Mismatch repair endonuclease PMS2

Exons 1 through 5 of these homologues share high degree of identity to human PMS2 [5] The product of this gene is involved in DNA mismatch repair.

Defects in this gene are associated with hereditary nonpolyposis colorectal cancer, with Turcot syndrome, and are a cause of supratentorial primitive neuroectodermal tumors.

[6] 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.

[13][14] Human PMS2 is expressed at very low levels and is not believed to be strongly cell cycle regulated.

[12] 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.

[12] 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.

[12] Upon DNA damage, p53 induces cell cycle arrest through the p21/WAF pathway and initiates repair by expression of MLH1 and PMS2.

[20] Heterozygous germline mutations in DNA mismatch repair genes like PMS2 lead to autosomal dominant Lynch syndrome.

[21] 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 such cases a child inherits the gene mutation from both parents and the condition is called Turcot syndrome or Constitutional MMR Deficiency (CMMR-D).

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

This is indicated by the brown color seen by immunostaining of PMS2 in most of the enterocytes in the crypt in panel A of the image in this section.

The tissue section in the image shown here was also counterstained with hematoxylin to stain DNA in nuclei a blue-gray color.

[31] The loss of MLH1 in sporadic cancers was due to epigenetic silencing caused by promoter methylation in 65 out of 66 cases.

Of these 16 cases, no cause was determined for 10, but 6 were found to have a heterozygous germline mutation in Pms2, followed by likely loss of heterozygosity in the tumor.

As indicated by Harper and Elledge,[37] defects in the ability to properly respond to and repair DNA damage underlie many forms of cancer.

Micrograph showing loss of staining for PMS2 in colorectal adenocarcinoma in keeping with DNA mismatch repair (left of image) and benign colorectal mucosa (right of image).
Sequential sections of the same colon crypt with immunohistochemical staining (brown) showing normal high expression of DNA repair proteins PMS2 (A), ERCC1 (B) and ERCC4 (XPF) (C). This crypt is from the biopsy of a 58-year-old male patient who never had colonic neoplasia and the crypt has high expression of these DNA repair proteins in absorptive cell nuclei throughout most of the crypt. Note that PMS2 and ERCC4 (XPF) expression (in panels A and C) are each reduced or absent in the nuclei of cells at the top of the crypt and within the surface of the colonic lumen between crypts. Original image, also in a publication. [ 27 ]
Sequential sections of a segment of colon epithelium near a colorectal cancer showing reduced or absent expression of PMS2 (A), ERCC1 (B) and ERCC4 (C) in the colon crypts. This tissue segment is from a histologically normal area of a colon resection of a male patient who had an adenocarcinoma in the sigmoid colon. For PMS2 (A), there is absent expression in cell nuclei of the crypt body, the crypt neck and the colonic lumen surface for all epithelial cells. For ERCC1 (B), there is reduced expression in most of the cell nuclei of the crypts, but there is high expression in cell nuclei at the neck of the crypts and in the adjacent colonic lumen surface. For ERCC4 (XPF) (C), there is absent expression in most of the cell nuclei of the crypts and in the colonic lumen in this area of tissue, but detectable expression at the neck of some crypts. The reductions or absence of expression of these DNA repair genes in this tissue appears to be due to epigenetic repression . [ 27 ] Original image, also in a publication. [ 27 ]