Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJZMG1Z)

• DOT Name: MutS protein homolog 4 (MSH4)
• Synonyms: hMSH4
• Gene Name: MSH4
• Related Disease:
  Anaplastic astrocytoma
  Breast cancer
  Breast carcinoma
  Female hypogonadism
  Glioblastoma multiforme
  Premature ovarian failure 20
  Schwannoma
• UniProt ID: MSH4_HUMAN
• Pfam ID: PF05188 ; PF05192 ; PF05190 ; PF00488
• Sequence:
  MLRPEISSTSPSAPAVSPSSGETRSPQGPRYNFGLQETPQSRPSVQVVSASTCPGTSGAA
  GDRSSSSSSLPCPAPNSRPAQGSYFGNKRAYAENTVASNFTFGASSSSARDTNYPQTLKT
  PLSTGNPQRSGYKSWTPQVGYSASSSSAISAHSPSVIVAVVEGRGLARGEIGMASIDLKN
  PQIILSQFADNTTYAKVITKLKILSPLEIIMSNTACAVGNSTKLFTLITENFKNVNFTTI
  QRKYFNETKGLEYIEQLCIAEFSTVLMEVQSKYYCLAAVAALLKYVEFIQNSVYAPKSLK
  ICFQGSEQTAMIDSSSAQNLELLINNQDYRNNHTLFGVLNYTKTPGGSRRLRSNILEPLV
  DIETINMRLDCVQELLQDEELFFGLQSVISRFLDTEQLLSVLVQIPKQDTVNAAESKITN
  LIYLKHTLELVDPLKIAMKNCNTPLLRAYYGSLEDKRFGIILEKIKTVINDDARYMKGCL
  NMRTQKCYAVRSNINEFLDIARRTYTEIVDDIAGMISQLGEKYSLPLRTSFSSARGFFIQ
  MTTDCIALPSDQLPSEFIKISKVKNSYSFTSADLIKMNERCQESLREIYHMTYMIVCKLL
  SEIYEHIHCLYKLSDTVSMLDMLLSFAHACTLSDYVRPEFTDTLAIKQGWHPILEKISAE
  KPIANNTYVTEGSNFLIITGPNMSGKSTYLKQIALCQIMAQIGSYVPAEYSSFRIAKQIF
  TRISTDDDIETNSSTFMKEMKEIAYILHNANDKSLILIDELGRGTNTEEGIGICYAVCEY
  LLSLKAFTLFATHFLELCHIDALYPNVENMHFEVQHVKNTSRNKEAILYTYKLSKGLTEE
  KNYGLKAAEVSSLPPSIVLDAKEITTQITRQILQNQRSTPEMERQRAVYHLATRLVQTAR
  NSQLDPDSLRIYLSNLKKKYKEDFPRTEQVPEKTEE
• Function: Involved in meiotic recombination. Required for reciprocal recombination and proper segregation of homologous chromosomes at meiosis.
• Tissue Specificity: Highly expressed in testis . Also expressed in the ovary .
• Reactome Pathway: Meiotic recombination (R-HSA-912446)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Anaplastic astrocytoma	DISSBE0K	Strong	Genetic Variation	[1]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[2]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[2]
Female hypogonadism	DISWASB4	Strong	Genetic Variation	[3]
Glioblastoma multiforme	DISK8246	Strong	Genetic Variation	[1]
Premature ovarian failure 20	DIST1J8J	Strong	Autosomal recessive	[4]
Schwannoma	DISTTVLA	Strong	Genetic Variation	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of MutS protein homolog 4 (MSH4).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of MutS protein homolog 4 (MSH4).	[9]
Glyphosate	DM0AFY7	Investigative	Glyphosate affects the methylation of MutS protein homolog 4 (MSH4).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of MutS protein homolog 4 (MSH4).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of MutS protein homolog 4 (MSH4).	[7]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of MutS protein homolog 4 (MSH4).	[8]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of MutS protein homolog 4 (MSH4).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of MutS protein homolog 4 (MSH4).	[11]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of MutS protein homolog 4 (MSH4).	[12]

References

• [1] TP53, MSH4, and LATS1 germline mutations in a family with clustering of nervous system tumors.Am J Pathol. 2014 Sep;184(9):2374-81. doi: 10.1016/j.ajpath.2014.05.017. Epub 2014 Jul 18.
• [2] Association of common variants in mismatch repair genes and breast cancer susceptibility: a multigene study.BMC Cancer. 2009 Sep 25;9:344. doi: 10.1186/1471-2407-9-344.
• [3] A homozygous donor splice-site mutation in the meiotic gene MSH4 causes primary ovarian insufficiency. Hum Mol Genet. 2017 Aug 15;26(16):3161-3166. doi: 10.1093/hmg/ddx199.
• [4] 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.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Chronic exposure to arsenic, estrogen, and their combination causes increased growth and transformation in human prostate epithelial cells potentially by hypermethylation-mediated silencing of MLH1. Prostate. 2013 Nov;73(15):1660-72. doi: 10.1002/pros.22701. Epub 2013 Jun 26.
• [8] DNA demethylation by 5-aza-2-deoxycytidine treatment abrogates 17 beta-estradiol-induced cell growth and restores expression of DNA repair genes in human breast cancer cells. Cancer Lett. 2012 Mar;316(1):62-9. doi: 10.1016/j.canlet.2011.10.022. Epub 2011 Oct 23.
• [9] 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.
• [10] Loss of TRIM33 causes resistance to BET bromodomain inhibitors through MYC- and TGF-beta-dependent mechanisms. Proc Natl Acad Sci U S A. 2016 Aug 2;113(31):E4558-66.
• [11] Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A. Int J Mol Sci. 2022 Oct 1;23(19):11620. doi: 10.3390/ijms231911620.
• [12] Cellular reactions to long-term volatile organic compound (VOC) exposures. Sci Rep. 2016 Dec 1;6:37842. doi: 10.1038/srep37842.
• [13] 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.