Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT46FP09)

DOT Name DNA mismatch repair protein Msh6 (MSH6)
Synonyms hMSH6; G/T mismatch-binding protein; GTBP; GTMBP; MutS protein homolog 6; MutS-alpha 160 kDa subunit; p160
Gene Name MSH6
Related Disease
Astrocytoma ( )
Endometrial cancer ( )
Gaucher disease type I ( )
Lynch syndrome ( )
Lynch syndrome 5 ( )
Mismatch repair cancer syndrome 1 ( )
Mismatch repair cancer syndrome 3 ( )
Adenocarcinoma ( )
Adenoma ( )
Adult glioblastoma ( )
Bone osteosarcoma ( )
Brain neoplasm ( )
Breast neoplasm ( )
Colon adenocarcinoma ( )
Colonic neoplasm ( )
Colorectal neoplasm ( )
Deafness dystonia syndrome ( )
Endometrium neoplasm ( )
Epithelial ovarian cancer ( )
Glioblastoma multiforme ( )
Hepatocellular carcinoma ( )
Hereditary neoplastic syndrome ( )
Lung adenocarcinoma ( )
Lymphoma ( )
Marinesco-Sjogren syndrome ( )
Medulloblastoma ( )
Osteosarcoma ( )
Ovarian cancer ( )
Pediatric lymphoma ( )
Pituitary adenoma ( )
Polyposis ( )
Prostate carcinoma ( )
Rectal carcinoma ( )
Rectal neoplasm ( )
Squamous cell carcinoma ( )
Trichohepatoenteric syndrome ( )
Malignant pancreatic neoplasm ( )
Muir-Torre syndrome ( )
Neuroblastoma ( )
Rhabdomyosarcoma ( )
Stomach cancer ( )
Thyroid gland carcinoma ( )
Thyroid tumor ( )
Hereditary breast carcinoma ( )
Breast cancer ( )
Carcinoma ( )
Colorectal adenocarcinoma ( )
Familial adenomatous polyposis 2 ( )
Lynch syndrome 1 ( )
Neurofibromatosis type 1 ( )
Ovarian neoplasm ( )
Pancreatic cancer ( )
Polyp of large intestine ( )
Prostate cancer ( )
Rheumatoid arthritis ( )
Triple negative breast cancer ( )
UniProt ID
MSH6_HUMAN
3D Structure
Download
2D Sequence (FASTA)
Download
3D Structure (PDB)
Download
PDB ID
2GFU; 2O8B; 2O8C; 2O8D; 2O8E; 2O8F; 6OQM; 8AG6
Pfam ID
PF01624 ; PF05188 ; PF05192 ; PF05190 ; PF00488 ; PF00855
Sequence
MSRQSTLYSFFPKSPALSDANKASARASREGGRAAAAPGASPSPGGDAAWSEAGPGPRPL
ARSASPPKAKNLNGGLRRSVAPAAPTSCDFSPGDLVWAKMEGYPWWPCLVYNHPFDGTFI
REKGKSVRVHVQFFDDSPTRGWVSKRLLKPYTGSKSKEAQKGGHFYSAKPEILRAMQRAD
EALNKDKIKRLELAVCDEPSEPEEEEEMEVGTTYVTDKSEEDNEIESEEEVQPKTQGSRR
SSRQIKKRRVISDSESDIGGSDVEFKPDTKEEGSSDEISSGVGDSESEGLNSPVKVARKR
KRMVTGNGSLKRKSSRKETPSATKQATSISSETKNTLRAFSAPQNSESQAHVSGGGDDSS
RPTVWYHETLEWLKEEKRRDEHRRRPDHPDFDASTLYVPEDFLNSCTPGMRKWWQIKSQN
FDLVICYKVGKFYELYHMDALIGVSELGLVFMKGNWAHSGFPEIAFGRYSDSLVQKGYKV
ARVEQTETPEMMEARCRKMAHISKYDRVVRREICRIITKGTQTYSVLEGDPSENYSKYLL
SLKEKEEDSSGHTRAYGVCFVDTSLGKFFIGQFSDDRHCSRFRTLVAHYPPVQVLFEKGN
LSKETKTILKSSLSCSLQEGLIPGSQFWDASKTLRTLLEEEYFREKLSDGIGVMLPQVLK
GMTSESDSIGLTPGEKSELALSALGGCVFYLKKCLIDQELLSMANFEEYIPLDSDTVSTT
RSGAIFTKAYQRMVLDAVTLNNLEIFLNGTNGSTEGTLLERVDTCHTPFGKRLLKQWLCA
PLCNHYAINDRLDAIEDLMVVPDKISEVVELLKKLPDLERLLSKIHNVGSPLKSQNHPDS
RAIMYEETTYSKKKIIDFLSALEGFKVMCKIIGIMEEVADGFKSKILKQVISLQTKNPEG
RFPDLTVELNRWDTAFDHEKARKTGLITPKAGFDSDYDQALADIRENEQSLLEYLEKQRN
RIGCRTIVYWGIGRNRYQLEIPENFTTRNLPEEYELKSTKKGCKRYWTKTIEKKLANLIN
AEERRDVSLKDCMRRLFYNFDKNYKDWQSAVECIAVLDVLLCLANYSRGGDGPMCRPVIL
LPEDTPPFLELKGSRHPCITKTFFGDDFIPNDILIGCEEEEQENGKAYCVLVTGPNMGGK
STLMRQAGLLAVMAQMGCYVPAEVCRLTPIDRVFTRLGASDRIMSGESTFFVELSETASI
LMHATAHSLVLVDELGRGTATFDGTAIANAVVKELAETIKCRTLFSTHYHSLVEDYSQNV
AVRLGHMACMVENECEDPSQETITFLYKFIKGACPKSYGFNAARLANLPEEVIQKGHRKA
REFEKMNQSLRLFREVCLASERSTVDAEAVHKLLTLIKEL
Function
Component of the post-replicative DNA mismatch repair system (MMR). Heterodimerizes with MSH2 to form MutS alpha, which binds to DNA mismatches thereby initiating DNA repair. When bound, MutS alpha bends the DNA helix and shields approximately 20 base pairs, and recognizes single base mismatches and dinucleotide insertion-deletion loops (IDL) in the DNA. After mismatch binding, forms a ternary complex with the MutL alpha heterodimer, which is thought to be responsible for directing the downstream MMR events, including strand discrimination, excision, and resynthesis. ATP binding and hydrolysis play a pivotal role in mismatch repair functions. The ATPase activity associated with MutS alpha regulates binding similar to a molecular switch: mismatched DNA provokes ADP-->ATP exchange, resulting in a discernible conformational transition that converts MutS alpha into a sliding clamp capable of hydrolysis-independent diffusion along the DNA backbone. This transition is crucial for mismatch repair. MutS alpha may also play a role in DNA homologous recombination repair. Recruited on chromatin in G1 and early S phase via its PWWP domain that specifically binds trimethylated 'Lys-36' of histone H3 (H3K36me3): early recruitment to chromatin to be replicated allowing a quick identification of mismatch repair to initiate the DNA mismatch repair reaction.
KEGG Pathway
Platinum drug resistance (hsa01524 )
Mismatch repair (hsa03430 )
Pathways in cancer (hsa05200 )
Colorectal cancer (hsa05210 )
Reactome Pathway
Defective Mismatch Repair Associated With MSH2 (R-HSA-5632928 )
Defective Mismatch Repair Associated With MSH6 (R-HSA-5632968 )
Mismatch repair (MMR) directed by MSH2 (R-HSA-5358565 )

Molecular Interaction Atlas (MIA) of This DOT

56 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Astrocytoma DISL3V18 Definitive Biomarker [1]
Endometrial cancer DISW0LMR Definitive Autosomal dominant [2]
Gaucher disease type I DIS87KKY Definitive Genetic Variation [3]
Lynch syndrome DIS3IW5F Definitive Autosomal dominant [4]
Lynch syndrome 5 DISRISCQ Definitive Autosomal dominant [5]
Mismatch repair cancer syndrome 1 DISB7J1A Definitive Autosomal recessive [4]
Mismatch repair cancer syndrome 3 DIS8YP0M Definitive Autosomal recessive [5]
Adenocarcinoma DIS3IHTY Strong Biomarker [6]
Adenoma DIS78ZEV Strong Genetic Variation [7]
Adult glioblastoma DISVP4LU Strong Altered Expression [8]
Bone osteosarcoma DIST1004 Strong Biomarker [9]
Brain neoplasm DISY3EKS Strong Genetic Variation [10]
Breast neoplasm DISNGJLM Strong Biomarker [11]
Colon adenocarcinoma DISDRE0J Strong Genetic Variation [12]
Colonic neoplasm DISSZ04P Strong Genetic Variation [13]
Colorectal neoplasm DISR1UCN Strong Genetic Variation [14]
Deafness dystonia syndrome DIS0480U Strong Biomarker [15]
Endometrium neoplasm DIS6OS2L Strong Genetic Variation [16]
Epithelial ovarian cancer DIS56MH2 Strong Biomarker [17]
Glioblastoma multiforme DISK8246 Strong Biomarker [18]
Hepatocellular carcinoma DIS0J828 Strong Biomarker [19]
Hereditary neoplastic syndrome DISGXLG5 Strong CausalMutation [20]
Lung adenocarcinoma DISD51WR Strong Biomarker [21]
Lymphoma DISN6V4S Strong Biomarker [22]
Marinesco-Sjogren syndrome DISKEU0B Strong Altered Expression [23]
Medulloblastoma DISZD2ZL Strong Genetic Variation [24]
Osteosarcoma DISLQ7E2 Strong Biomarker [9]
Ovarian cancer DISZJHAP Strong Autosomal dominant [5]
Pediatric lymphoma DIS51BK2 Strong Genetic Variation [12]
Pituitary adenoma DISJ5R1X Strong Altered Expression [25]
Polyposis DISZSPOK Strong Genetic Variation [26]
Prostate carcinoma DISMJPLE Strong Biomarker [27]
Rectal carcinoma DIS8FRR7 Strong Biomarker [28]
Rectal neoplasm DISB4UZ0 Strong Biomarker [29]
Squamous cell carcinoma DISQVIFL Strong Biomarker [30]
Trichohepatoenteric syndrome DISL3ODF Strong Biomarker [31]
Malignant pancreatic neoplasm DISH4FJX Moderate Autosomal dominant [32]
Muir-Torre syndrome DISKFFSW Moderate Autosomal dominant [5]
Neuroblastoma DISVZBI4 moderate Biomarker [33]
Rhabdomyosarcoma DISNR7MS Moderate Autosomal recessive [5]
Stomach cancer DISKIJSX moderate Biomarker [34]
Thyroid gland carcinoma DISMNGZ0 moderate Biomarker [35]
Thyroid tumor DISLVKMD moderate Biomarker [35]
Hereditary breast carcinoma DISAEZT5 Disputed Autosomal dominant [4]
Breast cancer DIS7DPX1 Limited Autosomal dominant [36]
Carcinoma DISH9F1N Limited Biomarker [37]
Colorectal adenocarcinoma DISPQOUB Limited Genetic Variation [38]
Familial adenomatous polyposis 2 DIS62W3Y Limited Altered Expression [39]
Lynch syndrome 1 DISSABLZ Limited CausalMutation [40]
Neurofibromatosis type 1 DIS53JH9 Limited Genetic Variation [11]
Ovarian neoplasm DISEAFTY Limited Biomarker [41]
Pancreatic cancer DISJC981 Limited Genetic Variation [42]
Polyp of large intestine DISRE1MK Limited CausalMutation [43]
Prostate cancer DISF190Y Limited Autosomal dominant [36]
Rheumatoid arthritis DISTSB4J Limited Biomarker [44]
Triple negative breast cancer DISAMG6N Limited Biomarker [45]
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⏷ Show the Full List of 56 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
4 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 DNA mismatch repair protein Msh6 (MSH6). [46]
TAK-243 DM4GKV2 Phase 1 TAK-243 increases the sumoylation of DNA mismatch repair protein Msh6 (MSH6). [68]
PMID28870136-Compound-52 DMFDERP Patented PMID28870136-Compound-52 decreases the phosphorylation of DNA mismatch repair protein Msh6 (MSH6). [69]
Coumarin DM0N8ZM Investigative Coumarin increases the phosphorylation of DNA mismatch repair protein Msh6 (MSH6). [69]
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36 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Ciclosporin DMAZJFX Approved Ciclosporin decreases the expression of DNA mismatch repair protein Msh6 (MSH6). [47]
Tretinoin DM49DUI Approved Tretinoin decreases the expression of DNA mismatch repair protein Msh6 (MSH6). [48]
Acetaminophen DMUIE76 Approved Acetaminophen increases the expression of DNA mismatch repair protein Msh6 (MSH6). [49]
Doxorubicin DMVP5YE Approved Doxorubicin decreases the expression of DNA mismatch repair protein Msh6 (MSH6). [50]
Cupric Sulfate DMP0NFQ Approved Cupric Sulfate decreases the expression of DNA mismatch repair protein Msh6 (MSH6). [51]
Cisplatin DMRHGI9 Approved Cisplatin decreases the expression of DNA mismatch repair protein Msh6 (MSH6). [52]
Estradiol DMUNTE3 Approved Estradiol decreases the expression of DNA mismatch repair protein Msh6 (MSH6). [53]
Ivermectin DMDBX5F Approved Ivermectin decreases the expression of DNA mismatch repair protein Msh6 (MSH6). [54]
Quercetin DM3NC4M Approved Quercetin decreases the expression of DNA mismatch repair protein Msh6 (MSH6). [55]
Hydrogen peroxide DM1NG5W Approved Hydrogen peroxide affects the expression of DNA mismatch repair protein Msh6 (MSH6). [56]
Decitabine DMQL8XJ Approved Decitabine increases the expression of DNA mismatch repair protein Msh6 (MSH6). [53]
Phenobarbital DMXZOCG Approved Phenobarbital affects the expression of DNA mismatch repair protein Msh6 (MSH6). [57]
Menadione DMSJDTY Approved Menadione affects the expression of DNA mismatch repair protein Msh6 (MSH6). [56]
Demecolcine DMCZQGK Approved Demecolcine decreases the expression of DNA mismatch repair protein Msh6 (MSH6). [58]
Cannabidiol DM0659E Approved Cannabidiol decreases the expression of DNA mismatch repair protein Msh6 (MSH6). [59]
Bortezomib DMNO38U Approved Bortezomib decreases the expression of DNA mismatch repair protein Msh6 (MSH6). [60]
Azathioprine DMMZSXQ Approved Azathioprine decreases the expression of DNA mismatch repair protein Msh6 (MSH6). [61]
Etoposide DMNH3PG Approved Etoposide decreases the expression of DNA mismatch repair protein Msh6 (MSH6). [52]
Piroxicam DMTK234 Approved Piroxicam decreases the expression of DNA mismatch repair protein Msh6 (MSH6). [62]
Mitomycin DMH0ZJE Approved Mitomycin decreases the expression of DNA mismatch repair protein Msh6 (MSH6). [52]
Colchicine DM2POTE Approved Colchicine decreases the expression of DNA mismatch repair protein Msh6 (MSH6). [52]
Hydroxyurea DMOQVU9 Approved Hydroxyurea decreases the expression of DNA mismatch repair protein Msh6 (MSH6). [52]
Adenine DMZLHKJ Approved Adenine decreases the expression of DNA mismatch repair protein Msh6 (MSH6). [52]
Urethane DM7NSI0 Phase 4 Urethane decreases the expression of DNA mismatch repair protein Msh6 (MSH6). [63]
Resveratrol DM3RWXL Phase 3 Resveratrol decreases the expression of DNA mismatch repair protein Msh6 (MSH6). [64]
Tamibarotene DM3G74J Phase 3 Tamibarotene decreases the expression of DNA mismatch repair protein Msh6 (MSH6). [48]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene decreases the expression of DNA mismatch repair protein Msh6 (MSH6). [55]
(+)-JQ1 DM1CZSJ Phase 1 (+)-JQ1 increases the expression of DNA mismatch repair protein Msh6 (MSH6). [66]
Leflunomide DMR8ONJ Phase 1 Trial Leflunomide decreases the expression of DNA mismatch repair protein Msh6 (MSH6). [67]
Celastrol DMWQIJX Preclinical Celastrol decreases the expression of DNA mismatch repair protein Msh6 (MSH6). [70]
Bisphenol A DM2ZLD7 Investigative Bisphenol A decreases the expression of DNA mismatch repair protein Msh6 (MSH6). [71]
Formaldehyde DM7Q6M0 Investigative Formaldehyde decreases the expression of DNA mismatch repair protein Msh6 (MSH6). [58]
Coumestrol DM40TBU Investigative Coumestrol increases the expression of DNA mismatch repair protein Msh6 (MSH6). [72]
Deguelin DMXT7WG Investigative Deguelin increases the expression of DNA mismatch repair protein Msh6 (MSH6). [73]
Manganese DMKT129 Investigative Manganese decreases the expression of DNA mismatch repair protein Msh6 (MSH6). [74]
2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE DMNQL17 Investigative 2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE increases the expression of DNA mismatch repair protein Msh6 (MSH6). [75]
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⏷ Show the Full List of 36 Drug(s)
1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT
Drug Name Drug ID Highest Status Interaction REF
DNCB DMDTVYC Phase 2 DNCB affects the binding of DNA mismatch repair protein Msh6 (MSH6). [65]
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References

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2 Germline mutation of MSH6 as the cause of hereditary nonpolyposis colorectal cancer. Nat Genet. 1997 Nov;17(3):271-2. doi: 10.1038/ng1197-271.
3 Phenotype diversity in type 1 Gaucher disease: discovering the genetic basis of Gaucher disease/hematologic malignancy phenotype by individual genome analysis.Blood. 2012 May 17;119(20):4731-40. doi: 10.1182/blood-2011-10-386862. Epub 2012 Apr 4.
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6 DNA mismatch repair deficiency but not ARID1A loss is associated with prognosis in small intestinal adenocarcinoma.Hum Pathol. 2019 Mar;85:18-26. doi: 10.1016/j.humpath.2018.10.013. Epub 2018 Oct 28.
7 Yield of Lynch Syndrome Surveillance for Patients With Pathogenic Variants in DNA Mismatch Repair Genes.Clin Gastroenterol Hepatol. 2020 May;18(5):1112-1120.e1. doi: 10.1016/j.cgh.2019.08.043. Epub 2019 Aug 27.
8 Up-regulation of MSH6 is associated with temozolomide resistance in human glioblastoma.Biochem Biophys Res Commun. 2018 Feb 19;496(4):1040-1046. doi: 10.1016/j.bbrc.2018.01.093. Epub 2018 Jan 31.
9 Inhibitory effect of MSH6 gene silencing in combination with cisplatin on cell proliferation of human osteosarcoma cell line MG63.J Cell Physiol. 2019 Jun;234(6):9358-9369. doi: 10.1002/jcp.27620. Epub 2018 Nov 19.
10 A novel infram deletion in MSH6 gene in glioma: Conversation on MSH6 mutations in brain tumors.J Cell Physiol. 2019 Jul;234(7):11092-11102. doi: 10.1002/jcp.27759. Epub 2018 Nov 27.
11 Delineating a new feature of constitutional mismatch repair deficiency (CMMRD) syndrome: breast cancer.Fam Cancer. 2019 Jan;18(1):105-108. doi: 10.1007/s10689-018-0088-0.
12 Constitutional mismatch repair deficiency and childhood leukemia/lymphoma--report on a novel biallelic MSH6 mutation.Haematologica. 2010 May;95(5):841-4. doi: 10.3324/haematol.2009.015503. Epub 2009 Dec 16.
13 Recently identified colon cancer predispositions: MYH and MSH6 mutations.Semin Oncol. 2007 Oct;34(5):418-24. doi: 10.1053/j.seminoncol.2007.07.005.
14 Role of microsatellite instability-low as a diagnostic biomarker of Lynch syndrome in colorectal cancer.Cancer Genet. 2014 Oct-Dec;207(10-12):495-502. doi: 10.1016/j.cancergen.2014.10.002. Epub 2014 Oct 13.
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17 Prevalence and molecular characteristics of defective mismatch repair epithelial ovarian cancer in a Japanese hospital-based population.Jpn J Clin Oncol. 2018 Aug 1;48(8):728-735. doi: 10.1093/jjco/hyy081.
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