Wild-type p53 binds to <i>MYC</i> promoter G-quadruplex

Petr, Marek; Helma, Robert; Polášková, Alena; Krejčí, Aneta; Dvořáková, Zuzana; Kejnovská, Iva; Navrátilová, Lucie; Adámik, Matej; Vorlı́čková, Michaela; Brázdová, Marie

doi:10.1042/bsr20160232

Cited by 33 publications

(27 citation statements)

References 58 publications

(73 reference statements)

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“…We found that 20% of all p53 peaks that appear in ≥2 data sets are within 1 kb of a G4 structure that was identified in vivo ( P -value < 0.0001; Supplementary Table ST5 ). Of the p53 peaks that do not contain a p53 motif, ∼28% are near G4s, which is consistent with the view that p53 may be able to bind G4 structures based on in vitro studies ( 61 , 62 ).…”

Section: Resultssupporting

confidence: 86%

Revealing a human p53 universe

Nguyen

Grimm

Bushel

et al. 2018

Nucleic Acids Research

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Abstractp53 transcriptional networks are well-characterized in many organisms. However, a global understanding of requirements for in vivo p53 interactions with DNA and relationships with transcription across human biological systems in response to various p53 activating situations remains limited. Using a common analysis pipeline, we analyzed 41 data sets from genome-wide ChIP-seq studies of which 16 have associated gene expression data, including our recent primary data with normal human lymphocytes. The resulting extensive analysis, accessible at p53 BAER hub via the UCSC browser, provides a robust platform to characterize p53 binding throughout the human genome including direct influence on gene expression and underlying mechanisms. We establish the impact of spacers and mismatches from consensus on p53 binding in vivo and propose that once bound, neither significantly influences the likelihood of expression. Our rigorous approach revealed a large p53 genome-wide cistrome composed of >900 genes directly targeted by p53. Importantly, we identify a core cistrome signature composed of genes appearing in over half the data sets, and we identify signatures that are treatment- or cell-specific, demonstrating new functions for p53 in cell biology. Our analysis reveals a broad homeostatic role for human p53 that is relevant to both basic and translational studies.

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Section: Resultssupporting

confidence: 86%

Revealing a human p53 universe

Nguyen

Grimm

Bushel

et al. 2018

Nucleic Acids Research

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“…This alternative DNA conformation forms when single-stranded guanine-rich regions fold into stable four-stranded helical structures. The vicinity of G4 s to p53 ChIP-Seq peaks was examined [32] because there is evidence that p53 can bind to some of these structural elements and by doing so it can control the expression of nearby gene [34]. Our data generate hypothesis that p53 may control the expression of NLRP1 from G4 element identified in its promoter region.…”

Section: Ectopic Expression Of P53 Upregulates Nlrx1 and Nlrp1 Promotersmentioning

confidence: 86%

Synergistic activation of p53 by actinomycin D and nutlin-3a is associated with the upregulation of crucial regulators and effectors of innate immunity

Krześniak

Zajkowicz

Gdowicz-Kłosok

et al. 2020

Cellular Signalling

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A B S T R A C TActinomycin D and nutlin-3a (A + N) activate p53, partly through induction of phosphorylation on Ser392. The death of A549 cells induced by A + N morphologically resembles inflammation-inducing pyroptosis -cell destruction triggered by activated caspase-1. The treatment with A + N (or camptothecin) strongly upregulated caspase-1 and its two activators: IFI16 and NLRP1, however, caspase-1 activation was not detected. A549 cells may have been primed for pyroptosis, with the absence of a crucial trigger. The investigation of additional innate immunity elements revealed that A + N (or camptothecin) stimulated the expression of NLRX1, STING (stimulator of interferon genes) and two antiviral proteins, IFIT1 and IFIT3. IFI16 and caspase-1 are coded by p53regulated genes which led us to investigate regulation of NLRP1, NLRX1, STING, IFIT1 and IFIT3 in p53-dependent mode. The upregulation of NLRP1, NLRX1 and STING was attenuated in p53 knockdown cells. The upsurge of the examined genes, and activation of p53, was inhibited by C16, an inhibitor of PKR kinase. PKR was tested due to its ability to phosphorylate p53 on Ser392. Surprisingly, C16 was active even in PKR knockdown cells. The ability of C16 to prevent activation of p53 and expression of innate immunity genes may be the source of its strong anti-inflammatory action. Moreover, cells exposed to A + N can influence neighboring cells in paracrine fashion, for instance, they shed ectodomain of COL17A1 protein and induce, in p53-dependent mode, the expression of gene for interleukin-7. Further, the activation of p53 also spurred the expression of SOCS1, an inhibitor of interferon triggered STAT1-dependent signaling. We conclude that, stimulation of p53 primes cells for the production of interferons (through upregulation of STING), and may activate negative-feedback within this signaling system by enhancing the production of SOCS1.

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“…Non-canonical DNA motifs are transcriptionally active for wild type and mutant p53 proteins [40] and local DNA structures are important determinants for protein-DNA binding [41]. Recently, the interaction of p53 with G4s has been demonstrated [26]. Even if it was demonstrated that G4 structures are often located in gene regulatory sequences in the human genome [42] and there are many studies of p53 target genes [16,39], a combined study of both features is missing.…”

Section: Discussionmentioning

confidence: 99%

“…p53-DNA interactions with p53 REs are sensitive to DNA topology and this is a key parameter contributing to p53-DNA affinity and specificity [18,23]. It was demonstrated that p53 also binds to various local DNA structures stabilized by DNA topological stress such as cruciforms [24,25], quadruplex [26], triplex [27], bulged [28], and hemicatenate [29] DNAs.…”

Section: Introductionmentioning

confidence: 99%

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

Porubiaková

Bohálová

Inga

et al. 2019

IJMS

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p53 is one of the most studied tumor suppressor proteins that plays an important role in basic biological processes including cell cycle, DNA damage response, apoptosis, and senescence. The human TP53 gene contains alternative promoters that produce N-terminally truncated proteins and can produce several isoforms due to alternative splicing. p53 function is realized by binding to a specific DNA response element (RE), resulting in the transactivation of target genes. Here, we evaluated the influence of quadruplex DNA structure on the transactivation potential of full-length and N-terminal truncated p53α isoforms in a panel of S. cerevisiae luciferase reporter strains. Our results show that a G-quadruplex prone sequence is not sufficient for transcription activation by p53α isoforms, but the presence of this feature in proximity to a p53 RE leads to a significant reduction of transcriptional activity and changes the dynamics between co-expressed p53α isoforms.

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Wild-type p53 binds to MYC promoter G-quadruplex

Abstract: We found that the p53 tumour suppressor protein binds specifically to the G-quadruplex DNA formed by MYC promoter sequence. We propose that p53 binding to G-quadruplexes can participate in regulation of p53 target genes.

Cited by 33 publications

References 58 publications

Revealing a human p53 universe

Revealing a human p53 universe

Synergistic activation of p53 by actinomycin D and nutlin-3a is associated with the upregulation of crucial regulators and effectors of innate immunity

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

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