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Abstract
The influence of p53 status on potentially lethal damage repair (PLDR) and DNA double-strand break (DSB) repair was studied in two isogenic human colorectal carcinoma cell lines: RKO (p53 wild-type) and RC10.1 (p53 null). They were treated with different doses of ionizing radiation, and survival and the induction of DNA-DSB were studied. PLDR was determined by using clonogenic assays and then comparing the survival of cells plated immediately with the survival of cells plated 24 h after irradiation. Doses varied from 0 to 8 Gy. Survival curves were analyzed using the linear-quadratic formula: S(D)/S(0) = exp-(αD+βD2). The γ-H2AX foci assay was used to study DNA DSB kinetics. Cells were irradiated with single doses of 0, 0.5, 1 and 2 Gy. Foci levels were studied in non-irradiated control cells and 30 min and 24 h after irradiation. Irradiation was performed with gamma rays from a 137Cs source, with a dose rate of 0.5 Gy/min. The RKO cells show higher survival rates after delayed plating than after immediate plating, while no such difference was found for the RC10.1 cells. Functional p53 seems to be a relevant characteristic regarding PLDR for cell survival. Decay of γ-H2AX foci after exposure to ionizing radiation is associated with DSB repair. More residual foci are observed in RC10.1 than in RKO, indicating that decay of γ-H2AX foci correlates with p53 functionality and PLDR in RKO cells.
Highlights
DNA double-strand breaks (DSBs) are biologically the most significant lesions produced by ionizing radiation
The level of potentially lethal damage repair (PLDR) was investigated in two cell lines, one with proficient p53 function (RKO) and one with abrogated p53 function (RC10.1)
As reported in earlier studies, an intact p53 status is required for the repair of potentially lethal damage [17,18,19]
Summary
DNA double-strand breaks (DSBs) are biologically the most significant lesions produced by ionizing radiation. Efficient DNA repair and correct activation of cell cycle checkpoints upon induction of DNA damage are of crucial importance for the maintenance of genomic integrity. Checkpoints induce actively dividing cells to pause and repair DNA damage before segregation of the replicated genome into daughter cells [1]. The malfunction of proteins that are not involved in the actual repair processes can still result in non- and misrepair of DNA DSBs. Protein p53 is one of the key proteins responsible for the correct activation of cell cycle checkpoints [13, 14]. Protein p53 is one of the key proteins responsible for the correct activation of cell cycle checkpoints [13, 14] It plays an important role in the regulation of apoptosis [15, 16]. Due to its role in G1-phase arrest, p53 status is thought to influence the repair of potentially lethal damage
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