Ionizing radiation-induced apoptosis via separate Pms2-and p53-dependent pathways

The cytotoxicity of ionizing radiation (IR) has been associated with both t he p53 pathway and with DNA mismatch repair (MMR). p53 mediates cell cycle arrest and apoptosis in response to X-ray damage, whereas the MMR complex i s thought to recognize damaged bases and initiate a signal transduction pat hway that can include phosphorylation of p53. To determine whether p53 and MMR mediate X-ray cytotoxicity via the same pathway, mice with targeted dis ruptions in either the p53 gene or the MutL homologue MMR gene Pms2 were in terbred and primary fibroblasts were established from the progeny with geno types of either wild type, p53 null, Pms2 null, or double null. Cells with either p53 or Pms2 separately disrupted showed reduced levels of apoptosis after IR in comparison with wild type, but the double null cells showed eve n lower levels, consistent with nonoverlapping roles for p53 and PMS2 in th e X-ray response. In transformed cell lines established from the primary ce lls at early passage, similar differences in the apoptotic response to IR w ere seen, and clonogenic survival assays following low dose rate IR further showed that nullizygosity for Pms2 confers increased survival on cells in both wild-type and p53 null backgrounds. These results indicate that both p 53 and MMR contribute to X-ray-induced apoptosis and that the role of MMR i n the cytotoxicity of IR does not depend on p53.