENTRSLLNDKRAVAAQRQRYEQYSVVVEEVPLQ
  PGESLPYHSVYYEDEYDDTYDGNQVGANDADSDDELISRRPFTIPQVLRTKVPREGQEED
  DDDEEDDADEEAPKPDHFVQDPAVLREKAEARRMAFLAKKGYRHDSSTAVAGSPRGHGQS
  RETTQERRKKEANKATRANHNRRTMADRKRSKGMIPS
• Function: Ubiquitin-binding protein involved in DNA repair and rescue of stalled ribosomes. Plays a role in DNA damage repair as component of the ASCC complex. Recruits ASCC3 and ALKBH3 to sites of DNA damage by binding to polyubiquitinated proteins that have 'Lys-63'-linked polyubiquitin chains. Part of the ASC-1 complex that enhances NF-kappa-B, SRF and AP1 transactivation. Involved in activation of the ribosome quality control (RQC) pathway, a pathway that degrades nascent peptide chains during problematic translation. Specifically recognizes and binds RPS20/uS10 ubiquitinated by ZNF598, promoting recruitment of the RQT (ribosome quality control trigger) complex on stalled ribosomes, followed by disassembly of stalled ribosomes.
• Tissue Specificity: Ubiquitous.
• Reactome Pathway: ALKBH3 mediated reversal of alkylation damage (R-HSA-112126)

Molecular Interaction Atlas (MIA) of This DOT

35 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
OPTN-related open angle glaucoma	DISDR98A	Definitive	Biomarker	[1]
Adult T-cell leukemia/lymphoma	DIS882XU	Strong	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Alzheimer disease	DISF8S70	Strong	Biomarker	[4]
B-cell lymphoma	DISIH1YQ	Strong	Biomarker	[5]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[6]
Bone disease	DISE1F82	Strong	Biomarker	[7]
Breast cancer	DIS7DPX1	Strong	Biomarker	[8]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[8]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[8]
Colitis	DISAF7DD	Strong	Genetic Variation	[9]
Colon cancer	DISVC52G	Strong	Altered Expression	[10]
Hepatitis C virus infection	DISQ0M8R	Strong	Altered Expression	[11]
Lung cancer	DISCM4YA	Strong	Altered Expression	[12]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[12]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[13]
Myelitis	DIS1KV65	Strong	Biomarker	[14]
Neoplasm	DISZKGEW	Strong	Biomarker	[12]
Neuromyelitis optica	DISBFGKL	Strong	Biomarker	[15]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[16]
Plasma cell myeloma	DIS0DFZ0	Strong	Biomarker	[17]
Pneumonia	DIS8EF3M	Strong	Altered Expression	[18]
Pneumonitis	DIS88E0K	Strong	Altered Expression	[18]
T-cell leukaemia	DISJ6YIF	Strong	Biomarker	[2]
Attention deficit hyperactivity disorder	DISL8MX9	moderate	Genetic Variation	[19]
Optic neuritis	DISDYCHC	Disputed	Biomarker	[15]
Type-1 diabetes	DIS7HLUB	Disputed	Biomarker	[20]
Adult lymphoma	DISK8IZR	Limited	Genetic Variation	[21]
Anxiety	DISIJDBA	Limited	Biomarker	[22]
Anxiety disorder	DISBI2BT	Limited	Biomarker	[22]
Lymphoma	DISN6V4S	Limited	Genetic Variation	[21]
Pediatric lymphoma	DIS51BK2	Limited	Genetic Variation	[21]
Phenylketonuria	DISCU56J	Limited	Biomarker	[23]
Primary cutaneous T-cell lymphoma	DIS35WVW	Limited	Genetic Variation	[21]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Activating signal cointegrator 1 complex subunit 2 (ASCC2).	[25]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Activating signal cointegrator 1 complex subunit 2 (ASCC2).	[26]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Activating signal cointegrator 1 complex subunit 2 (ASCC2).	[27]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Activating signal cointegrator 1 complex subunit 2 (ASCC2).	[28]
Selenium	DM25CGV	Approved	Selenium increases the expression of Activating signal cointegrator 1 complex subunit 2 (ASCC2).	[29]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Activating signal cointegrator 1 complex subunit 2 (ASCC2).	[31]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Activating signal cointegrator 1 complex subunit 2 (ASCC2).	[30]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Activating signal cointegrator 1 complex subunit 2 (ASCC2).	[32]

References

• [1] A comparative study of structural, functional and circulatory parameters in glaucoma diagnostics.PLoS One. 2018 Aug 23;13(8):e0201599. doi: 10.1371/journal.pone.0201599. eCollection 2018.
• [2] Human T-cell leukemia virus type I Tax associates with and is negatively regulated by the NF-kappa B2 p100 gene product: implications for viral latency.Mol Cell Biol. 1994 Feb;14(2):1374-82. doi: 10.1128/mcb.14.2.1374-1382.1994.
• [3] The Transitional Endoplasmic Reticulum ATPase p97 Regulates the Alternative Nuclear Factor NF-B Signaling via Partial Degradation of the NF-B Subunit p100.J Biol Chem. 2015 Aug 7;290(32):19558-68. doi: 10.1074/jbc.M114.630061. Epub 2015 Jun 25.
• [4] Electrophysiological evidence of altered facial expressions recognition in Alzheimer's disease: A comprehensive ERP study.Clin Neurophysiol. 2019 Oct;130(10):1813-1824. doi: 10.1016/j.clinph.2019.06.229. Epub 2019 Jul 12.
• [5] Molecular impact of selective NFKB1 and NFKB2 signaling on DLBCL phenotype.Oncogene. 2017 Jul 20;36(29):4224-4232. doi: 10.1038/onc.2017.90. Epub 2017 Apr 3.
• [6] Systematic review of cognitive event related potentials in euthymic bipolar disorder.Clin Neurophysiol. 2018 Sep;129(9):1854-1865. doi: 10.1016/j.clinph.2018.05.025. Epub 2018 Jun 27.
• [7] NF-kappaB p100 limits TNF-induced bone resorption in mice by a TRAF3-dependent mechanism.J Clin Invest. 2009 Oct;119(10):3024-34. doi: 10.1172/JCI38716. Epub 2009 Sep 21.
• [8] Opposing roles of Nfkb2 gene products p100 and p52 in the regulation of breast cancer stem cells. Breast Cancer Res Treat. 2017 Apr;162(3):465-477. doi: 10.1007/s10549-017-4149-0. Epub 2017 Feb 11.
• [9] Hydroalcoholic extract of Brazilian red propolis exerts protective effects on acetic acid-induced ulcerative colitis in a rodent model.Biomed Pharmacother. 2017 Jan;85:687-696. doi: 10.1016/j.biopha.2016.11.080. Epub 2016 Dec 7.
• [10] SND1, a component of RNA-induced silencing complex, is up-regulated in human colon cancers and implicated in early stage colon carcinogenesis.Cancer Res. 2007 Oct 1;67(19):9568-76. doi: 10.1158/0008-5472.CAN-06-2707.
• [11] The ribonuclease L-dependent antiviral roles of human 2',5'-oligoadenylate synthetase family members against hepatitis C virus.FEBS Lett. 2013 Jan 16;587(2):156-64. doi: 10.1016/j.febslet.2012.11.010. Epub 2012 Nov 26.
• [12] p100 functions as a metastasis activator and is targeted by tumor suppressing microRNA-320a in lung cancer.Thorac Cancer. 2018 Jan;9(1):152-158. doi: 10.1111/1759-7714.12564. Epub 2017 Nov 21.
• [13] Relationship between thiol-disulphide homeostasis and visual evoked potentials in patients with multiple sclerosis.Neurol Sci. 2019 Feb;40(2):385-391. doi: 10.1007/s10072-018-3660-3. Epub 2018 Dec 1.
• [14] Gender effect on neuromyelitis optica spectrum disorder with aquaporin4-immunoglobulin G.Mult Scler. 2017 Jul;23(8):1104-1111. doi: 10.1177/1352458516674366. Epub 2016 Oct 19.
• [15] Longitudinal optic neuritis-unrelated visual evoked potential changes in NMO spectrum disorders.Neurology. 2020 Jan 28;94(4):e407-e418. doi: 10.1212/WNL.0000000000008684. Epub 2019 Dec 3.
• [16] Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes.Nat Genet. 2018 Apr;50(4):559-571. doi: 10.1038/s41588-018-0084-1. Epub 2018 Apr 9.
• [17] The effect of marrow stromal cells on TRAF6 expression levels in myeloma cells.Oncol Lett. 2017 Aug;14(2):1464-1470. doi: 10.3892/ol.2017.6322. Epub 2017 Jun 6.
• [18] Loss of negative feedback control of nuclear factor-kappaB2 activity in lymphocytes leads to fatal lung inflammation.Am J Pathol. 2010 Jun;176(6):2646-57. doi: 10.2353/ajpath.2010.090751. Epub 2010 Apr 2.
• [19] Genetic Overlap Between Attention-Deficit/Hyperactivity Disorder and Bipolar Disorder: Evidence From Genome-wide Association Study Meta-analysis.Biol Psychiatry. 2017 Nov 1;82(9):634-641. doi: 10.1016/j.biopsych.2016.08.040. Epub 2016 Oct 18.
• [20] Neurophysiological Evidence for a Compensatory Activity during a Simple Oddball Task in Adolescents with Type 1 Diabetes Mellitus.J Diabetes Res. 2018 Jul 8;2018:8105407. doi: 10.1155/2018/8105407. eCollection 2018.
• [21] Transcriptional regulatory effects of lymphoma-associated NFKB2/lyt10 protooncogenes.Oncogene. 2000 Mar 2;19(10):1334-45. doi: 10.1038/sj.onc.1203432.
• [22] A Rodent Model of Anxiety: The Effect of Perinatal Immune Challenges on Gastrointestinal Inflammation and Integrity.Neuroimmunomodulation. 2018;25(3):163-175. doi: 10.1159/000493320. Epub 2018 Nov 9.
• [23] Effects of LC-PUFA Supplementation in Patients with Phenylketonuria: A Systematic Review of Controlled Trials.Nutrients. 2019 Jul 6;11(7):1537. doi: 10.3390/nu11071537.
• [24] Pattern Visual Evoked Potential Changes in Diabetic Patients without Retinopathy.J Ophthalmol. 2017;2017:8597629. doi: 10.1155/2017/8597629. Epub 2017 Mar 14.
• [25] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [26] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [27] 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.
• [28] 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.
• [29] 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.
• [30] 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.
• [31] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [32] 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.