Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTG5XDD8)

• DOT Name: DNA mismatch repair protein Mlh1 (MLH1)
• Synonyms: MutL protein homolog 1
• Gene Name: MLH1
• Related Disease:
  Lynch syndrome
  Lynch syndrome 2
  Mismatch repair cancer syndrome 1
  Muir-Torre syndrome
  Lynch syndrome 1
  Ovarian cancer
  Malignant pancreatic neoplasm
  Rhabdomyosarcoma
  Breast cancer
  Prostate cancer
  Hereditary breast carcinoma
• UniProt ID: MLH1_HUMAN
• PDB ID: 3RBN; 4P7A; 5U5P; 6WBA; 6WBB; 6WBC; 7M60
• Pfam ID: PF01119 ; PF13589 ; PF16413
• Sequence:
  MSFVAGVIRRLDETVVNRIAAGEVIQRPANAIKEMIENCLDAKSTSIQVIVKEGGLKLIQ
  IQDNGTGIRKEDLDIVCERFTTSKLQSFEDLASISTYGFRGEALASISHVAHVTITTKTA
  DGKCAYRASYSDGKLKAPPKPCAGNQGTQITVEDLFYNIATRRKALKNPSEEYGKILEVV
  GRYSVHNAGISFSVKKQGETVADVRTLPNASTVDNIRSIFGNAVSRELIEIGCEDKTLAF
  KMNGYISNANYSVKKCIFLLFINHRLVESTSLRKAIETVYAAYLPKNTHPFLYLSLEISP
  QNVDVNVHPTKHEVHFLHEESILERVQQHIESKLLGSNSSRMYFTQTLLPGLAGPSGEMV
  KSTTSLTSSSTSGSSDKVYAHQMVRTDSREQKLDAFLQPLSKPLSSQPQAIVTEDKTDIS
  SGRARQQDEEMLELPAPAEVAAKNQSLEGDTTKGTSEMSEKRGPTSSNPRKRHREDSDVE
  MVEDDSRKEMTAACTPRRRIINLTSVLSLQEEINEQGHEVLREMLHNHSFVGCVNPQWAL
  AQHQTKLYLLNTTKLSEELFYQILIYDFANFGVLRLSEPAPLFDLAMLALDSPESGWTEE
  DGPKEGLAEYIVEFLKKKAEMLADYFSLEIDEEGNLIGLPLLIDNYVPPLEGLPIFILRL
  ATEVNWDEEKECFESLSKECAMFYSIRKQYISEESTLSGQQSEVPGSIPNSWKWTVEHIV
  YKALRSHILPPKHFTEDGNILQLANLPDLYKVFERC
• Function: Heterodimerizes with PMS2 to form MutL alpha, a component of the post-replicative DNA mismatch repair system (MMR). DNA repair is initiated by MutS alpha (MSH2-MSH6) or MutS beta (MSH2-MSH3) binding to a dsDNA mismatch, then MutL alpha is recruited to the heteroduplex. Assembly of the MutL-MutS-heteroduplex ternary complex in presence of RFC and PCNA is sufficient to activate endonuclease activity of PMS2. It introduces single-strand breaks near the mismatch and thus generates new entry points for the exonuclease EXO1 to degrade the strand containing the mismatch. DNA methylation would prevent cleavage and therefore assure that only the newly mutated DNA strand is going to be corrected. MutL alpha (MLH1-PMS2) interacts physically with the clamp loader subunits of DNA polymerase III, suggesting that it may play a role to recruit the DNA polymerase III to the site of the MMR. Also implicated in DNA damage signaling, a process which induces cell cycle arrest and can lead to apoptosis in case of major DNA damages. Heterodimerizes with MLH3 to form MutL gamma which plays a role in meiosis.
• Tissue Specificity: Colon, lymphocytes, breast, lung, spleen, testis, prostate, thyroid, gall bladder and heart.
• KEGG Pathway:
  Platinum drug resistance (hsa01524)
  Mismatch repair (hsa03430)
  Fanconi anemia pathway (hsa03460)
  Pathways in cancer (hsa05200)
  Colorectal cancer (hsa05210)
  Endometrial cancer (hsa05213)
  Gastric cancer (hsa05226)
• Reactome Pathway:
  Mismatch repair (MMR) directed by MSH2 (R-HSA-5358606)
  Defective Mismatch Repair Associated With MLH1 (R-HSA-5545483)
  Defective Mismatch Repair Associated With PMS2 (R-HSA-5632987)
  TP53 Regulates Transcription of DNA Repair Genes (R-HSA-6796648)
  Meiotic recombination (R-HSA-912446)
  Mismatch repair (MMR) directed by MSH2 (R-HSA-5358565)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lynch syndrome	DIS3IW5F	Definitive	Autosomal dominant	[1]
Lynch syndrome 2	DISRLYU1	Definitive	Autosomal dominant	[2]
Mismatch repair cancer syndrome 1	DISB7J1A	Definitive	Autosomal recessive	[1]
Muir-Torre syndrome	DISKFFSW	Definitive	Autosomal dominant	[3]
Lynch syndrome 1	DISSABLZ	Strong	Autosomal dominant	[4]
Ovarian cancer	DISZJHAP	Strong	Autosomal dominant	[5]
Malignant pancreatic neoplasm	DISH4FJX	Moderate	Autosomal dominant	[6]
Rhabdomyosarcoma	DISNR7MS	Moderate	Autosomal recessive	[5]
Breast cancer	DIS7DPX1	Disputed	Autosomal dominant	[2]
Prostate cancer	DISF190Y	Limited	Autosomal dominant	[2]
Hereditary breast carcinoma	DISAEZT5	Refuted	Autosomal dominant	[1]

This DOT Affected the Drug Response of 6 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Temozolomide	DMKECZD	Approved	DNA mismatch repair protein Mlh1 (MLH1) affects the response to substance of Temozolomide.	[27]
Fluorouracil	DMUM7HZ	Approved	DNA mismatch repair protein Mlh1 (MLH1) increases the response to substance of Fluorouracil.	[28]
Irinotecan	DMP6SC2	Approved	DNA mismatch repair protein Mlh1 (MLH1) affects the response to substance of Irinotecan.	[29]
DTI-015	DMXZRW0	Approved	DNA mismatch repair protein Mlh1 (MLH1) affects the response to substance of DTI-015.	[27]
Floxuridine	DM04LR2	Approved	DNA mismatch repair protein Mlh1 (MLH1) decreases the response to substance of Floxuridine.	[30]
2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE	DMNQL17	Investigative	DNA mismatch repair protein Mlh1 (MLH1) affects the response to substance of 2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE.	[31]

18 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 DNA mismatch repair protein Mlh1 (MLH1).	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of DNA mismatch repair protein Mlh1 (MLH1).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of DNA mismatch repair protein Mlh1 (MLH1).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of DNA mismatch repair protein Mlh1 (MLH1).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of DNA mismatch repair protein Mlh1 (MLH1).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of DNA mismatch repair protein Mlh1 (MLH1).	[12]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of DNA mismatch repair protein Mlh1 (MLH1).	[13]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of DNA mismatch repair protein Mlh1 (MLH1).	[15]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of DNA mismatch repair protein Mlh1 (MLH1).	[16]
Gefitinib	DM15F0X	Approved	Gefitinib decreases the expression of DNA mismatch repair protein Mlh1 (MLH1).	[17]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate increases the expression of DNA mismatch repair protein Mlh1 (MLH1).	[18]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of DNA mismatch repair protein Mlh1 (MLH1).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of DNA mismatch repair protein Mlh1 (MLH1).	[20]
Arecoline	DMFJZK3	Phase 1	Arecoline decreases the expression of DNA mismatch repair protein Mlh1 (MLH1).	[21]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of DNA mismatch repair protein Mlh1 (MLH1).	[23]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride decreases the expression of DNA mismatch repair protein Mlh1 (MLH1).	[24]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of DNA mismatch repair protein Mlh1 (MLH1).	[25]
BRN-3548355	DM4KXT0	Investigative	BRN-3548355 decreases the expression of DNA mismatch repair protein Mlh1 (MLH1).	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of DNA mismatch repair protein Mlh1 (MLH1).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of DNA mismatch repair protein Mlh1 (MLH1).	[22]

References

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• [13] 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.
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• [15] Expression and promoter methylation status of mismatch repair gene hMLH1 and hMSH2 in epithelial ovarian cancer. Aust N Z J Obstet Gynaecol. 2008 Oct;48(5):505-9. doi: 10.1111/j.1479-828X.2008.00892.x.
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• [17] Identification of genes linked to gefitinib treatment in prostate cancer cell lines with or without resistance to androgen: a clue to application of gefitinib to hormone-resistant prostate cancer. Oncol Rep. 2006 Jun;15(6):1453-60.
• [18] Tea polyphenol (-)-epigallocatechin-3-gallate inhibits DNA methyltransferase and reactivates methylation-silenced genes in cancer cell lines. Cancer Res. 2003 Nov 15;63(22):7563-70.
• [19] Counteraction of Oxidative Stress by Vitamin E Affects Epigenetic Regulation by Increasing Global Methylation and Gene Expression of MLH1 and DNMT1 Dose Dependently in Caco-2 Cells. Oxid Med Cell Longev. 2018 Mar 22;2018:3734250. doi: 10.1155/2018/3734250. eCollection 2018.
• [20] Benzo[a]pyrene-induced DNA damage associated with mutagenesis in primary human activated T lymphocytes. Biochem Pharmacol. 2017 Aug 1;137:113-124.
• [21] Characterization of arecoline-induced effects on cytotoxicity in normal human gingival fibroblasts by global gene expression profiling. Toxicol Sci. 2007 Nov;100(1):66-74.
• [22] Genome-wide alteration in DNA hydroxymethylation in the sperm from bisphenol A-exposed men. PLoS One. 2017 Jun 5;12(6):e0178535. doi: 10.1371/journal.pone.0178535. eCollection 2017.
• [23] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [24] Nickel induces transcriptional down-regulation of DNA repair pathways in tumorigenic and non-tumorigenic lung cells. Carcinogenesis. 2017 Jun 1;38(6):627-637.
• [25] Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic Biol Med. 2002 Nov 15;33(10):1419-32.
• [26] The Effect of NNK, A Tobacco Smoke Carcinogen, on the miRNA and Mismatch DNA Repair Expression Profiles in Lung and Head and Neck Squamous Cancer Cells. Cells. 2020 Apr 21;9(4):1031. doi: 10.3390/cells9041031.
• [27] Carmustine-resistant cancer cells are sensitized to temozolomide as a result of enhanced mismatch repair during the development of carmustine resistance. Mol Pharmacol. 2008 Jul;74(1):82-91. doi: 10.1124/mol.107.041988. Epub 2008 Apr 22.
• [28] Decreased expression of hMLH1 correlates with reduced 5-fluorouracil-mediated apoptosis in colon cancer cells. Oncol Rep. 2007 Nov;18(5):1129-37.
• [29] Oncoprotein Bcl-2 and microsatellite instability are associated with disease-free survival and treatment response in colorectal cancer. Oncol Rep. 2008 Nov;20(5):999-1004.
• [30] Checkpoint signaling, base excision repair, and PARP promote survival of colon cancer cells treated with 5-fluorodeoxyuridine but not 5-fluorouracil. PLoS One. 2011;6(12):e28862. doi: 10.1371/journal.pone.0028862. Epub 2011 Dec 15.
• [31] Heterocyclic amine induced apoptotic response in the human lymphoblastoid cell line TK6 is linked to mismatch repair status. Mutat Res. 2001 Jul 12;486(2):155-64. doi: 10.1016/s0921-8777(01)00090-8.