p53 protein at the hub of cellular DNA damage response pathways through sequence-specific and non-sequence-specific DNA binding

Abstract

Our environment contains physical, chemical and pathological agents that challenge the integrity of our DNA. In addition to DNA repair, higher multicellular organisms have evolved multiple pathways of response to damage including programmed cell death-apoptosis. The p53 protein appears to sense multiple types of DNA damage and coordinate with multiple options for cellular response. The p53 protein activities depend upon its DNA binding. Specific p53 protein post-translational modifications are required for efficient sequence-specific binding and transcriptional activities. Non-sequence-specific DNA binding may involve a wide spectrum of p53 proteins and predominate as DNA damage is more severe or p53 protein is more highly induced. p53 protein is not strictly required for DNA damage sensing and repair. Rather, p53 protein may govern an apoptosis checkpoint through competition with DNA repair proteins for non-sequence-specific binding to exposed single-stranded regions in the DNA duplex. This model provides a framework for testing mechanisms of p53-mediated apoptosis dependent upon the p53 protein modification state, the level of p53 protein accumulation, the level of DNA damage and the capacity of the damaged cell to repair.

Reciprocally Regulated Chromatin Association of Cockayne Syndrome Protein B and p53 Protein

“…The ATP-dependent chromatin remodeler CSB has been shown to interact with the tumor suppressor p53, and both proteins play important roles in a variety of overlapping nuclear processes (8,11,15,22,36). In this study, we have found that the association of CSB and p53 with chromatin is reciprocally regulated, and we have provided mechanistic insights into this regulation and how these two proteins may coordinate their activities.…”

p53 is a potential mediator of pregnancy and hormone-induced resistance to mammary carcinogenesis

“…The consequence of hormone exposure is the induction of persistent differences in molecular pathways between the epithelial cells in the hormone-treated and mature mammary gland that dictate the proliferative responses upon a carcinogenic insult. Additional data to support this hypothesis have been published recently (19)(20)(21).The tumor suppressor protein p53 protein, which is situated in the hub of cellular DNA damage pathways in higher organisms, is central to the cellular response to a variety of potentially damaging extracellular stimuli including UV light, ␥-irradiation, chemical carcinogens, and chemotherapeutic agents (22,23). Depending on the insult it can evoke cell cycle arrest (24-28), DNA repair (29), or apoptosis (30, 31) through sequence-specific and nonsequence-specific DNA binding and through both positive and negative mechanisms (32).…”

“…The tumor suppressor protein p53 protein, which is situated in the hub of cellular DNA damage pathways in higher organisms, is central to the cellular response to a variety of potentially damaging extracellular stimuli including UV light, ␥-irradiation, chemical carcinogens, and chemotherapeutic agents (22,23). Depending on the insult it can evoke cell cycle arrest (24)(25)(26)(27)(28), DNA repair (29), or apoptosis (30, 31) through sequence-specific and nonsequence-specific DNA binding and through both positive and negative mechanisms (32).…”

Analysis of Pro-apoptotic Protein Trafficking to and from Mitochondria

“…Thus, p53 oscillates between latent and active sequencespecifi c DNA binding conformations and is differentially activated through posttranslational modifi cations including phosphorylation, acetylation and ubiquitination. On the other side, nonsequencespecifi c DNA binding may mediate other p53 actions [ 10 ]. In addition, p53 is also involved in mitochondrial-dependent cell death, collaborating in the execution of the apoptotic pathway.…”