Decision Making by p53: Life versus Death

Abstract

Cellular response to DNA damage is multifacted in nature and involves a complex signaling network in which p53 functions as a "molecular node" for converging signals. p53 has been implicated in a variety of cellular processes primarily functioning as a transcription factor and also in a transcription-independent manner. It is rapidly activated following DNA damage with phosphorylation as one of the initial signals. Cellular context as well as the type and severity of DNA damage determine p53 activation code, and its activities are regulated predominantly through protein degradation, post-translational modification and interactions with various cellular co-factors. These events are crucial in decision making by p53 as it has the ability to receive, assess and integrate different signals and route them accordingly to induce cell death or promote cell survival. In this decision making process, its transcriptional role to activate a specific subset of target genes linked to inducing cell cycle arrest or apoptosis is critical that is further fine-tuned by its transcription-independent function. This article reviews the current state of knowledge about the role of p53 in determining the fate of cells that have incurred DNA damage.

Figure 1. Functional domains of the p53 protein

Amino acid numbers covering each domain are indicated above or below each corresponding domain. Abbreviations: NES, nuclear export signal; NLS, nuclear localization signal. Drawn based on information from (3).

Figure 2. Transcription-dependent functions of p53 in response to DNA damage

Representative targets of p53 in the three major pathways are indicated in matching colors. Drawn based on information from (69).

Figure 3. Post-translational modifications of p53

Abbreviations: P, Phosphorylation; Ac, Acetylation; G, O linked N-acetylglusamine; M, Methylation; SUMO, Sumoylation; N, Neddylation; Ub, Ubiquitination. Modified from (69).

Figure 4

Sequential phosphorylation cascade in p53 activation in response to DNA double strand breaks.

Figure 5. Determinants in p53 decision making

Abbreviations: P, Phosphorylation; Ac, Acetylation; G, O linked N-acetylglusamine; M, Methylation; SUMO, Sumoylation; N, Neddylation; Ub, Ubiquitination. Adopted from (58).