Unlocking p53 response elements: DNA shape is the key

Farkas, Marina; McMahon, Steven B.

doi:10.1080/23723556.2021.1905489

Cited by 3 publications

(2 citation statements)

References 9 publications

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“…The p53 binding site in the DNA reflects and co-evolved with the quaternary conformation of the protein. As the active protein structure is a p53 tetramer, so the p53 REs comprise an arrangement of four binding sites, consisting of five nucleotides, which are organized as inverted repeat dimers (i.e., a half-site), and two such dimers are placed adjacent or closely spaced to form an entire site [ 25 , 26 , 27 , 28 , 29 ]. Many studies based both on in vivo approaches, such as ChIP-seq or ChIP-Exo, and in vitro assays, such as Selex-seq, have derived the features of the p53 consensus RE and cataloged the many variants present in genomes (reviewed in [ 28 , 30 , 31 ]).…”

Section: Introductionmentioning

confidence: 99%

Structural Basis of Mutation-Dependent p53 Tetramerization Deficiency

Rigoli

Spagnolli

Lorengo

et al. 2022

IJMS

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The formation of a tetrameric assembly is essential for the ability of the tumor suppressor protein p53 to act as a transcription factor. Such a quaternary conformation is driven by a specific tetramerization domain, separated from the central DNA-binding domain by a flexible linker. Despite the distance, functional crosstalk between the two domains has been reported. This phenomenon can explain the pathogenicity of some inherited or somatically acquired mutations in the tetramerization domain, including the widespread R337H missense mutation present in the population in south Brazil. In this work, we combined computational predictions through extended all-atom molecular dynamics simulations with functional assays in a genetically defined yeast-based model system to reveal structural features of p53 tetramerization domains and their transactivation capacity and specificity. In addition to the germline and cancer-associated R337H and R337C, other rationally designed missense mutations targeting a significant salt-bridge interaction that stabilizes the p53 tetramerization domain were studied (i.e., R337D, D352R, and the double-mutation R337D plus D352R). The simulations revealed a destabilizing effect of the pathogenic mutations within the p53 tetramerization domain and highlighted the importance of electrostatic interactions between residues 337 and 352. The transactivation assay, performed in yeast by tuning the expression of wild-type and mutant p53 proteins, revealed that p53 tetramerization mutations could decrease the transactivation potential and alter transactivation specificity, in particular by better tolerating negative features in weak DNA-binding sites. These results establish the effect of naturally occurring variations at positions 337 and 352 on p53’s conformational stability and function.

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Section: Introductionmentioning

confidence: 99%

Structural Basis of Mutation-Dependent p53 Tetramerization Deficiency

Rigoli

Spagnolli

Lorengo

et al. 2022

IJMS

View full text Add to dashboard Cite

show abstract

“…The p53 binding site in the DNA reflects and co-evolved with the quaternary conformation of the protein. As the active protein structure is a p53 tetramer, so the p53 REs comprises an arrangement of four binding sites, consisting of 5 nucleotides, which are organized as inverted repeat dimers (i.e., a half-site), and two such dimers are placed adjacent or closely spaced to form an entire site [23][24][25][26][27][28] . Many studies based both on in vivo approaches, such as ChIP-seq or ChIP-Exo, and in vitro assays, such as Selex-seq, have derived the features of the p53 consensus RE and cataloged the many variants present in genomes (reviewed in 26,28,29 ).…”

Section: Introductionmentioning

confidence: 99%

Structural Basis of Mutation-Dependent p53 Tetramerization Deficiency

Rigoli

Spagnolli

Lorengo

et al. 2022

Preprint

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The formation of a tetrameric assembly is essential for the ability of the tumor suppressor protein p53 to act as a transcription factor. Such a quaternary conformation is driven by a specific tetramerization domain, separated from the central DNA binding domain by a flexible linker. Despite the distance, functional crosstalk between the two domains has been reported. This phenomenon can explain the pathogenicity of some inherited or somatically acquired mutations in the tetramerization domain, including the widespread R337H missense mutation occurring in the population of south Brazil. In this work, we have combined computational predictions through extended all-atom molecular dynamics simulations with functional assays in a genetically defined yeast-based model system to reveal structural features of p53 tetramerization domains and their transactivation capacity and specificity. Besides the germline and cancer-associated R337H and R337C, other rationally designed missense mutations targeting a significant salt bridge interaction that stabilizes the p53 tetramerization domain were studied (R337D, D352R, and the double mutation R337D plus D352R). Simulations revealed a destabilizing effect of pathogenic mutations within the p53 tetramerization domain and highlighted the importance of electrostatic interactions between residues 337 and 352. The transactivation assay performed in yeast by tuning the expression of wild-type and mutant p53 proteins revealed that p53 tetramerization mutations could decrease transactivation potential and alter transactivation specificity, in particular, by better tolerating the negative features in weak DNA binding sites. These results establish the effect of naturally occurring variations at positions 337 and 352 on p53 conformational stability and function.

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The Importance of the Immune System and Molecular Cell Signaling Pathways in the Pathogenesis and Progression of Lung Cancer

Smok-Kalwat

Mertowska

Mertowski

et al. 2023

IJMS

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Lung cancer is a disease that in recent years has become one of the greatest threats to modern society. Every year there are more and more new cases and the percentage of deaths caused by this type of cancer increases. Despite many studies, scientists are still looking for answers regarding the mechanisms of lung cancer development and progression, with particular emphasis on the role of the immune system. The aim of this literature review was to present the importance of disorders of the immune system and the accompanying changes at the level of cell signaling in the pathogenesis of lung cancer. The collected results showed that in the process of immunopathogenesis of almost all subtypes of lung cancer, changes in the tumor microenvironment, deregulation of immune checkpoints and abnormalities in cell signaling pathways are involved, which contribute to the multistage and multifaceted carcinogenesis of this type of cancer. We, therefore, suggest that in future studies, researchers should focus on a detailed analysis of tumor microenvironmental immune checkpoints, and to validate their validity, perform genetic polymorphism analyses in a wide range of patients and healthy individuals to determine the genetic susceptibility to lung cancer development. In addition, further research related to the analysis of the tumor microenvironment; immune system disorders, with a particular emphasis on immunological checkpoints and genetic differences may contribute to the development of new personalized therapies that improve the prognosis of patients.

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Unlocking p53 response elements: DNA shape is the key

Cited by 3 publications

References 9 publications

Structural Basis of Mutation-Dependent p53 Tetramerization Deficiency

Structural Basis of Mutation-Dependent p53 Tetramerization Deficiency

Structural Basis of Mutation-Dependent p53 Tetramerization Deficiency

The Importance of the Immune System and Molecular Cell Signaling Pathways in the Pathogenesis and Progression of Lung Cancer

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