Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAXB34N)

• DOT Name: MMS19 nucleotide excision repair protein homolog (MMS19)
• Synonyms: hMMS19; MET18 homolog; MMS19-like protein
• Gene Name: MMS19
• Related Disease:
  Advanced cancer
  Bone osteosarcoma
  Leukopenia
  Non-small-cell lung cancer
  Osteosarcoma
  Pancreatic cancer
  Thrombocytopenia
  Epithelial ovarian cancer
  Neoplasm
  Prostate cancer
  Prostate carcinoma
  Xeroderma pigmentosum group D
• UniProt ID: MMS19_HUMAN
• Pfam ID: PF12460 ; PF14500
• Sequence:
  MAAAAAVEAAAPMGALWGLVHDFVVGQQEGPADQVAADVKSGNYTVLQVVEALGSSLENP
  EPRTRARAIQLLSQVLLHCHTLLLEKEVVHLILFYENRLKDHHLVIPSVLQGLKALSLCV
  ALPPGLAVSVLKAIFQEVHVQSLPQVDRHTVYNIITNFMRTREEELKSLGADFTFGFIQV
  MDGEKDPRNLLVAFRIVHDLISRDYSLGPFVEELFEVTSCYFPIDFTPPPNDPHGIQRED
  LILSLRAVLASTPRFAEFLLPLLIEKVDSEVLSAKLDSLQTLNACCAVYGQKELKDFLPS
  LWASIRREVFQTASERVEAEGLAALHSLTACLSRSVLRADAEDLLDSFLSNILQDCRHHL
  CEPDMKLVWPSAKLLQAAAGASARACDSVTSNVLPLLLEQFHKHSQSSQRRTILEMLLGF
  LKLQQKWSYEDKDQRPLNGFKDQLCSLVFMALTDPSTQLQLVGIRTLTVLGAQPDLLSYE
  DLELAVGHLYRLSFLKEDSQSCRVAALEASGTLAALYPVAFSSHLVPKLAEELRVGESNL
  TNGDEPTQCSRHLCCLQALSAVSTHPSIVKETLPLLLQHLWQVNRGNMVAQSSDVIAVCQ
  SLRQMAEKCQQDPESCWYFHQTAIPCLLALAVQASMPEKEPSVLRKVLLEDEVLAAMVSV
  IGTATTHLSPELAAQSVTHIVPLFLDGNVSFLPENSFPSRFQPFQDGSSGQRRLIALLMA
  FVCSLPRNVEIPQLNQLMRELLELSCCHSCPFSSTAAAKCFAGLLNKHPAGQQLDEFLQL
  AVDKVEAGLGSGPCRSQAFTLLLWVTKALVLRYHPLSSCLTARLMGLLSDPELGPAAADG
  FSLLMSDCTDVLTRAGHAEVRIMFRQRFFTDNVPALVQGFHAAPQDVKPNYLKGLSHVLN
  RLPKPVLLPELPTLLSLLLEALSCPDCVVQLSTLSCLQPLLLEAPQVMSLHVDTLVTKFL
  NLSSSPSMAVRIAALQCMHALTRLPTPVLLPYKPQVIRALAKPLDDKKRLVRKEAVSARG
  EWFLLGSPGS
• Function: Key component of the cytosolic iron-sulfur protein assembly (CIA) complex, a multiprotein complex that mediates the incorporation of iron-sulfur cluster into apoproteins specifically involved in DNA metabolism and genomic integrity. In the CIA complex, MMS19 acts as an adapter between early-acting CIA components and a subset of cellular target iron-sulfur proteins such as ERCC2/XPD, FANCJ and RTEL1, thereby playing a key role in nucleotide excision repair (NER), homologous recombination-mediated double-strand break DNA repair, DNA replication and RNA polymerase II (POL II) transcription. As part of the mitotic spindle-associated MMXD complex, plays a role in chromosome segregation, probably by facilitating iron-sulfur (Fe-S) cluster assembly into ERCC2/XPD. Together with CIAO2, facilitates the transfer of Fe-S clusters to the motor protein KIF4A, which ensures proper localization of KIF4A to mitotic machinery components to promote the progression of mitosis. Indirectly acts as a transcriptional coactivator of estrogen receptor (ER), via its role in iron-sulfur insertion into some component of the TFIIH-machinery.
• Tissue Specificity: Ubiquitously expressed with higher expression in testis.
• Reactome Pathway: Cytosolic iron-sulfur cluster assembly (R-HSA-2564830)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Bone osteosarcoma	DIST1004	Strong	Genetic Variation	[2]
Leukopenia	DISJMBMM	Strong	Biomarker	[3]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[4]
Osteosarcoma	DISLQ7E2	Strong	Genetic Variation	[2]
Pancreatic cancer	DISJC981	Strong	Genetic Variation	[5]
Thrombocytopenia	DISU61YW	Strong	Biomarker	[3]
Epithelial ovarian cancer	DIS56MH2	Limited	Genetic Variation	[6]
Neoplasm	DISZKGEW	Limited	Biomarker	[6]
Prostate cancer	DISF190Y	Limited	Biomarker	[7]
Prostate carcinoma	DISMJPLE	Limited	Biomarker	[7]
Xeroderma pigmentosum group D	DISFFE93	Limited	Biomarker	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of MMS19 nucleotide excision repair protein homolog (MMS19).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of MMS19 nucleotide excision repair protein homolog (MMS19).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of MMS19 nucleotide excision repair protein homolog (MMS19).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of MMS19 nucleotide excision repair protein homolog (MMS19).	[12]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of MMS19 nucleotide excision repair protein homolog (MMS19).	[13]
Selenium	DM25CGV	Approved	Selenium increases the expression of MMS19 nucleotide excision repair protein homolog (MMS19).	[14]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of MMS19 nucleotide excision repair protein homolog (MMS19).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of MMS19 nucleotide excision repair protein homolog (MMS19).	[16]

1 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 affects the methylation of MMS19 nucleotide excision repair protein homolog (MMS19).	[15]

References

• [1] Cytosolic Iron-Sulfur Assembly Is Evolutionarily Tuned by a Cancer-Amplified Ubiquitin Ligase.Mol Cell. 2018 Jan 4;69(1):113-125.e6. doi: 10.1016/j.molcel.2017.11.010. Epub 2017 Dec 7.
• [2] Single nucleotide polymorphisms in the NER pathway and clinical outcome of patients with bone malignant tumors.Asian Pac J Cancer Prev. 2013;14(3):2049-52. doi: 10.7314/apjcp.2013.14.3.2049.
• [3] Association between single nucleotide polymorphisms (SNPs) and toxicity of advanced non-small-cell lung cancer patients treated with chemotherapy.PLoS One. 2012;7(10):e48350. doi: 10.1371/journal.pone.0048350. Epub 2012 Oct 31.
• [4] MMS19 as a potential predictive marker of adjuvant chemotherapy benefit in resected non-small cell lung cancer.Cancer Biomark. 2016 Sep 26;17(3):323-333. doi: 10.3233/CBM-160644.
• [5] Nucleotide excision repair pathway polymorphisms and pancreatic cancer risk: evidence for role of MMS19L.Cancer Epidemiol Biomarkers Prev. 2009 Apr;18(4):1295-302. doi: 10.1158/1055-9965.EPI-08-1109. Epub 2009 Mar 24.
• [6] The role of single nucleotide polymorphisms of the ERCC1 and MMS19 genes in predicting platinum-sensitivity, progression-free and overall survival in advanced epithelial ovarian cancer.Gynecol Oncol. 2013 Aug;130(2):377-82. doi: 10.1016/j.ygyno.2013.04.054. Epub 2013 Apr 28.
• [7] Polymorphisms of DNA repair-related genes with susceptibility and prognosis of prostate cancer.Genet Mol Res. 2014 Jan 24;13(2):4419-24. doi: 10.4238/2014.January.24.20.
• [8] MMXD, a TFIIH-independent XPD-MMS19 protein complex involved in chromosome segregation.Mol Cell. 2010 Aug 27;39(4):632-40. doi: 10.1016/j.molcel.2010.07.029.
• [9] 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.
• [10] 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.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] 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.
• [13] Drinking-water arsenic exposure modulates gene expression in human lymphocytes from a U.S. population. Environ Health Perspect. 2008 Apr;116(4):524-31. doi: 10.1289/ehp.10861.
• [14] 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.
• [15] 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.
• [16] 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.