Genome wide expression analysis of radiation-induced DNA damage responses in isogenic HCT116 p53+/+ and HCT116 p53-/- colorectal carcinoma cell lines.

PURPOSE

To study the kinetics of gene expression alterations following radiation exposure of isogenic HCT116 p53 +/+ and HCT116 p53-/- cell lines.

MATERIALS AND METHODS

Cells were exposed to 5 Gy of irradiation (Cs-137) and genome-wide temporal expression analysis using Illumina bead chip arrays was performed. Signalling pathways were explored using Metacore (Genego). Biological responses including cell cycle checkpoint activation, centrosome amplification and senescence induction were analyzed.

RESULTS

Significant differences in the radiation response were observed between the p53+/+ and the p53-/- cell lines. In p53+/+ cells concurrent G1- and G2-arrests were activated followed by senescence induction. Increased expression of genes associated with senescence, senescence associated secretory phenotype (SASP) and repression of genes essential for G2-M transition were detected. P53-/- cells arrested mainly in G2 followed by centrosome amplification, mitotic slippage and a subsequent increase of polyploid cells. Furthermore, changes in expression correlated well with these signs of mitotic catastrophe.

CONCLUSIONS

The presence or absence of p53 triggers different signalling cascades with different endpoints. Elucidating these differences is important as it enables improvement of radiation treatment and could be used to develop new combination treatments with specific inhibitors of key regulators of these cell death modalities.