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. Clinical significance Mutations 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. Comprehensive genomic profiling of 100,000 human cancer samples revealed that mutations in the promoter region of PMS2 are significantly associated with high tumor mutational burden (TMB), particularly in melanoma. TMB has been shown to be a reliable predictor of whether a patient may respond 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. 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). Up until 2011, 36 patients with brain tumors