Reversal of the ATM/ATR-mediated DNA damage response by the oncogenic phosphatase PPM1D.

The eukaryotic cell has evolved a sophisticated set of cell signaling pathways that respond to DNA damage and efficiently repair that damage, protecting the cell from deleterious mutations, genomic instability, and transformation into a cancerous state. The ATM and ATR serine/threonine kinases are key sensors and transducers of DNA damage signals through phosphorylation of an array of signaling molecules that mediate all aspects of the DNA damage response, including enforcement of cell cycle checkpoints and direct repair of damaged DNA. We have shown that a type 2C serine/threonine phosphatase, PPM1D (or Wip1), can reverse the phosphorylation status of ATM/ATR-phosphorylated proteins p53 and Chk1. This dephosphorylation of p53 and Chk1 by PPM1D may result in reduced functional activities and is accompanied by suppression of DNA damage-induced cell cycle checkpoints and some aspects of DNA repair. Because PPM1D is transcriptionally activated by p53 in response to DNA damage, PPM1D may serve as a critical component of a p53 negative feedback regulatory loop since it now appears that PPM1D can inhibit p53 activity by at least four different molecular mechanisms. This may explain why PPM1D is amplified and overexpressed in a subset of human breast cancers that invariably retain wild type p53 alleles. We hypothesize that PPM1D is a homeostatic regulator of the DNA damage response that returns the cell to a more normal unstressed state following repair of the damage.