P53 Suppression of Homologous Recombination and Tumorigenesis.

摘要

Maintaining genomic stability is critical for organismal fitness. Consequently, the absence of tumor suppressor gene activity, such as p53, results in increased genomic instability and increased cancer predisposition. Homologous recombination (HR), as measured by the in vivo pun assay, is a DNA repair mechanism that our laboratory uses to measure genomic instability. We compared eyespot frequency in normal wild type mice, mice that are absent in p53 protein (null) and those that have the hotspot mutations R172H and R172P (equivalent to R175 in human breast cancer). Previously, we have shown that in the absence of p53 the normal frequency of spontaneous HR is significantly elevated. However, the mechanism by which p53 suppresses HR is unclear. The p53 R172P mutant mice retains limited transcriptional functionality (regulating cell cycle genes but not apoptotic genes) while the p53 R172H mutant mice lack any transcriptional activity but retain some protein: protein interaction capability. We observed significantly increased HR frequency in the p53 R172H mutant versus the p53 R172P mutant mice. This suggests that p53 regulation of cell cycle genes but not apoptotic genes may be responsible for its ability to suppress HR frequency. Also, the loss of key protein: protein interactions may have contributed to this suppression. It has been previously reported that p53 R172H mutant mice come down with early aggressive tumors compared to the p53 R172P mutant mice. This correlates with the increased HR frequency we observed in the R172H mutant mice implicating p53 suppression of genomic instability as a major mechanism for p53 tumor suppression. This work provides novel insight into the mechanism of cancer development in the absence or mutation of p53 and the mechanism of p53 control of HR in an in vivo system. p53 is often a targeted therapy and further insight into the function of p53 in DNA repair pathways can be vital to finding novel points of targeted therapy.