Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT91PPBI)

• DOT Name: DNA mismatch repair protein Mlh3 (MLH3)
• Synonyms: MutL protein homolog 3
• Gene Name: MLH3
• Related Disease:
  Carcinoma of esophagus
  Advanced cancer
  Azoospermia
  Bladder cancer
  Breast cancer
  Breast carcinoma
  Endometrial cancer
  Endometrial carcinoma
  Friedreich ataxia 1
  Friedreich's ataxia
  Glioma
  Huntington disease
  Marinesco-Sjogren syndrome
  Obesity
  Oligospermia
  Prostate cancer
  Prostate carcinoma
  Trichohepatoenteric syndrome
  Urinary bladder cancer
  Urinary bladder neoplasm
  Cervical carcinoma
  Colonic neoplasm
  Colorectal cancer, hereditary nonpolyposis, type 7
  Colorectal neoplasm
  Human papillomavirus infection
  Lynch syndrome 1
  Lynch syndrome 2
  Male infertility
  Mismatch repair cancer syndrome
  Neoplasm
  Esophageal cancer
  Familial adenomatous polyposis
  Neoplasm of esophagus
  Polyposis
• UniProt ID: MLH3_HUMAN
• Pfam ID: PF01119 ; PF13589 ; PF08676
• Sequence:
  MIKCLSVEVQAKLRSGLAISSLGQCVEELALNSIDAEAKCVAVRVNMETFQVQVIDNGFG
  MGSDDVEKVGNRYFTSKCHSVQDLENPRFYGFRGEALANIADMASAVEISSKKNRTMKTF
  VKLFQSGKALKACEADVTRASAGTTVTVYNLFYQLPVRRKCMDPRLEFEKVRQRIEALSL
  MHPSISFSLRNDVSGSMVLQLPKTKDVCSRFCQIYGLGKSQKLREISFKYKEFELSGYIS
  SEAHYNKNMQFLFVNKRLVLRTKLHKLIDFLLRKESIICKPKNGPTSRQMNSSLRHRSTP
  ELYGIYVINVQCQFCEYDVCMEPAKTLIEFQNWDTLLFCIQEGVKMFLKQEKLFVELSGE
  DIKEFSEDNGFSLFDATLQKRVTSDERSNFQEACNNILDSYEMFNLQSKAVKRKTTAENV
  NTQSSRDSEATRKNTNDAFLYIYESGGPGHSKMTEPSLQNKDSSCSESKMLEQETIVASE
  AGENEKHKKSFLEHSSLENPCGTSLEMFLSPFQTPCHFEESGQDLEIWKESTTVNGMAAN
  ILKNNRIQNQPKRFKDATEVGCQPLPFATTLWGVHSAQTEKEKKKESSNCGRRNVFSYGR
  VKLCSTGFITHVVQNEKTKSTETEHSFKNYVRPGPTRAQETFGNRTRHSVETPDIKDLAS
  TLSKESGQLPNKKNCRTNISYGLENEPTATYTMFSAFQEGSKKSQTDCILSDTSPSFPWY
  RHVSNDSRKTDKLIGFSKPIVRKKLSLSSQLGSLEKFKRQYGKVENPLDTEVEESNGVTT
  NLSLQVEPDILLKDKNRLENSDVCKITTMEHSDSDSSCQPASHILNSEKFPFSKDEDCLE
  QQMPSLRESPMTLKELSLFNRKPLDLEKSSESLASKLSRLKGSERETQTMGMMSRFNELP
  NSDSSRKDSKLCSVLTQDFCMLFNNKHEKTENGVIPTSDSATQDNSFNKNSKTHSNSNTT
  ENCVISETPLVLPYNNSKVTGKDSDVLIRASEQQIGSLDSPSGMLMNPVEDATGDQNGIC
  FQSEESKARACSETEESNTCCSDWQRHFDVALGRMVYVNKMTGLSTFIAPTEDIQAACTK
  DLTTVAVDVVLENGSQYRCQPFRSDLVLPFLPRARAERTVMRQDNRDTVDDTVSSESLQS
  LFSEWDNPVFARYPEVAVDVSSGQAESLAVKIHNILYPYRFTKGMIHSMQVLQQVDNKFI
  ACLMSTKTEENGEAGGNLLVLVDQHAAHERIRLEQLIIDSYEKQQAQGSGRKKLLSSTLI
  PPLEITVTEEQRRLLWCYHKNLEDLGLEFVFPDTSDSLVLVGKVPLCFVEREANELRRGR
  STVTKSIVEEFIREQLELLQTTGGIQGTLPLTVQKVLASQACHGAIKFNDGLSLQESCRL
  IEALSSCQLPFQCAHGRPSMLPLADIDHLEQEKQIKPNLTKLRKMAQAWRLFGKAECDTR
  QSLQQSMPPCEPP
• Function: Probably involved in the repair of mismatches in DNA.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway: Mismatch repair (hsa03430)
• Reactome Pathway: Meiotic recombination (R-HSA-912446)

Molecular Interaction Atlas (MIA) of This DOT

34 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Carcinoma of esophagus	DISS6G4D	Definitive	Genetic Variation	[1]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[2]
Azoospermia	DIS94181	Strong	Genetic Variation	[3]
Bladder cancer	DISUHNM0	Strong	Biomarker	[4]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[5]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[5]
Endometrial cancer	DISW0LMR	Strong	Genetic Variation	[6]
Endometrial carcinoma	DISXR5CY	Strong	Genetic Variation	[6]
Friedreich ataxia 1	DIS285GE	Strong	Biomarker	[7]
Friedreich's ataxia	DIS5DV35	Strong	Altered Expression	[7]
Glioma	DIS5RPEH	Strong	Posttranslational Modification	[8]
Huntington disease	DISQPLA4	Strong	Genetic Variation	[9]
Marinesco-Sjogren syndrome	DISKEU0B	Strong	Genetic Variation	[10]
Obesity	DIS47Y1K	Strong	Biomarker	[11]
Oligospermia	DIS6YJF3	Strong	Genetic Variation	[12]
Prostate cancer	DISF190Y	Strong	Genetic Variation	[13]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[13]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Altered Expression	[14]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[4]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[4]
Cervical carcinoma	DIST4S00	moderate	Genetic Variation	[15]
Colonic neoplasm	DISSZ04P	moderate	Biomarker	[5]
Colorectal cancer, hereditary nonpolyposis, type 7	DIS9KPML	Moderate	Autosomal dominant	[16]
Colorectal neoplasm	DISR1UCN	moderate	Genetic Variation	[17]
Human papillomavirus infection	DISX61LX	moderate	Genetic Variation	[15]
Lynch syndrome 1	DISSABLZ	moderate	Biomarker	[17]
Lynch syndrome 2	DISRLYU1	moderate	Biomarker	[17]
Male infertility	DISY3YZZ	moderate	Biomarker	[18]
Mismatch repair cancer syndrome	DISIXHJ2	moderate	Genetic Variation	[19]
Neoplasm	DISZKGEW	moderate	Genetic Variation	[5]
Esophageal cancer	DISGB2VN	Limited	Genetic Variation	[1]
Familial adenomatous polyposis	DISW53RE	Limited	Genetic Variation	[20]
Neoplasm of esophagus	DISOLKAQ	Limited	Genetic Variation	[1]
Polyposis	DISZSPOK	Limited	Biomarker	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of DNA mismatch repair protein Mlh3 (MLH3).	[21]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of DNA mismatch repair protein Mlh3 (MLH3).	[22]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of DNA mismatch repair protein Mlh3 (MLH3).	[23]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of DNA mismatch repair protein Mlh3 (MLH3).	[24]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of DNA mismatch repair protein Mlh3 (MLH3).	[25]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of DNA mismatch repair protein Mlh3 (MLH3).	[24]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of DNA mismatch repair protein Mlh3 (MLH3).	[26]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of DNA mismatch repair protein Mlh3 (MLH3).	[28]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of DNA mismatch repair protein Mlh3 (MLH3).	[30]

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 DNA mismatch repair protein Mlh3 (MLH3).	[27]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of DNA mismatch repair protein Mlh3 (MLH3).	[29]

References

• [1] Mutation screening of mismatch repair gene Mlh3 in familial esophageal cancer.World J Gastroenterol. 2006 Sep 7;12(33):5281-6. doi: 10.3748/wjg.v12.i33.5281.
• [2] The first functional study of MLH3 mutations found in cancer patients.Genes Chromosomes Cancer. 2008 Sep;47(9):803-9. doi: 10.1002/gcc.20581.
• [3] The role of MSH5 C85T and MLH3 C2531T polymorphisms in the risk of male infertility with azoospermia or severe oligozoospermia.Clin Chim Acta. 2010 Jan;411(1-2):49-52. doi: 10.1016/j.cca.2009.09.038. Epub 2009 Oct 3.
• [4] Gene Expression, DNA Methylation and Prognostic Significance of DNA Repair Genes in Human Bladder Cancer.Cell Physiol Biochem. 2017;42(6):2404-2417. doi: 10.1159/000480182. Epub 2017 Aug 21.
• [5] Biallelic germline nonsense variant of MLH3 underlies polyposis predisposition.Genet Med. 2019 Aug;21(8):1868-1873. doi: 10.1038/s41436-018-0405-x. Epub 2018 Dec 21.
• [6] MLH3 mutation in endometrial cancer.Cancer Res. 2006 Aug 1;66(15):7502-8. doi: 10.1158/0008-5472.CAN-06-0248.
• [7] GAATTC repeat expansion in human cells is mediated by mismatch repair complex MutL and depends upon the endonuclease domain in MLH3 isoform one.Nucleic Acids Res. 2018 May 4;46(8):4022-4032. doi: 10.1093/nar/gky143.
• [8] Genetic and epigenetic characterization of low-grade gliomas reveals frequent methylation of the MLH3 gene.Genes Chromosomes Cancer. 2015 Nov;54(11):655-67. doi: 10.1002/gcc.22266. Epub 2015 Aug 25.
• [9] Mismatch repair genes Mlh1 and Mlh3 modify CAG instability in Huntington's disease mice: genome-wide and candidate approaches.PLoS Genet. 2013 Oct;9(10):e1003930. doi: 10.1371/journal.pgen.1003930. Epub 2013 Oct 31.
• [10] Germline and somatic mutation analyses in the DNA mismatch repair gene MLH3: Evidence for somatic mutation in colorectal cancers.Hum Mutat. 2001 May;17(5):389-96. doi: 10.1002/humu.1114.
• [11] Genome wide DNA differential methylation regions in colorectal cancer patients in relation to blood related family members, obese and non-obese controls - a preliminary report. Oncotarget. 2018 May 22;9(39):25557-25571.
• [12] Single-nucleotide polymorphism rs 175080 in the MLH3 gene and its relation to male infertility.J Assist Reprod Genet. 2015 Dec;32(12):1795-9. doi: 10.1007/s10815-015-0594-z. Epub 2015 Oct 31.
• [13] TEX15: A DNA repair gene associated with prostate cancer risk in Han Chinese.Prostate. 2017 Sep;77(12):1271-1278. doi: 10.1002/pros.23387. Epub 2017 Jul 21.
• [14] Reduced MLH3 Expression in the Syndrome of Gan-Shen Yin Deficiency in Patients with Different Diseases.Evid Based Complement Alternat Med. 2017;2017:4109828. doi: 10.1155/2017/4109828. Epub 2017 Sep 26.
• [15] Mismatch repair gene MLH3 Pro844Leu and Thr942Ile polymorphisms and the susceptibility to cervical carcinoma and HPV infection: a case-control study in a Chinese population.PLoS One. 2014 Apr 23;9(4):e96224. doi: 10.1371/journal.pone.0096224. eCollection 2014.
• [16] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [17] Biochemical characterization of MLH3 missense mutations does not reveal an apparent role of MLH3 in Lynch syndrome.Genes Chromosomes Cancer. 2009 Apr;48(4):340-50. doi: 10.1002/gcc.20644.
• [18] Embryological Results of Couples Undergoing ICSI-ET Treatments with Males Carrying the Single Nucleotide Polymorphism rs175080 of the MLH3 Gene.Int J Mol Sci. 2017 Feb 2;18(2):314. doi: 10.3390/ijms18020314.
• [19] An infant with MLH3 variants, FOXG1-duplication and multiple, benign cranial and spinal tumors: A clinical exome sequencing study.Genes Chromosomes Cancer. 2016 Feb;55(2):131-42. doi: 10.1002/gcc.22319. Epub 2015 Nov 6.
• [20] Update on genetic predisposition to colorectal cancer and polyposis.Mol Aspects Med. 2019 Oct;69:10-26. doi: 10.1016/j.mam.2019.03.001. Epub 2019 Mar 18.
• [21] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [22] 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.
• [23] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [24] 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.
• [25] 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.
• [26] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [27] 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.
• [28] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [29] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [30] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.