Details of Drug Off-Target (DOT)

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

• DOT Name: Mismatch repair endonuclease PMS2 (PMS2)
• Synonyms: EC 3.1.-.-; DNA mismatch repair protein PMS2; PMS1 protein homolog 2
• Gene Name: PMS2
• Related Disease:
  Lynch syndrome
  Lynch syndrome 4
  Mismatch repair cancer syndrome 1
  Adenocarcinoma
  Adenoma
  Brain neoplasm
  Carcinoma
  Clear cell renal carcinoma
  Colon cancer
  Colon carcinoma
  Colon polyp
  Colorectal neoplasm
  Endometrial cancer
  Endometrial carcinoma
  Epithelial ovarian cancer
  Fanconi anemia complementation group A
  Fanconi's anemia
  Gastric cancer
  Glioblastoma multiforme
  Glioma
  Hepatocellular carcinoma
  Hereditary breast ovarian cancer syndrome
  Hereditary neoplastic syndrome
  Lymphoma
  Lynch syndrome 1
  Malignant neoplasm
  Malignant soft tissue neoplasm
  Mismatch repair cancer syndrome 4
  Polyposis
  Primitive neuroectodermal tumor
  Prostate neoplasm
  Rectal carcinoma
  Rectal neoplasm
  Sarcoma
  Squamous cell carcinoma
  Trichohepatoenteric syndrome
  Colorectal adenocarcinoma
  Hyperinsulinemia
  Lung cancer
  Malignant pancreatic neoplasm
  Medulloblastoma
  Muir-Torre syndrome
  Ovarian cancer
  Rhabdomyosarcoma
  Hereditary breast carcinoma
  Adult glioblastoma
  Breast cancer
  Familial adenomatous polyposis
  Marinesco-Sjogren syndrome
  Ovarian neoplasm
  Prostate cancer
• UniProt ID: PMS2_HUMAN
• PDB ID: 1EA6; 1H7S; 1H7U; 5U5R; 6MFQ; 7RCB; 7RCI; 7RCK
• EC Number: 3.1.-.-
• Pfam ID: PF01119 ; PF13589 ; PF08676
• Sequence:
  MERAESSSTEPAKAIKPIDRKSVHQICSGQVVLSLSTAVKELVENSLDAGATNIDLKLKD
  YGVDLIEVSDNGCGVEEENFEGLTLKHHTSKIQEFADLTQVETFGFRGEALSSLCALSDV
  TISTCHASAKVGTRLMFDHNGKIIQKTPYPRPRGTTVSVQQLFSTLPVRHKEFQRNIKKE
  YAKMVQVLHAYCIISAGIRVSCTNQLGQGKRQPVVCTGGSPSIKENIGSVFGQKQLQSLI
  PFVQLPPSDSVCEEYGLSCSDALHNLFYISGFISQCTHGVGRSSTDRQFFFINRRPCDPA
  KVCRLVNEVYHMYNRHQYPFVVLNISVDSECVDINVTPDKRQILLQEEKLLLAVLKTSLI
  GMFDSDVNKLNVSQQPLLDVEGNLIKMHAADLEKPMVEKQDQSPSLRTGEEKKDVSISRL
  REAFSLRHTTENKPHSPKTPEPRRSPLGQKRGMLSSSTSGAISDKGVLRPQKEAVSSSHG
  PSDPTDRAEVEKDSGHGSTSVDSEGFSIPDTGSHCSSEYAASSPGDRGSQEHVDSQEKAP
  KTDDSFSDVDCHSNQEDTGCKFRVLPQPTNLATPNTKRFKKEEILSSSDICQKLVNTQDM
  SASQVDVAVKINKKVVPLDFSMSSLAKRIKQLHHEAQQSEGEQNYRKFRAKICPGENQAA
  EDELRKEISKTMFAEMEIIGQFNLGFIITKLNEDIFIVDQHATDEKYNFEMLQQHTVLQG
  QRLIAPQTLNLTAVNEAVLIENLEIFRKNGFDFVIDENAPVTERAKLISLPTSKNWTFGP
  QDVDELIFMLSDSPGVMCRPSRVKQMFASRACRKSVMIGTALNTSEMKKLITHMGEMDHP
  WNCPHGRPTMRHIANLGVISQN
• Function: Component of the post-replicative DNA mismatch repair system (MMR). Heterodimerizes with MLH1 to form MutL alpha. 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. Possesses an ATPase activity, but in the absence of gross structural changes, ATP hydrolysis may not be necessary for proficient mismatch repair.
• KEGG Pathway:
  Mismatch repair (hsa03430)
  Fanconi anemia pathway (hsa03460)
• 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)
  Mismatch repair (MMR) directed by MSH2 (R-HSA-5358565)

Molecular Interaction Atlas (MIA) of This DOT

51 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 4	DISYXI3L	Definitive	Autosomal dominant	[2]
Mismatch repair cancer syndrome 1	DISB7J1A	Definitive	Autosomal recessive	[1]
Adenocarcinoma	DIS3IHTY	Strong	Genetic Variation	[3]
Adenoma	DIS78ZEV	Strong	Biomarker	[4]
Brain neoplasm	DISY3EKS	Strong	Genetic Variation	[5]
Carcinoma	DISH9F1N	Strong	Biomarker	[6]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[7]
Colon cancer	DISVC52G	Strong	Altered Expression	[8]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[8]
Colon polyp	DIS7V594	Strong	Genetic Variation	[9]
Colorectal neoplasm	DISR1UCN	Strong	Genetic Variation	[10]
Endometrial cancer	DISW0LMR	Strong	Genetic Variation	[11]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[12]
Epithelial ovarian cancer	DIS56MH2	Strong	Genetic Variation	[13]
Fanconi anemia complementation group A	DIS8PZLI	Strong	Biomarker	[14]
Fanconi's anemia	DISGW6Q8	Strong	Biomarker	[14]
Gastric cancer	DISXGOUK	Strong	Biomarker	[15]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[16]
Glioma	DIS5RPEH	Strong	Genetic Variation	[17]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[18]
Hereditary breast ovarian cancer syndrome	DISWDUGU	Strong	Genetic Variation	[19]
Hereditary neoplastic syndrome	DISGXLG5	Strong	CausalMutation	[20]
Lymphoma	DISN6V4S	Strong	Biomarker	[21]
Lynch syndrome 1	DISSABLZ	Strong	CausalMutation	[22]
Malignant neoplasm	DISS6SNG	Strong	Genetic Variation	[23]
Malignant soft tissue neoplasm	DISTC6NO	Strong	Biomarker	[24]
Mismatch repair cancer syndrome 4	DIS6VUN8	Strong	Autosomal recessive	[25]
Polyposis	DISZSPOK	Strong	Genetic Variation	[25]
Primitive neuroectodermal tumor	DISFHXHA	Strong	Biomarker	[26]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[27]
Rectal carcinoma	DIS8FRR7	Strong	Genetic Variation	[28]
Rectal neoplasm	DISB4UZ0	Strong	Biomarker	[29]
Sarcoma	DISZDG3U	Strong	Biomarker	[24]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[30]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Biomarker	[31]
Colorectal adenocarcinoma	DISPQOUB	moderate	Biomarker	[32]
Hyperinsulinemia	DISIDWT6	moderate	Genetic Variation	[33]
Lung cancer	DISCM4YA	moderate	Genetic Variation	[34]
Malignant pancreatic neoplasm	DISH4FJX	Moderate	Autosomal dominant	[35]
Medulloblastoma	DISZD2ZL	moderate	Genetic Variation	[36]
Muir-Torre syndrome	DISKFFSW	Moderate	Autosomal recessive	[37]
Ovarian cancer	DISZJHAP	Moderate	Autosomal dominant	[37]
Rhabdomyosarcoma	DISNR7MS	Moderate	Autosomal recessive	[38]
Hereditary breast carcinoma	DISAEZT5	Disputed	Autosomal dominant	[1]
Adult glioblastoma	DISVP4LU	Limited	Biomarker	[39]
Breast cancer	DIS7DPX1	Limited	Autosomal dominant	[40]
Familial adenomatous polyposis	DISW53RE	Limited	Genetic Variation	[41]
Marinesco-Sjogren syndrome	DISKEU0B	Limited	Biomarker	[42]
Ovarian neoplasm	DISEAFTY	Limited	Genetic Variation	[13]
Prostate cancer	DISF190Y	Limited	Autosomal dominant	[40]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Mismatch repair endonuclease PMS2 (PMS2).	[43]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Mismatch repair endonuclease PMS2 (PMS2).	[44]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Mismatch repair endonuclease PMS2 (PMS2).	[45]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Mismatch repair endonuclease PMS2 (PMS2).	[44]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Mismatch repair endonuclease PMS2 (PMS2).	[46]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Mismatch repair endonuclease PMS2 (PMS2).	[47]

References

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• [23] PMS2 inactivation by a complex rearrangement involving an HERV retroelement and the inverted 100-kb duplicon on 7p22.1.Eur J Hum Genet. 2016 Nov;24(11):1598-1604. doi: 10.1038/ejhg.2016.75. Epub 2016 Jun 22.
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