Coordination between p21 and DDB2 in the Cellular Response to UV Radiation

Hao Li,Xiao-Peng Zhang,Feng Liu,Bin Xue

doi:10.1371/journal.pone.0080111

Abstract

The tumor suppressor p53 guides the cellular response to DNA damage mainly by regulating expression of target genes. The cyclin-dependent kinase inhibitor p21, which is induced by p53, can both arrest the cell cycle and inhibit apoptosis. Interestingly, p53-inducible DDB2 (damaged-DNA binding protein 2) promotes apoptosis by mediating p21 degradation after ultraviolet (UV)-induced DNA damage. Here, we developed an integrated model of the p53 network to explore how the UV-irradiated cell makes a decision between survival and death and how the activities of p21 and DDB2 are modulated. By numerical simulations, we found that p53 is activated progressively and the promoter selectivity of p53 depends on its concentration. For minor DNA damage, p53 settles at an intermediate level. p21 is induced by p53 to arrest the cell cycle via inhibiting E2F1 activity, allowing for DNA repair. The proapoptotic genes are expressed at low levels. For severe DNA damage, p53 undergoes a two-phase behavior and accumulates to high levels in the second phase. Consequently, those proapoptotic proteins accumulate remarkably. Bax activates the release of cytochrome c, while DDB2 promotes the degradation of p21, which leads to activation of E2F1 and induction of Apaf-1. Finally, the caspase cascade is activated to trigger apoptosis. We revealed that the downregulation of p21 is necessary for apoptosis induction and PTEN promotes apoptosis by amplifying p53 activation. This work demonstrates that how the dynamics of the p53 network can be finely regulated through feed-forward and feedback loops within the network and emphasizes the importance of p21 regulation in the DNA damage response.

Highlights

The tumor suppressor p53 has a critical role in maintaining genome integrity by mediating the cellular response to various stresses including DNA damage [1]. p53 mainly functions as a transcription factor, regulating expression of target genes to elicit multiple cellular processes including cell cycle arrest and apoptosis [2]
damaged-DNA binding protein 2 (DDB2) promotes the degradation of p21 after UV radiation, thereby releasing cells from the apoptosis inhibition by p21 [23]
We developed an integrated model of the p53 network to explore the cell-fate decision after UV radiation, focusing on the dual roles of p21

Summary

Introduction

The tumor suppressor p53 has a critical role in maintaining genome integrity by mediating the cellular response to various stresses including DNA damage [1]. p53 mainly functions as a transcription factor, regulating expression of target genes to elicit multiple cellular processes including cell cycle arrest and apoptosis [2]. P53 mainly functions as a transcription factor, regulating expression of target genes to elicit multiple cellular processes including cell cycle arrest and apoptosis [2]. Since many theoretical models have been developed to clarify the dynamic mechanism for p53-mediated cell-fate decision following DNA damage. Zhang et al and we proposed that the cell fate can be determined by the number of p53 pulses, which depends on the severity of DNA damage [6,7]. Phosphorylated p53, whose concentration undergoes pulses with low amplitudes, induces cell cycle arrest in the early phase of the response, while fully phosphorylated p53 accumulates to high levels and triggers apoptosis in the late phase of the response to severe damage. It is intriguing to probe how the UV-irradiated cells make a decision between survival and death

Methods

Results

Conclusion