Stable G-Quadruplex Structures of Oncogene Promoters Induce Potassium-Dependent Stops of Thermostable DNA Polymerase

Chashchina, Galina V.; Бениаминов, А. Д.; Kaluzhny, Dmitry N.

doi:10.1134/s0006297919050109

Cited by 10 publications

(8 citation statements)

References 23 publications

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“…Interestingly, G4s are often located in promoter sequences as shown for many human genes [69][70][71], including P53 targets; in fact, the presence of G4 prone sequences has been found around P53 RE in the promoter of the P53-induced apoptotic PUMA protein [34]. Therefore, the presence and the formation of a G4 structure could be an important transcriptional regulatory element, as previously observed in various organisms including humans [72][73][74].…”

Section: Discussionmentioning

confidence: 63%

Evaluating the Influence of a G-Quadruplex Prone Sequence on the Transactivation Potential by Wild-Type and/or Mutant P53 Family Proteins through a Yeast-Based Functional Assay

Monti

Brázda

Bohálová

et al. 2021

Genes

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P53, P63, and P73 proteins belong to the P53 family of transcription factors, sharing a common gene organization that, from the P1 and P2 promoters, produces two groups of mRNAs encoding proteins with different N-terminal regions; moreover, alternative splicing events at C-terminus further contribute to the generation of multiple isoforms. P53 family proteins can influence a plethora of cellular pathways mainly through the direct binding to specific DNA sequences known as response elements (REs), and the transactivation of the corresponding target genes. However, the transcriptional activation by P53 family members can be regulated at multiple levels, including the DNA topology at responsive promoters. Here, by using a yeast-based functional assay, we evaluated the influence that a G-quadruplex (G4) prone sequence adjacent to the p53 RE derived from the apoptotic PUMA target gene can exert on the transactivation potential of full-length and N-terminal truncated P53 family α isoforms (wild-type and mutant). Our results show that the presence of a G4 prone sequence upstream or downstream of the P53 RE leads to significant changes in the relative activity of P53 family proteins, emphasizing the potential role of structural DNA features as modifiers of P53 family functions at target promoter sites.

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Section: Discussionmentioning

confidence: 63%

Evaluating the Influence of a G-Quadruplex Prone Sequence on the Transactivation Potential by Wild-Type and/or Mutant P53 Family Proteins through a Yeast-Based Functional Assay

Monti

Brázda

Bohálová

et al. 2021

Genes

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“…The observed DNA polymerase stalling at the center of the (A 2 G 3 ) 10 strand strongly implicates H-r DNA triplex formation (Figure 1D ). The lack of a potassium cation due to optimal Thermo Sequenase reaction conditions renders G-quadruplex formation less likely ( 46 , 47 ). Furthermore, G-quadruplex-forming sequences usually stall polymerases directly at the 3′ end of the sequence ( 47 , 48 ), rather than at the center.…”

Section: Resultsmentioning

confidence: 99%

“…The lack of a potassium cation due to optimal Thermo Sequenase reaction conditions renders G-quadruplex formation less likely ( 46 , 47 ). Furthermore, G-quadruplex-forming sequences usually stall polymerases directly at the 3′ end of the sequence ( 47 , 48 ), rather than at the center. The minor stall within the nonpathogenic (A 4 G) 10 repeat template is likely caused by a much weaker H-r DNA triplex.…”

Section: Resultsmentioning

confidence: 99%

Pathogenic CANVAS (AAGGG)n repeats stall DNA replication due to the formation of alternative DNA structures

Hisey,

Radchenko,

Mandel

et al. 2024

Nucleic Acids Research

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CANVAS is a recently characterized repeat expansion disease, most commonly caused by homozygous expansions of an intronic (A2G3)n repeat in the RFC1 gene. There are a multitude of repeat motifs found in the human population at this locus, some of which are pathogenic and others benign. In this study, we conducted structure-functional analyses of the pathogenic (A2G3)n and nonpathogenic (A4G)n repeats. We found that the pathogenic, but not the nonpathogenic, repeat presents a potent, orientation-dependent impediment to DNA polymerization in vitro. The pattern of the polymerization blockage is consistent with triplex or quadruplex formation in the presence of magnesium or potassium ions, respectively. Chemical probing of both repeats in vitro reveals triplex H-DNA formation by only the pathogenic repeat. Consistently, bioinformatic analysis of S1-END-seq data from human cell lines shows preferential H-DNA formation genome-wide by (A2G3)n motifs over (A4G)n motifs. Finally, the pathogenic, but not the nonpathogenic, repeat stalls replication fork progression in yeast and human cells. We hypothesize that the CANVAS-causing (A2G3)n repeat represents a challenge to genome stability by folding into alternative DNA structures that stall DNA replication.

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“…Stable G4s formed in the genomic DNA in the presence of potassium ions act as the barrier for DNA polymerase. It often becomes an obstacle for PCR amplification in genome regions including GC-rich sites prone to the formation of G4 structures [ 46 ]. The approach based on high-performance sequencing of the errors occurring in the presence of potassium ions is currently considered the best in the experimental prediction of the G4 refolding potential in genomic DNA [ 47 ].…”

Section: Dna Methylation Homeostasismentioning

confidence: 99%

DNA Methylation: Genomewide Distribution, Regulatory Mechanism and Therapy Target

et al. 2023

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DNA methylation is the most important epigenetic modification involved in the regulation of transcription, imprinting, establishment of X-inactivation, and the formation of a chromatin structure. DNA methylation in the genome is often associated with transcriptional repression and the formation of closed heterochromatin. However, the results of genome-wide studies of the DNA methylation pattern and transcriptional activity of genes have nudged us toward reconsidering this paradigm, since the promoters of many genes remain active despite their methylation. The differences in the DNA methylation distribution in normal and pathological conditions allow us to consider methylation as a diagnostic marker or a therapy target. In this regard, the need to investigate the factors affecting DNA methylation and those involved in its interpretation becomes pressing. Recently, a large number of protein factors have been uncovered, whose ability to bind to DNA depends on their methylation. Many of these proteins act not only as transcriptional activators or repressors, but also affect the level of DNA methylation. These factors are considered potential therapeutic targets for the treatment of diseases resulting from either a change in DNA methylation or a change in the interpretation of its methylation level. In addition to protein factors, a secondary DNA structure can also affect its methylation and can be considered as a therapy target. In this review, the latest research into the DNA methylation landscape in the genome has been summarized to discuss why some DNA regions avoid methylation and what factors can affect its level or interpretation and, therefore, can be considered a therapy target.

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Stable G-Quadruplex Structures of Oncogene Promoters Induce Potassium-Dependent Stops of Thermostable DNA Polymerase

Cited by 10 publications

References 23 publications

Evaluating the Influence of a G-Quadruplex Prone Sequence on the Transactivation Potential by Wild-Type and/or Mutant P53 Family Proteins through a Yeast-Based Functional Assay

Evaluating the Influence of a G-Quadruplex Prone Sequence on the Transactivation Potential by Wild-Type and/or Mutant P53 Family Proteins through a Yeast-Based Functional Assay

Pathogenic CANVAS (AAGGG)n repeats stall DNA replication due to the formation of alternative DNA structures

DNA Methylation: Genomewide Distribution, Regulatory Mechanism and Therapy Target

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