The Rich World of p53 DNA Binding Targets: The Role of DNA Structure

Abstract

The tumor suppressor functions of p53 and its roles in regulating the cell cycle, apoptosis, senescence, and metabolism are accomplished mainly by its interactions with DNA. p53 works as a transcription factor for a significant number of genes. Most p53 target genes contain so-called p53 response elements in their promoters, consisting of 20 bp long canonical consensus sequences. Compared to other transcription factors, which usually bind to one concrete and clearly defined DNA target, the p53 consensus sequence is not strict, but contains two repeats of a 5′RRRCWWGYYY3′ sequence; therefore it varies remarkably among target genes. Moreover, p53 binds also to DNA fragments that at least partially and often completely lack this consensus sequence. p53 also binds with high affinity to a variety of non-B DNA structures including Holliday junctions, cruciform structures, quadruplex DNA, triplex DNA, DNA loops, bulged DNA, and hemicatenane DNA. In this review, we summarize information of the interactions of p53 with various DNA targets and discuss the functional consequences of the rich world of p53 DNA binding targets for its complex regulatory functions.

The Influence of Quadruplex Structure in Proximity to P53 Target Sequences on the Transactivation Potential of P53 Alpha Isoforms

“…p53 is part of an extensive transcriptional network that coordinates the response to intracellular and extracellular stresses or damage [5]. The main function of p53 is provided by its interaction with DNA [15][16][17][18][19]. p53 regulates target gene expression mainly by activation of p53-responsive promoters.…”

Characterization of p53 Family Homologs in Evolutionary Remote Branches of Holozoa

“…It is accepted that p53 family proteins (p53, p63 and p73) arose from a common ancestral gene (most similar to contemporary p63 found in human [5]) and their functions diversified after gene duplications and rearrangements [6]. All three contemporary p53 family members are transcription factors that execute their functions through binding to DNA consensus sequences that are often located within locally structured regions [7][8][9][10]. The typical p53 consensus binding site has internal symmetry and two copies of the motif 5'-RRRCWWGYYY-3' [11], although non-canonical half sites [12], targets with long spacers [9] and with various structural features [13,14] are also recognized by p63 and p73 [15].…”

The changes in the p53 protein across the animal kingdom pointing to its involvement in longevity

“…For example, the p53 protein plays roles in metabolism (Vousden & Lane, 2007), cell cycle arrest (Chen, 2016;Hafner et al, 2019), apoptosis (Aubrey et al, 2018), angiogenesis (Pfaff et al, 2018), DNA repair (Nicolai et al, 2015) and cell senescence (Itahana et al, 2001;Rufini et al, 2013). As a DNAbinding protein, p53 functions as a transcription factor and recognizes and binds to multiple target genes (Brázda & Fojta, 2019;El-Deiry et al, 1992;Vyas et al, 2017). Owing to its crucial role in protection against DNA damage, p53 is called "the guardian of the genome" (Lane, 1992;Toufektchan & Toledo, 2018).…”