Open Access Articles- Top Results for PMS2


External IDsOMIM600259 MGI104288 HomoloGene133560 GeneCards: PMS2 Gene
RNA expression pattern
File:PBB GE PMS2 209805 at tn.png
More reference expression data
RefSeq (mRNA)NM_000535NM_008886
RefSeq (protein)NP_000526NP_032912
Location (UCSC)Chr 7:
6.01 – 6.05 Mb
Chr 5:
143.91 – 143.94 Mb
PubMed search[1][2]

Mismatch repair endonuclease PMS2 is an enzyme that in humans is encoded by the PMS2 gene.[1]


This gene is one of the PMS2 gene family members which are found in clusters on chromosome 7. Human PMS2 related genes are located at bands 7p12, 7p13, 7q11, and 7q22. Exons 1 through 5 of these homologues share high degree of identity to human PMS2 [2] The product of this gene is involved in DNA mismatch repair. The protein forms a heterodimer with MLH1 and this complex interacts with MSH2 bound to mismatched bases. Defects in this gene are associated with hereditary nonpolyposis colorectal cancer, with Turcot syndrome, and are a cause of supratentorial primitive neuroectodermal tumors. Alternatively spliced transcript variants have been observed.[3]

Mismatch repair and endonuclease activity

PMS2 is involved in mismatch repair and is known to have latent endonuclease activity that depends on the integrity of the meta-binding motif in MutL homologs. As an endonuclease, PMS2 introduces nicks into a discontinous DNA strand.[4]


PMS2 is a gene that encodes for DNA repair proteins involved in mismatch repair. The PMS2 gene is located on chromosome 7p22 and it consists of 15 exons. Exon 11 of the PMS2 gene has a coding repeat of eight adenosines.[5]

Heterozygous germline mutations in DNA mismatch repair genes like PMS2 lead to autosomal dominant Lynch syndrome. Only 2% of families that have Lynch syndrome have mutations in the PMS2 gene.[6] The age of patients when they first presented with PMS2-associated Lynch syndrome varies greatly, with a reported range of 23 to 77 years.[7]

In rare cases, a homozygous defect may cause this syndrome. In such cases a child inherits the gene mutation from both parents and the condition is called Turcot syndrome or Constitutional MMR Deficiency (CMMR-D).[8] Up until 2011, 36 patients with brain tumors due to biallelic PMS2 germline mutations have been reported.[8] Inheritance of Turcot syndrome can be dominant or recessive. Recessive inheritance of Turcot syndrome is caused by compound heterozygous mutations in PMS2.[9] 31 out of 57 families reported with CMMR-D have germline PMS2 mutations.[10] 19 out of 60 PMS2 homozygous or compound heterozygous mutation carriers had gastrointestinal cancer or adenomas as the first manifestation of CMMR-D.[10] Presence of pseudogenes can cause confusion when identifying mutations in PMS2, leading to false positive conclusions of the presence of mutated PMS2.[5]

Deficiency and overexpression

Overexpression of PMS2 results in hypermutability and DNA damage tolerance.[11] Deficiency of PMS2 also contributes to genetic instability by allowing for mutations to propagate due to reduced MMR function.[11] It has been shown that PMS2-/- mice developed lymphomas and sarcomas. It was also shown that male mice that are PMS2-/- are sterile, indicating that PMS2 may have a role in spermatogenesis.[4]


PMS2 has been shown to interact with MLH1 by forming the heterodimer MutLα.[12][13][14][15][16][17] There is competition between MLH3, PMS1, and PMS2 for the interacting domain on MLH1, which is located in residues 492-742.[13]

The interacting domains in PMS2 have heptad repeats that are characteristic of leucine zipper proteins.[13] MLH1 interacts with PMS2 at residues 506-756.[14]

The MutS heterodimers, MutSα and MutSβ, associate with MutLα upon mismatch binding. MutLα is believed to join the mismatch recognition step to other processes, including: removal of mismatches from the new DNA strand, resynthesis of the degraded DNA, and repair of the nick in the DNA.[17] MutLα is shown to have weak ATPase activity and also possesses endonuclease activity that introduces nicks into the discontinuous strand of DNA. This facilitates 5' to 3' degradation of the mismatched DNA strand by EXO1.[17] The active site of MutLα is located on the PMS2 subunit. PMS1 and PMS2 compete for interaction with MLH1.[17] Cannavo et al. list some of the proteins in the interactome of PMS2 identified by tandem affinity purification.[17][18]

Human PMS2 is expressed at very low levels and is not believed to be strongly cell cycle regulated.[19]

Interactions involving p53 and p73

PMS2 has also been shown to interact with p53 and p73. In the absence of p53, PMS2-deficient and PMS2-proficient cells are still capable of arresting the cell cycle at the G2/M checkpoint when treated with cisplatin.[20] Cells that are deficient in p53 and PMS2, exhibit increased sensitivity to anticancer agents. PMS2 is a protective mediator of cell survival in p53-deficient cells and modulates protective DNA damage response pathways independently of p53.[20] PMS2 and MLH1 can protect cells from cell death by counteracting p73-mediated apoptosis in a mismatch repair dependent manner.[20]

PMS2 can interact with p73 to enhance cisplatin-induced apoptosis by stabilizing p73. Cisplatin stimulates the interaction between PMS2 and p73, which is dependent on c-Abl.[16] The MutLα complex may function as an adapter to bring p73 to the site of damaged DNA and also act as an activator of p73, due to the presence of PMS2.[16] It may also be possibly for overexpressed PMS2 to stimulate apoptosis in the absence of MLH1 and in the presence of p73 and cisplatin due to the stabilizing actions of PMS2 on p73.[16] Upon DNA damage, p53 induces cell cycle arrest through the p21/WAF pathway and initiates repair by expression of MLH1 and PMS2.[15] The MSH1/PMS2 complex acts as a sensor of the extent of the damage to the DNA, and initiates apoptosis by stabilizing p73 if the damage is beyond repair.[15] Loss of PMS2 does not always lead to instability of MLH1 since it can also form complexes with MLH3 and PMS1.[21]


  1. Nicolaides NC, Papadopoulos N, Liu B, Wei YF, Carter KC, Ruben SM et al. (Sep 1994). "Mutations of two PMS homologues in hereditary nonpolyposis colon cancer". Nature 371 (6492): 75–80. PMID 8072530. doi:10.1038/371075a0. 
  2. Nicolaides NC, Carter KC, Shell BK, Papadopoulos N, Vogelstein B, Kinzler KW (November 1995). "Genomic organization of the human PMS2 gene family". Genomics 30 (2): 195–206. PMID 8586419. doi:10.1006/geno.1995.9885. 
  3. "Entrez Gene: PMS2 PMS2 postmeiotic segregation increased 2 (S. cerevisiae)". 
  4. 4.0 4.1 van Oers JM, Roa S, Werling U, Liu Y, Genschel J, Hou H et al. (12 July 2010). "PMS2 endonuclease activity has distinct biological functions and is essential for genome maintenance". Proc. Natl. Acad. Sci. U.S.A. 107 (30): 13384–9. PMID 20624957. doi:10.1073/pnas.1008589107. 
  5. 5.0 5.1 Chadwick RB, Meek JE, Prior TW, Peltomaki P, de La Chapelle A (December 2000). "Polymorphisms in a pseudogene highly homologous to PMS2". Hum. Mutat. 16 (6): 530. PMID 11102987. doi:10.1002/1098-1004(200012)16:6<530::AID-HUMU15>3.0.CO;2-6. 
  6. "PMS2 - PMS2 postmeiotic segregation increased 2 (S. cerevisiae)". Genetics Home Reference. U.S. National Library of Medicine. 
  7. Senter L, Clendenning M, Sotamaa K, Hampel H, Green J, Potter JD et al. (August 2008). "The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations". Gastroenterology 135 (2): 419–28. PMC 2759321. PMID 18602922. doi:10.1053/j.gastro.2008.04.026. 
  8. 8.0 8.1 Johannesma PC, van der Klift HM, van Grieken NC, Troost D, Te Riele H, Jacobs MA et al. (September 2011). "Childhood brain tumours due to germline bi-allelic mismatch repair gene mutations". Clin. Genet. 80 (3): 243–55. PMID 21261604. doi:10.1111/j.1399-0004.2011.01635.x. 
  9. De Rosa M, Fasano C, Panariello L, Scarano MI, Belli G, Iannelli A et al. (March 2000). "Evidence for a recessive inheritance of Turcot's syndrome caused by compound heterozygous mutations within the PMS2 gene". Oncogene 19 (13): 1719–23. PMID 10763829. doi:10.1038/sj.onc.1203447. 
  10. 10.0 10.1 Herkert JC, Niessen RC, Olderode-Berends MJ, Veenstra-Knol HE, Vos YJ, van der Klift HM et al. (May 2011). "Paediatric intestinal cancer and polyposis due to bi-allelic PMS2 mutations: case series, review and follow-up guidelines". Eur. J. Cancer 47 (7): 965–82. PMID 21376568. doi:10.1016/j.ejca.2011.01.013. 
  11. 11.0 11.1 Gibson SL, Narayanan L, Hegan DC, Buermeyer AB, Liskay RM, Glazer PM (December 2006). "Overexpression of the DNA mismatch repair factor, PMS2, confers hypermutability and DNA damage tolerance". Cancer Lett. 244 (2): 195–202. PMID 16426742. doi:10.1016/j.canlet.2005.12.009. 
  12. Mac Partlin M, Homer E, Robinson H, McCormick CJ, Crouch DH, Durant ST et al. (February 2003). "Interactions of the DNA mismatch repair proteins MLH1 and MSH2 with c-MYC and MAX". Oncogene 22 (6): 819–25. PMID 12584560. doi:10.1038/sj.onc.1206252. 
  13. 13.0 13.1 13.2 Kondo E, Horii A, Fukushige S (April 2001). "The interacting domains of three MutL heterodimers in man: hMLH1 interacts with 36 homologous amino acid residues within hMLH3, hPMS1 and hPMS2". Nucleic Acids Res. 29 (8): 1695–702. PMC 31313. PMID 11292842. doi:10.1093/nar/29.8.1695. 
  14. 14.0 14.1 Guerrette S, Acharya S, Fishel R (March 1999). "The interaction of the human MutL homologues in hereditary nonpolyposis colon cancer". J. Biol. Chem. 274 (10): 6336–41. PMID 10037723. doi:10.1074/jbc.274.10.6336. 
  15. 15.0 15.1 15.2 Chen J, Sadowski I (March 2005). "Identification of the mismatch repair genes PMS2 and MLH1 as p53 target genes by using serial analysis of binding elements". Proc. Natl. Acad. Sci. U.S.A. 102 (13): 4813–8. PMC 555698. PMID 15781865. doi:10.1073/pnas.0407069102. 
  16. 16.0 16.1 16.2 16.3 Shimodaira H, Yoshioka-Yamashita A, Kolodner RD, Wang JY (March 2003). "Interaction of mismatch repair protein PMS2 and the p53-related transcription factor p73 in apoptosis response to cisplatin". Proc. Natl. Acad. Sci. U.S.A. 100 (5): 2420–5. PMC 151356. PMID 12601175. doi:10.1073/pnas.0438031100. 
  17. 17.0 17.1 17.2 17.3 17.4 Cannavo E, Gerrits B, Marra G, Schlapbach R, Jiricny J (February 2007). "Characterization of the interactome of the human MutL homologues MLH1, PMS1, and PMS2". J. Biol. Chem. 282 (5): 2976–86. PMID 17148452. doi:10.1074/jbc.M609989200. 
  18. "PMS2 Gene". The GeneCards Human Gene Database. Weizmann Institute of Science. 
  19. Meyers M, Theodosiou M, Acharya S, Odegaard E, Wilson T, Lewis JE et al. (January 1997). "Cell cycle regulation of the human DNA mismatch repair genes hMSH2, hMLH1, and hPMS2". Cancer Res. 57 (2): 206–8. PMID 9000555. 
  20. 20.0 20.1 20.2 Fedier A, Ruefenacht UB, Schwarz VA, Haller U, Fink D (October 2002). "Increased sensitivity of p53-deficient cells to anticancer agents due to loss of Pms2". Br. J. Cancer 87 (9): 1027–33. PMC 2364320. PMID 12434296. doi:10.1038/sj.bjc.6600599. 
  21. Nakagawa H, Lockman JC, Frankel WL, Hampel H, Steenblock K, Burgart LJ et al. (July 2004). "Mismatch repair gene PMS2: disease-causing germline mutations are frequent in patients whose tumors stain negative for PMS2 protein, but paralogous genes obscure mutation detection and interpretation". Cancer Res. 64 (14): 4721–7. PMID 15256438. doi:10.1158/0008-5472.CAN-03-2879. 

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