p53 mRNA Metabolism Links with the DNA Damage Response

Gnanasundram, Sivakumar Vadivel; Bonczek, Ondřej; Wang, Lixiao; Chen, Sa; Fåhræus, Robin

doi:10.3390/genes12091446

Cited by 16 publications

(11 citation statements)

References 130 publications

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“…Nodes with a high degree, also known as hubs, are more likely to play an essential role (He and Zhang, 2006). In line with this, multiple review articles have described the key role of MDM2 in the p53-MDM2-signaling axis as part of the DDR (Nag et al, 2013;Haronikova et al, 2019;Gnanasundram et al, 2021;Okazaki, 2022). In addition, we found that MDM2 is targeted by 44 different miRNAs.…”

Section: Figuresupporting

confidence: 76%

A workflow for the creation of regulatory networks integrating miRNAs and lncRNAs associated with exposure to ionizing radiation using open source data and tools

Freiesleben

Unverricht-Yeboah²,

Gütebier³

et al. 2022

Front. Syst. Biol.

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MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are involved in the modulation of the DNA-damage response (DDR) and upon exposure to ionizing radiation (IR), their expression fluctuates. In this study, we propose a workflow that enables the creation of regulatory networks by integrating transcriptomics data as well as regulatory data in order to better understand the interplay between genes, transcription factors (TFs), miRNAs, and lncRNAs in the cellular response to IR. We preprocessed and analyzed publicly available gene expression profiles and then applied our consensus and integration approach using open source data and tools. To exemplify the benefits of our proposed workflow, we identified a total of 32 differentially expressed transcripts corresponding to 20 unique differentially expressed genes (DEGs) and using these DEGs, we constructed a regulatory network consisting of 106 interactions and 100 nodes (11 DEGs, 78 miRNAs, 1 DEG acting as a TF, and 10 lncRNAs). Overrepresentation analyses (ORAs) furthermore linked our DEGs and miRNAs to annotations pertaining to the DDR and to IR. Our results show that MDM2 and E2F7 function as network hubs, and E2F7, miR-25-3p, let-7a-5p, and miR-497-5p are the four nodes with the highest betweenness centrality. In brief, our workflow, that is based on open source data and tools, and that generates a regulatory network, provides novel insights into the regulatory mechanisms involving miRNAs and lncRNAs in the cellular response to IR.

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Section: Figuresupporting

confidence: 76%

A workflow for the creation of regulatory networks integrating miRNAs and lncRNAs associated with exposure to ionizing radiation using open source data and tools

Freiesleben

Unverricht-Yeboah²,

Gütebier³

et al. 2022

Front. Syst. Biol.

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“…It was shown, that endothelial p53 prevents eNOS phosphorylation and impairs endothelium-dependent vasodilatation; its overexpression in Mdm2/Mdm4 deficient mice leads to impaired endothelial function [ 22 , 23 , 24 ]. Moreover, the p53 plays the important role in the DNA damage response by halting the cell cycle and facilitating the DNA damage repair [ 25 , 26 ]. On the other hand, MDM2 is a component of the TRIM28/KAP1-ERBB4-MDM2 complex which links growth factor and DNA damage response pathways [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

Identification of Key Genes and Pathways in Genotoxic Stress Induced Endothelial Dysfunction: Results of Whole Transcriptome Sequencing

et al. 2022

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Atherosclerosis is a leading cause of cardiovascular morbidity and mortality worldwide. Endothelial disfunction underlying the atherogenesis can be triggered by genotoxic stress in endothelial cells. In the presented research whole transcriptome sequencing (RNA-seq) of human coronary artery (HCAEC) and internal thoracic artery (HITAEC) endothelial cells in vitro exposed to 500 ng/mL mitomycin C (treatment group) or 0.9% NaCl (control group) was performed. Resulting to bioinformatic analysis, 56 upregulated differentially expressed genes (DEGs) and 6 downregulated DEGs with absolute fold change ≥ 2 and FDR p-value < 0.05 were selected in HCAEC exposed to mitomycin C compared to the control group; in HITAEC only one upregulated DEG was found. According to Gene Ontology enrichment analysis, DEGs in HCAEC were classified into 25 functional groups of biological processes, while in HITAEC we found no statistically significant (FDR p-value < 0.05) groups. The four largest groups containing more than 50% DEGs (“signal transduction”, “response to stimulus”, “biological regulation”, and “regulation of biological process”) were identified. Finally, candidate DEGs and pathways underlying the genotoxic stress induced endothelial disfunction have been discovered that could improve our understanding of fundamental basis of atherogenesis and help to justification of genotoxic stress as a novel risk factor for atherosclerosis.

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“…p53 plays an important role in maintaining cell homeostasis [ 1 , 2 , 3 ]. This protein is a transcription factor which regulates the expression of many genes, especially in stress conditions, under which the p53 level is elevated.…”

Section: Introductionmentioning

confidence: 99%

“…In a healthy cell, the p53 level is low due to its ubiquitination by Mdm2 and then its degradation. In response to stress conditions, p53 is phosphorylated to prevent the Mdm2–p53 interaction and the p53 level gets higher [ 1 , 2 , 3 ]. Besides the full-length p53, there are several isoforms of this protein in the cell whose expression results from the usage of various transcription promotors, alternative splicing and various translation initiation sites [ 4 , 5 , 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

Structural Characteristics of the 5′-Terminal Region of Mouse p53 mRNA and Identification of Proteins That Bind to This mRNA Region

Szpotkowska

Szpotkowski

Ciesiołka

2022

IJMS

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A mouse model has often been used in studies of p53 gene expression. Detailed interpretation of functional studies is, however, hampered by insufficient knowledge of the impact of mouse p53 mRNA’s structure and its interactions with proteins in the translation process. In particular, the 5′-terminal region of mouse p53 mRNA is an important region which takes part in the regulation of the synthesis of p53 protein and its N-truncated isoform Δ41p53. In this work, the spatial folding of the 5′-terminal region of mouse p53 mRNA and its selected sub-fragments was proposed based on the results of the SAXS method and the RNAComposer program. Subsequently, RNA-assisted affinity chromatography was used to identify proteins present in mouse fibroblast cell lysates that are able to bind the RNA oligomer, which corresponds to the 5′-terminal region of mouse p53 mRNA. Possible sites to which the selected, identified proteins can bind were proposed. Interestingly, most of these binding sites coincide with the sites determined as accessible to hybridization of complementary oligonucleotides. Finally, the high binding affinity of hnRNP K and PCBP2 to the 5′-terminal region of mouse p53 mRNA was confirmed and their possible binding sites were proposed.

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p53 mRNA Metabolism Links with the DNA Damage Response

Cited by 16 publications

References 130 publications

A workflow for the creation of regulatory networks integrating miRNAs and lncRNAs associated with exposure to ionizing radiation using open source data and tools

A workflow for the creation of regulatory networks integrating miRNAs and lncRNAs associated with exposure to ionizing radiation using open source data and tools

Identification of Key Genes and Pathways in Genotoxic Stress Induced Endothelial Dysfunction: Results of Whole Transcriptome Sequencing

Structural Characteristics of the 5′-Terminal Region of Mouse p53 mRNA and Identification of Proteins That Bind to This mRNA Region

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