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

Area of Science:

• Molecular Biology
• Radiation Biology
• Genetics

Background:

• Ionizing radiation (IR) cytotoxicity is linked to the p53 pathway and DNA mismatch repair (MMR).
• p53 induces cell cycle arrest and apoptosis following X-ray damage.
• MMR recognizes damaged bases and can signal to p53.

Purpose of the Study:

• To investigate if p53 and MMR mediate X-ray cytotoxicity through the same cellular pathway.
• To elucidate the distinct or overlapping roles of p53 and PMS2 in the cellular response to IR.

Main Methods:

• Generation of mice with targeted disruptions in p53 or the MMR gene Pms2.
• Establishment of primary fibroblasts from progeny with genotypes: wild type, p53 null, Pms2 null, and double null.
• Assessment of apoptosis levels post-IR and clonogenic survival assays following low-dose rate IR.

Main Results:

• Cells with disrupted p53 or Pms2 showed reduced apoptosis after IR compared to wild type.
• Double null cells (lacking both p53 and Pms2) exhibited even lower apoptosis levels.
• Pms2 nullizygosity increased cell survival on both wild-type and p53 null backgrounds after IR.

Conclusions:

• Both p53 and MMR contribute to IR-induced apoptosis.
• The roles of p53 and PMS2 in the cellular response to X-ray damage are non-overlapping.
• The DNA mismatch repair system's contribution to IR cytotoxicity is independent of p53.