p53 induced by ionizing radiation mediates DNA end-jointing activity, but not apoptosis of thryroid cells

Liu

Proc. Natl. Acad. Sci. U.S.A.

et al. 2009

223

208

The tumor suppressor p53 plays a crucial role in cellular response to various stresses. Recent experiments have shown that p53 level exhibits a series of pulses after DNA damage caused by ionizing radiation (IR). However, how the p53 pulses govern cell survival and death remains unclear. Here, we develop an integrated model with four modules for the p53 network and explore the mechanism for cell fate decision based on the dynamics of the network. By numerical simulations, the following processes are characterized. First, DNA repair proteins bind to IR-induced double-strand breaks, forming complexes, which are then detected by ataxia telangiectasia mutated (ATM). Activated ATM initiates the p53 oscillator to produce pulses. Consequently, the target genes of p53 are selectively induced to control cell fate. We propose that p53 promotes the repair of minor DNA damage but suppresses the repair of severe damage. We demonstrate that cell fate is determined by the number of p53 pulses relying on the extent of DNA damage. At low damage levels, few p53 pulses evoke cell cycle arrest by inducing p21 and promote cell survival, whereas at high damage levels, sustained p53 pulses trigger apoptosis by inducing p53AIP1. We find that p53 can effectively maintain genomic integrity by regulating the efficiency and fidelity of DNA repair. We also show that stochasticity in the generation and repair of DNA damage leads to variability in cell fate. These findings are consistent with experimental observations and advance our understanding of the dynamics and functions of the p53 network.p53 network ͉ DNA repair ͉ apoptosis ͉ variability T he tumor suppressor protein p53 is a key mediator of cellular response to various stresses (1), and it performs its function primarily as a transcription factor, controlling the expression of a number of target genes (2). In response to DNA damage, the p53 signaling network is activated to induce cell cycle arrest, DNA repair, and apoptosis (1). Previously, it was proposed that p53 responds to DNA damage in an analog mode, i.e., a low level of p53 promotes cell survival by inducing cell cycle arrest and facilitating DNA repair, whereas a high level of p53 induces apoptosis to destroy irreparably damaged cells (1). Recently, damped oscillations of p53 level have been observed upon IR at the population level in several human cell lines and transgenic mice (3-6), with the amplitude of oscillations depending on the IR dose (5). More interestingly, pulses of p53 level were revealed in individual MCF7 cells, and the mean number of pulses, rather than the amplitude, was found to be related to the IR dose (7). This was suggested as a digital mode of p53 response (7). Later, it was further found that some MCF7 cells exhibit permanent p53 pulses whereas a few cells still show a finite number of p53 pulses during long-term observations (8). Such permanent oscillations may be related to the deficiency in DNA repair and apoptosis induction in those transformed cells (9-11). Moreover, the damped oscillations obse...

mentioning

confidence: 77%

Cell fate decision mediated by p53 pulses

Liu

Proc. Natl. Acad. Sci. U.S.A.

et al. 2009

223

208

“…p53 certainly plays a role in DNA repair, but its regulatory role in non-homologous end joining is complicated and controversial (32). Some studies revealed that p53 can promote the rejoining of DNA with lesions (33,34), whereas inhibitory effects of p53 on non-homologous end joining were also reported (35,36). For simplicity, we did not consider the effect of p53 on DNA repair.…”

Section: Methodsmentioning

confidence: 99%

Coordination between Cell Cycle Progression and Cell Fate Decision by the p53 and E2F1 Pathways in Response to DNA Damage

Journal of Biological Chemistry

Liu

Wang

2010

After DNA damage, cells must decide between different fates including growth arrest, DNA repair, and apoptosis. Both p53 and E2F1 are transcription factors involved in the decision process. However, the mechanism for cross-talk between the p53 and E2F1 pathways still remains unclear. Here, we proposed a four-module kinetic model of the decision process and explored the interplay between these two pathways in response to ionizing radiation via computer simulation. In our model the levels of p53 and E2F1 separately exhibit pulsatile and switching behaviors. Upon DNA damage, p53 is first activated, whereas E2F1 is inactivated, leading to cell cycle arrest in the G 1 phase. We found that the ultimate decision between cell life and death is determined by the number of p53 pulses depending on the extent of DNA damage. For repairable DNA damage, the cell can survive and reenter the S phase because of the activation of E2F1 and inactivation of p53. For irreparable DNA damage, growth arrest is overcome by growth factors, and activated p53 and E2F1 cooperate to initiate apoptosis. We showed that E2F1 promotes apoptosis by up-regulating the proapoptotic cofactors of p53 and procaspases. It was also revealed that deregulated E2F1 by oncogene activation can make cells sensitive to DNA damage even in low serum medium. Our model consistently recapitulates the experimental observations of the intricate relationship between p53 and E2F1 in the DNA damage response. This work underscores the significance of E2F1 in p53-mediated cell fate decision and may provide clues to cancer therapy.The tumor suppressor p53 has a crucial role in preventing tumorigenesis (1). Upon various stresses, p53 is stabilized and activated to function primarily as a transcription factor, regulating the expression of a large number of genes involved in cell cycle arrest, DNA repair, or apoptosis (2). Thus, p53 is at the hub of numerous signaling pathways triggered by various stresses. Previously, it was proposed that cell fate after DNA damage is governed by p53 levels, i.e. a low level of p53 leads to transient growth arrest and cell survival, whereas a high level promotes irreversible apoptosis (3). Recently, it has been reported that p53 levels can exhibit oscillations in response to DNA damage induced by ionizing radiation (IR) (4, 5). Whereas damped oscillations of p53 levels were observed at the population level (4), a series of undamped pulses was observed at the single-cell level (5). In such a digital mode, it is the number of p53 pulses rather than their amplitudes and duration that is related to the extent of DNA damage and determines cell fate (5). p53 pulses can be generated by negative feedback loops with time delay (6 -8) or coupled positive and negative feedback loops (9, 10).How stressed cells exploit p53 pulses to translate various stresses into different cellular outcomes is not completely understood. Several studies have explored the functional roles of p53 pulses in response to DNA damage. Tyson and co-workers (10) classified active p5...

“…The relation between P53 and NHEJ is even less clear and somewhat contradictory (Bill et al, 1997;Yang et al, 1997;DiBiase et al, 1999;Tang et al, 1999), possibly because of the use of different cell types and assays in different studies. A recent report using an ISceI endonuclease-based cell system in human leukemic and lymphoblastoid cells demonstrated that expression of wild-type P53 in P53 null cells inhibits HRR as well as microhomology-directed NHEJ.…”

Section: Role Of P53 and Other Tumor Suppressors In Dsb Repairmentioning

confidence: 99%

Regulation and mechanisms of mammalian double-strand break repair

2003

The double-strand break (DSB) is believed to be one of the most severe types of DNA damage, and if left unrepaired is lethal to the cell. Several different types of repair act on the DSB. The most important in mammalian cells are nonhomologous end-joining (NHEJ) and homologous recombination repair (HRR). NHEJ is the predominant type of DSB repair in mammalian cells, as opposed to lower eucaryotes, but HRR has recently been implicated in critical cell signaling and regulatory functions that are essential for cell viability. Whereas NHEJ repair appears constitutive, HRR is regulated by the cell cycle and inducible signal transduction pathways. More is known about the molecular details of NHEJ than HRR in mammalian cells. This review focuses on the mechanisms and regulation of DSB repair in mammalian cells, the signaling pathways that regulate these processes and the potential crosstalk between NHEJ and HRR, and between repair and other stress-induced pathways with emphasis on the regulatory circuitry associated with the ataxia telangiectasia mutated (ATM) protein.