PMS2

1EA6, 1H7S, 1H7U539518861ENSG00000122512n/aP54278P54279NM_001322007NM_001322008NM_001322009NM_001322010NM_001322011NM_001322012NM_001322013NM_001322014NM_001322015NM_008886NP_001308936NP_001308937NP_001308938NP_001308939NP_001308940NP_001308941NP_001308942NP_001308943NP_001308944n/aMismatch repair endonuclease PMS2 is an enzyme that in humans is encoded by the PMS2 gene.1ea6: N-TERMINAL 40KDA FRAGMENT OF NHPMS2 COMPLEXED WITH ADP1h7s: N-TERMINAL 40KDA FRAGMENT OF HUMAN PMS21h7u: HPMS2-ATPGS Mismatch repair endonuclease PMS2 is an enzyme that in humans is encoded by the PMS2 gene. 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 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. 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 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, which is located in residues 492-742. The interacting domains in PMS2 have heptad repeats that are characteristic of leucine zipper proteins. MLH1 interacts with PMS2 at residues 506-756. 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. 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. The active site of MutLα is located on the PMS2 subunit. PMS1 and PMS2 compete for interaction with MLH1. Proteins in the interactome of PMS2 have been identified by tandem affinity purification. Human PMS2 is expressed at very low levels and is not believed to be strongly cell cycle regulated. 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. 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. PMS2 and MLH1 can protect cells from cell death by counteracting p73-mediated apoptosis in a mismatch repair dependent manner. 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. 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. 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. Upon DNA damage, p53 induces cell cycle arrest through the p21/WAF pathway and initiates repair by expression of MLH1 and PMS2. 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. Loss of PMS2 does not always lead to instability of MLH1 since it can also form complexes with MLH3 and PMS1.