PMS2 - Interactions - Interactions Involving P53 and P73

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. 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 adaptor 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.