Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT24ZO59)

• DOT Name: Mitotic spindle assembly checkpoint protein MAD2B (MAD2L2)
• Synonyms: Mitotic arrest deficient 2-like protein 2; MAD2-like protein 2; REV7 homolog; hREV7
• Gene Name: MAD2L2
• Related Disease:
  Prostate cancer
  Prostate carcinoma
  Acute monocytic leukemia
  Acute myelogenous leukaemia
  B-cell lymphoma
  Bacillary dysentery
  Chromosomal disorder
  Colon cancer
  Colon carcinoma
  Colorectal neoplasm
  Esophageal squamous cell carcinoma
  Fanconi anemia complementation group A
  Glioma
  Haematological malignancy
  Lung cancer
  Lung carcinoma
  Myelodysplastic syndrome
  Obesity
  Pancytopenia
  Renal cell carcinoma
  Renal fibrosis
  Breast cancer
  Breast carcinoma
  Colorectal carcinoma
  Nasopharyngeal carcinoma
  Fanconi's anemia
  Neoplasm
  Epithelial ovarian cancer
  Fanconi anemia complementation group V
• UniProt ID: MD2L2_HUMAN
• PDB ID: 3ABD; 3ABE; 3VU7; 4EXT; 4GK0; 4GK5; 5XPT; 5XPU; 6BC8; 6BCD; 6BI7; 6K07; 6K08; 6KEA; 6KTO; 6M7A; 6M7B; 6NIF; 6VE5; 6WS0; 6WS5; 6WW9; 6WWA; 7L9P
• Pfam ID: PF02301
• Sequence:
  MTTLTRQDLNFGQVVADVLCEFLEVAVHLILYVREVYPVGIFQKRKKYNVPVQMSCHPEL
  NQYIQDTLHCVKPLLEKNDVEKVVVVILDKEHRPVEKFVFEITQPPLLSISSDSLLSHVE
  QLLRAFILKISVCDAVLDHNPPGCTFTVLVHTREAATRNMEKIQVIKDFPWILADEQDVH
  MHDPRLIPLKTMTSDILKMQLYVEERAHKGS
• Function: Adapter protein able to interact with different proteins and involved in different biological processes. Mediates the interaction between the error-prone DNA polymerase zeta catalytic subunit REV3L and the inserter polymerase REV1, thereby mediating the second polymerase switching in translesion DNA synthesis. Translesion DNA synthesis releases the replication blockade of replicative polymerases, stalled in presence of DNA lesions. Component of the shieldin complex, which plays an important role in repair of DNA double-stranded breaks (DSBs). During G1 and S phase of the cell cycle, the complex functions downstream of TP53BP1 to promote non-homologous end joining (NHEJ) and suppress DNA end resection. Mediates various NHEJ-dependent processes including immunoglobulin class-switch recombination, and fusion of unprotected telomeres. May also regulate another aspect of cellular response to DNA damage through regulation of the JNK-mediated phosphorylation and activation of the transcriptional activator ELK1. Inhibits the FZR1- and probably CDC20-mediated activation of the anaphase promoting complex APC thereby regulating progression through the cell cycle. Regulates TCF7L2-mediated gene transcription and may play a role in epithelial-mesenchymal transdifferentiation.
• Tissue Specificity: Ubiquitously expressed.
• KEGG Pathway:
  Cell cycle (hsa04110)
  Oocyte meiosis (hsa04114)
  Progesterone-mediated oocyte maturation (hsa04914)
  Bacterial invasion of epithelial cells (hsa05100)
• Reactome Pathway:
  Translesion synthesis by POLK (R-HSA-5655862)
  Translesion synthesis by POLI (R-HSA-5656121)
  Translesion synthesis by REV1 (R-HSA-110312)

Molecular Interaction Atlas (MIA) of This DOT

29 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Prostate cancer	DISF190Y	Definitive	Biomarker	[1]
Prostate carcinoma	DISMJPLE	Definitive	Biomarker	[1]
Acute monocytic leukemia	DIS28NEL	Strong	Biomarker	[2]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[2]
B-cell lymphoma	DISIH1YQ	Strong	Biomarker	[3]
Bacillary dysentery	DISFZHKN	Strong	Biomarker	[4]
Chromosomal disorder	DISM5BB5	Strong	Biomarker	[5]
Colon cancer	DISVC52G	Strong	Biomarker	[6]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[6]
Colorectal neoplasm	DISR1UCN	Strong	Altered Expression	[6]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[7]
Fanconi anemia complementation group A	DIS8PZLI	Strong	Altered Expression	[8]
Glioma	DIS5RPEH	Strong	Altered Expression	[9]
Haematological malignancy	DISCDP7W	Strong	Altered Expression	[3]
Lung cancer	DISCM4YA	Strong	Biomarker	[10]
Lung carcinoma	DISTR26C	Strong	Biomarker	[10]
Myelodysplastic syndrome	DISYHNUI	Strong	Biomarker	[2]
Obesity	DIS47Y1K	Strong	Biomarker	[11]
Pancytopenia	DISVKEHV	Strong	Altered Expression	[8]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[12]
Renal fibrosis	DISMHI3I	Strong	Biomarker	[13]
Breast cancer	DIS7DPX1	moderate	Biomarker	[14]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[14]
Colorectal carcinoma	DIS5PYL0	moderate	Biomarker	[15]
Nasopharyngeal carcinoma	DISAOTQ0	moderate	Altered Expression	[16]
Fanconi's anemia	DISGW6Q8	Supportive	Autosomal recessive	[8]
Neoplasm	DISZKGEW	Disputed	Biomarker	[7]
Epithelial ovarian cancer	DIS56MH2	Limited	Biomarker	[17]
Fanconi anemia complementation group V	DISH1JM2	Limited	Autosomal recessive	[18]

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 Mitotic spindle assembly checkpoint protein MAD2B (MAD2L2).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Mitotic spindle assembly checkpoint protein MAD2B (MAD2L2).	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Mitotic spindle assembly checkpoint protein MAD2B (MAD2L2).	[20]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Mitotic spindle assembly checkpoint protein MAD2B (MAD2L2).	[21]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Mitotic spindle assembly checkpoint protein MAD2B (MAD2L2).	[22]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Mitotic spindle assembly checkpoint protein MAD2B (MAD2L2).	[23]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Mitotic spindle assembly checkpoint protein MAD2B (MAD2L2).	[24]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Mitotic spindle assembly checkpoint protein MAD2B (MAD2L2).	[25]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Mitotic spindle assembly checkpoint protein MAD2B (MAD2L2).	[23]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Mitotic spindle assembly checkpoint protein MAD2B (MAD2L2).	[27]

References

• [1] DNA damage signalling barrier, oxidative stress and treatment-relevant DNA repair factor alterations during progression of human prostate cancer.Mol Oncol. 2016 Jun;10(6):879-94. doi: 10.1016/j.molonc.2016.02.005. Epub 2016 Mar 3.
• [2] Germline Genetic Predisposition to Hematologic Malignancy.J Clin Oncol. 2017 Mar 20;35(9):1018-1028. doi: 10.1200/JCO.2016.70.8644. Epub 2017 Feb 13.
• [3] High expression of REV7 is an independent prognostic indicator in patients with diffuse large B-cell lymphoma treated with rituximab.Int J Hematol. 2015 Dec;102(6):662-9. doi: 10.1007/s12185-015-1880-3. Epub 2015 Oct 8.
• [4] A bacterial effector targets Mad2L2, an APC inhibitor, to modulate host cell cycling.Cell. 2007 Aug 24;130(4):611-23. doi: 10.1016/j.cell.2007.06.043.
• [5] Expression changes of the MAD mitotic checkpoint gene family in renal cell carcinomas characterized by numerical chromosome changes.Virchows Arch. 2007 Apr;450(4):379-85. doi: 10.1007/s00428-007-0386-7. Epub 2007 Feb 28.
• [6] Expression of the mitotic checkpoint gene MAD2L2 has prognostic significance in colon cancer.Int J Cancer. 2007 Jan 1;120(1):207-11. doi: 10.1002/ijc.22155.
• [7] REV7 confers radioresistance of esophagus squamous cell carcinoma by recruiting PRDX2.Cancer Sci. 2019 Mar;110(3):962-972. doi: 10.1111/cas.13946. Epub 2019 Feb 8.
• [8] Biallelic inactivation of REV7 is associated with Fanconi anemia. J Clin Invest. 2016 Sep 1;126(9):3580-4. doi: 10.1172/JCI88010. Epub 2016 Aug 8.
• [9] Mitotic arrest deficient protein MAD2B is overexpressed in human glioma, with depletion enhancing sensitivity to ionizing radiation.J Clin Neurosci. 2011 Jun;18(6):827-33. doi: 10.1016/j.jocn.2010.11.009. Epub 2011 Apr 21.
• [10] Mitotic Arrest-Deficient Protein 2B Overexpressed in Lung Cancer Promotes Proliferation, EMT, and Metastasis.Oncol Res. 2019 Aug 8;27(8):859-869. doi: 10.3727/096504017X15049209129277. Epub 2017 Sep 11.
• [11] Visceral obesity stimulates anaphase bridge formation and spindle assembly checkpoint dysregulation in radioresistant oesophageal adenocarcinoma.Clin Transl Oncol. 2016 Jun;18(6):632-40. doi: 10.1007/s12094-015-1411-y. Epub 2015 Oct 16.
• [12] Overexpression of the mitotic checkpoint genes BUB1 and BUBR1 is associated with genomic complexity in clear cell kidney carcinomas.Cell Oncol. 2008;30(5):389-95. doi: 10.3233/clo-2008-0439.
• [13] MAD2B-mediated SnoN downregulation is implicated in fibroblast activation and tubulointerstitial fibrosis.Am J Physiol Renal Physiol. 2016 Jul 1;311(1):F207-16. doi: 10.1152/ajprenal.00600.2015. Epub 2016 Apr 27.
• [14] Knockdown of REV7 Inhibits Breast Cancer Cell Migration and Invasion.Oncol Res. 2016;24(5):315-325. doi: 10.3727/096504016X14666990347590.
• [15] MAD2L2 inhibits colorectal cancer growth by promoting NCOA3 ubiquitination and degradation.Mol Oncol. 2018 Mar;12(3):391-405. doi: 10.1002/1878-0261.12173. Epub 2018 Feb 13.
• [16] Inactivation of human MAD2B in nasopharyngeal carcinoma cells leads to chemosensitization to DNA-damaging agents.Cancer Res. 2006 Apr 15;66(8):4357-67. doi: 10.1158/0008-5472.CAN-05-3602.
• [17] Suppression of REV7 enhances cisplatin sensitivity in ovarian clear cell carcinoma cells.Cancer Sci. 2014 May;105(5):545-52. doi: 10.1111/cas.12390. Epub 2014 Apr 7.
• [18] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [19] 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.
• [20] 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.
• [21] 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.
• [22] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [23] Analysis of the in vitro synergistic effect of 5-fluorouracil and cisplatin on cervical carcinoma cells. Int J Gynecol Cancer. 2006 May-Jun;16(3):1321-9.
• [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] 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.
• [27] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.