Selective binding of tumor suppressor p53 protein to topologically constrained DNA: Modulation by intercalative drugs

Pivoňková, Hana; Šebest, Peter; Pečínka, Petr; Tichá, Olga; Němcová, Kateřina; Brázdová, Marie; Jagelská, Eva Brázdová; Brázda, Václav; Fojta, Miroslav

doi:10.1016/j.bbrc.2010.02.120

Cited by 21 publications

(18 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It should be noted that the combination of anticancer agents ϩ chloroquine has already been postulated (e.g., temozolomide and chloroquine in glioblastoma or tamoxifen and chloroquine in breast cancer) and therefore our observation might also have translational implications (www.clinicaltrials.gov; Kondo et al, 2005). Although the effect of chloroquine is most likely caused by its effect on autophagy, we cannot exclude that it might be related to its effect on DNA, because it is a known intercalating agent (Pivonková et al, 2010). Obviously, FK866 induces a concentration-dependent NAD decrease, and it is likely that at higher concentrations (and therefore lower NAD levels) other modes of cell death might take over.…”

Section: Discussionmentioning

confidence: 87%

Reciprocal Potentiation of the Antitumoral Activities of FK866, an Inhibitor of Nicotinamide Phosphoribosyltransferase, and Etoposide or Cisplatin in Neuroblastoma Cells

Travelli¹,

Drago²,

Maldi

et al. 2011

J Pharmacol Exp Ther

View full text Add to dashboard Cite

NAD is an essential coenzyme involved in numerous metabolic pathways. Its principal role is in redox reactions, and as such it is not heavily "consumed" by cells. Yet a number of signaling pathways that bring about its consumption have recently emerged. This has brought about the hypothesis that the enzymes that lead to its biosynthesis may be targets for anticancer therapy. In particular, inhibition of the enzyme nicotinamide phosphoribosyl transferase has been shown to be an effective treatment in a number of preclinical studies, and two lead molecules [N-[4-(1-benzoyl-4-piperidinyl)butyl]-3-(3-pyridinyl)-2E-propenamide (FK866) and (E)-1-[6-(4-chlorophenoxy)hexyl]-2-cyano-3-(pyridin-4-yl)guanidine (CHS 828)] have now entered preclinical trials. Yet, the full potential of these drugs is still unclear. In the present study we have investigated the role of FK866 in neuroblastoma cell lines. We now confirm that FK866 alone in neuroblastoma cells induces autophagy, and its effects are potentiated by chloroquine and antagonized by 3-methyladenine or by down-regulating autophagy-related protein 7. Autophagy, in this model, seems to be crucial for FK866-induced cell death. On the other hand, a striking potentiation of the effects of cisplatin and etoposide is given by cotreatment of cells with ineffective concentrations of FK866 (1 nM). The effect of etoposide on DNA damage is potentiated by FK866 treatment, whereas the effect of FK866 on cytosolic NAD depletion is potentiated by etoposide. Even more strikingly, cotreatment with etoposide/cisplatin and FK866 unmasks an effect on mitochondrial NAD depletion.

show abstract

Section: Discussionmentioning

confidence: 87%

Reciprocal Potentiation of the Antitumoral Activities of FK866, an Inhibitor of Nicotinamide Phosphoribosyltransferase, and Etoposide or Cisplatin in Neuroblastoma Cells

Travelli¹,

Drago²,

Maldi

et al. 2011

J Pharmacol Exp Ther

View full text Add to dashboard Cite

show abstract

“…For example, a recent study indicated that p53 has a higher affinity for DNA treated with various concentrations of ethidium bromide. 43 We thus opted for broad-spectrum nucleases in our analyses. To our surprise, more than 80% of the WRN interactors were removed with the addition of Benzonase and RNase A prior to immunoprecipitation and mass spectrometry.…”

Section: Discussionmentioning

confidence: 99%

Proteome-wide Identification of WRN-Interacting Proteins in Untreated and Nuclease-Treated Samples

et al. 2011

View full text Add to dashboard Cite

Werner syndrome (WS) is characterized by the premature onset of several age-associated pathologies. The protein defective in WS patients (WRN) is a helicase/exonuclease involved in DNA repair, replication, telomere maintenance, and transcription. Here, we present the results of a large-scale proteome analysis to determine protein partners of WRN. We expressed fluorescent tagged-WRN (eYFP-WRN) in human 293 embryonic kidney cells and detected interacting proteins by co-immunoprecipitation from cell extract. We identified by mass spectrometry 220 nuclear proteins that complexed with WRN. This number was reduced to 40 when broad-spectrum nucleases were added to the lysate. We consider these 40 proteins as directly interacting with WRN. Some of these proteins have previously been shown to interact with WRN, whereas most are new partners. Among the top 15 hits, we find the new interactors TMPO, HNRNPU, RPS3, RALY, RPS9 DDX21, and HNRNPM. These proteins are likely important components in understanding the function of WRN in preventing premature aging and deserve further investigation. We have confirmed endogenous WRN interaction with endogenous RPS3, a ribosomal protein with endonuclease activities involved in oxidative DNA damage recognition. Our results suggest that the use of nucleases during cell lysis severely restricts interacting protein partners and thus enhances specificity.

show abstract

“…Interestingly, cruciform structures, which can be stabilized by DNA supercoiling, share two or three structural parts (four-way junction and the stem) with Holliday junctions. It is therefore not surprising that p53 interacts with topologically constrained DNA [105,122] and with cruciforms [108,123]. By electron and scanning force microscopy it was demonstrated that the p53 core domain binds to cruciform in plasmids with an inserted sequence (AT)34 (Figure 5) [123,124].…”

Section: Interaction Of P53 With Dnamentioning

confidence: 99%

Recognition of Local DNA Structures by p53 Protein

Brázda

Coufal

2017

IJMS

Self Cite

View full text Add to dashboard Cite

p53 plays critical roles in regulating cell cycle, apoptosis, senescence and metabolism and is commonly mutated in human cancer. These roles are achieved by interaction with other proteins, but particularly by interaction with DNA. As a transcription factor, p53 is well known to bind consensus target sequences in linear B-DNA. Recent findings indicate that p53 binds with higher affinity to target sequences that form cruciform DNA structure. Moreover, p53 binds very tightly to non-B DNA structures and local DNA structures are increasingly recognized to influence the activity of wild-type and mutant p53. Apart from cruciform structures, p53 binds to quadruplex DNA, triplex DNA, DNA loops, bulged DNA and hemicatenane DNA. In this review, we describe local DNA structures and summarize information about interactions of p53 with these structural DNA motifs. These recent data provide important insights into the complexity of the p53 pathway and the functional consequences of wild-type and mutant p53 activation in normal and tumor cells.

show abstract

Selective binding of tumor suppressor p53 protein to topologically constrained DNA: Modulation by intercalative drugs

Cited by 21 publications

References 24 publications

Reciprocal Potentiation of the Antitumoral Activities of FK866, an Inhibitor of Nicotinamide Phosphoribosyltransferase, and Etoposide or Cisplatin in Neuroblastoma Cells

Reciprocal Potentiation of the Antitumoral Activities of FK866, an Inhibitor of Nicotinamide Phosphoribosyltransferase, and Etoposide or Cisplatin in Neuroblastoma Cells

Proteome-wide Identification of WRN-Interacting Proteins in Untreated and Nuclease-Treated Samples

Recognition of Local DNA Structures by p53 Protein

Contact Info

Product

Resources

About