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



Gene location Chromosome 7.



This gene is one of the PMS2 gene family members which are found in clusters on chromosome 7. 



PMS2 is a gene that encodes for DNA repair proteins involved in mismatch repair. 



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.



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, Turcot syndrome, and are a cause of supratentorial primitive neuroectodermal tumors. 



It is involved in mismatch repair and is known to have latent endonuclease activity.



As an endonuclease, it introduces nicks into a discontinuous DNA strand.



PMS2 has been shown to interact with MLH1 by forming the heterodimer MutLα.



There is competition between MLH3, PMS1, and PMS2 for the interacting domain on MLH1.



MLH1 interacts with PMS2 at residues 506-756.



It is expressed at very low levels and is not believed to be strongly cell cycle regulated.



It interacts with p53 and p73. 



Cells that are deficient in p53 and PMS2, exhibit increased sensitivity to anticancer agents. 



PMS2 is a protective of cell survival in p53-deficient cells and modulates protective DNA damage response pathways independently of p53.



PMS2 and MLH1 protect cells from cell death by counteracting p73-mediated apoptosis in a mismatch repair dependent manner.



PMS2 interacts with p73 to enhance cisplatin-induced apoptosis by stabilizing p73. 



The MSH1/PMS2 complex assesses extent of the damage to the DNA, and initiates apoptosis by stabilizing p73 if the damage is beyond repair.



Loss of PMS2 does not always lead to instability of MLH1 since it can also form complexes with MLH3 and PMS1.



The PMS2 gene is located on chromosome 7p22 and it consists of 15 exons.



 utations in the promoter region of PMS2 are significantly associated with high tumor mutational burden (TMB), particularly in melanoma.



Tumor mutational burden is a  has been reliable predictor of the response  to cancer immunotherapy, where high TMB is associated with more favorable treatment outcomes.



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.



The age of patients when they first presented with PMS2-associated Lynch syndrome varies greatly, with a reported range of 23 to 77 years.



In rare cases, a homozygous defect may cause this syndrome. 



If the gene mutation is inherited from both parents and the condition is called Turcot syndrome or Constitutional MMR Deficiency.



Inheritance of Turcot syndrome can be dominant or recessive. 



Recessive inheritance of Turcot syndrome is caused by compound heterozygous mutations in PMS2.



Homozygous or compound heterozygous mutation carriers had gastrointestinal cancer or adenomas as the first manifestation of CMMR-D.



Overexpression of PMS2 results in hypermutability and DNA damage tolerance.



Deficiency of PMS2 contributes to genetic instability by allowing for mutations to propagate due to reduced MMR function.



PMS2 is usually expressed at a high level in cell nuclei of enterocytes within the colonic crypts.



DNA repair, involves  expression of PMS2, ERCC1 and ERCC4 proteins.



Such proteins are very active in colon crypts in normal, non-neoplastic colonic epithelium. 



PMS2 expression level in normal colonic epithelium is high in 77% to 100% of crypts.



Cells are produced at the crypt base and migrate upward to be  shed into the colonic lumen days later.



There are 5 to 6 stem cells at the bases of the crypts, and If the stem cells at the base express PMS2, generally all several thousand cells of the crypt will express PMS2. 



ERCC4 (XPF) and ERCC1 expression occur in the thousands of enterocytes in each colonic crypt of the normal colonic epithelium.



About 88% of cells of epithelial origin in colon cancers, and about 50% of the colon crypts in the epithelium within 10 cm adjacent to cancers  have reduced or absent expression of PMS2.



PMS2 deficiency in colon epithelium appear to mostly be due to epigenetic repression. 



In tumors classified as mismatch repair deficient and lacking, in a majority PMS2 expression is deficient because of lack of its pairing partner MLH1.



The loss of MLH1 in sporadic cancers was due to epigenetic silencing  caused by promoter methylation.



The reductions or absence of expression of these DNA repair genes in this tissue appears to be due to epigenetic repression.



When PMS2 is reduced in colonic crypts it is commonly associated with reduced expression of DNA repair enzymes ERCC1 and ERCC4.



ERCC1 and/or ERCC4 deficiencies are associated with  DNA damage accumulation. 



Excess DNA damage often leads to apoptosis, but an added defect in PMS2 can inhibit this apoptosis.



Colonic cell deficiency in both ERCC1 and PMS2 causes genome instability. 



If  cells are doubly defective for PMS2 and ERCC4 (XPF) instability would likely enhance progression to colon cancer.




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