Elsevier

DNA Repair

Volume 3, Issues 8–9, August–September 2004, Pages 1049-1056
DNA Repair

Review
The p53 response to DNA damage

https://doi.org/10.1016/j.dnarep.2004.03.027Get rights and content

Abstract

The p53 tumour suppressor protein is a highly potent transcription factor which, under normal circumstances, is maintained at low levels through the action of MDM2, an E3 ubiquitin ligase which directs p53 ubiquitylation and degradation. Expression of the mdm2 gene is stimulated by p53 and this reciprocal relationship forms the basis of a negative feedback loop. Both genotoxic and non-genotoxic stresses that induce p53 focus principally on interruption of the p53-MDM2 loop with the consequence that p53 becomes stabilised, leading to changes in the expression of p53-responsive genes. The biological outcome of inducing this pathway can be either growth arrest or apoptosis: factors affecting the functioning of the loop, the biochemical activity of p53 itself and the cellular environment govern the choice between these outcomes in a cell type- and stress-specific manner.

Section snippets

The p53 pathway

The p53 tumour suppressor protein plays a pivotal role in the cellular response to a range of environmental and intracellular stresses including agents which cause DNA strand breaks, ultraviolet radiation, hyper-proliferation and hypoxia (for reviews see [1], [2], [3], [4]). p53 acts as a node or hub for incoming stress signals which are then transduced, mainly through the ability of p53 to act as a transcription factor that binds to specific sites in the regulatory regions of p53-responsive

The p53-MDM2 feedback loop

Under normal circumstances, p53 is tightly regulated through its interaction with MDM2, a negative regulatory partner. MDM2 is an E3 ubiquitin ligase which, together with the p300 “transcriptional co-activator” protein (acting as an E4 polyubiquitin ligase), mediates both the ubiquitylation and proteasome-dependent degradation of p53 [2]. The binding of MDM2 to the transactivation domain within the N-terminus of p53 plays an additional role of blocking the interaction of p53 with the

The p53 response following DNA strand breaks

Of the various cellular stresses that initiate a p53 response, the molecular mechanisms by which p53 is activated following DNA double strand breaks are perhaps the most comprehensively understood. Activation of p53 by DNA damage occurs at two levels: the stabilisation of the p53 protein, leading to its accumulation in the nucleus, and activation of biochemical functions encompassed within the p53 protein.

Stabilisation of p53 occurs through inhibition of its degradation by MDM2 and is mediated

Growth arrest or apoptosis?

Different types of cells often show different biological responses to a given stress [1]. For example, thymocytes and splenocytes undergo p53-dependent apoptosis in vivo in response to low levels of ionising radiation. In contrast, fibroblasts arrest in a p53-dependent manner following DNA damage but will nevertheless undergo p53-dependent apoptosis following a different type of stress such as oncogenic transformation. These different cell types may therefore exhibit low and high thresholds,

Concluding remarks

Induction of p53 can occur in response to a range of genotoxic or non-genotoxic stresses leading to the biological outcomes of growth arrest or apoptosis. It is now clear that there is a large and complex range of factors that contribute to the choice between these two general outcomes including the cell type, the type and intensity of initiating stress, p53 levels, the presence of p53 co-activators or regulators and the p53-MDM2 regulatory feedback loop which is itself the major target of

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