Cancer cells and normal cells differ in the way they respond to DNA damage, and much of this difference is dependent on the function of the tumor suppressor p53. Although the function of the p53 protein appeared to be understood in the early 1990's, it is becoming clear that there are additional functions of p53 above and beyond its functions as transcriptional activator of cell-cycle checkpoints and apoptosis. In the previous funding period, we characterized two functions of p53 in relation to double-strand break repair. The first is that p53 suppressed the rate of spontaneous homologous recombination b approximately 30-fold, and this may be relevant to some aspects of genetic instability in tumor cells. The second is that the efficiency of double-strand break rejoining is enhanced after cells are exposed to ionizing radiation in a p53-dependent manner. The effect of p53 on non-homologous end joining, the other major, and perhaps dominant, pathway of double-strand break repair in mammalian cells, is newly described. The evidence suggested that the C-terminal domain of p53 plays a key role in mediating this effect, but the pathway targeted in this response is unknown. Whether the effect is mediated by DNA-PK/XRCC4/LigaseIV or an alternative by-pass pathway will be determined. The domains and functions of p53 necessary to produce enhance rejoining will be established, together with the structure of the DNA termini that are required to see this effect. The link between this pathway and tumor suppression is not obvious, but loss of p53 function results in less end-joining and more homologous recombination, especially in response to DNA damage, implying that homologous recombination may be the dominant pathway of double-strand break repair in tumors.
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