Genotoxic stress response: What is the role of cytoplasmic mRNA fate?

Mohanan, Gayatri; Das, Amiyaranjan; Rajyaguru, Purusharth I

doi:10.1002/bies.202000311

Cited by 9 publications

(6 citation statements)

References 131 publications

(198 reference statements)

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“…Our previous results on the proteome of HL-60 cells treated with ATRA suggest the involvement of major DNA repair regulators such as poly(ADP-ribose) polymerase 1 (PARP1) [11]. A recent study shows that mRNA translation and degradation play a critical role in response to genotoxic stress [32]. At the same time, changes related to endoplasmic reticulum stress could be associated with a putative regulatory mechanism involving components, which could be affected pharmacologically.…”

Section: Discussionmentioning

confidence: 99%

Systems Biology for Drug Target Discovery in Acute Myeloid Leukemia

Novikova,

Tolstova,

Kurbatov

et al. 2024

IJMS

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Combining new therapeutics with all-trans-retinoic acid (ATRA) could improve the efficiency of acute myeloid leukemia (AML) treatment. Modeling the process of ATRA-induced differentiation based on the transcriptomic profile of leukemic cells resulted in the identification of key targets that can be used to increase the therapeutic effect of ATRA. The genome-scale transcriptome analysis revealed the early molecular response to the ATRA treatment of HL-60 cells. In this study, we performed the transcriptomic profiling of HL-60, NB4, and K562 cells exposed to ATRA for 3-72 h. After treatment with ATRA for 3, 12, 24, and 72 h, we found 222, 391, 359, and 1032 differentially expressed genes (DEGs) in HL-60 cells, as well as 641, 1037, 1011, and 1499 DEGs in NB4 cells. We also found 538 and 119 DEGs in K562 cells treated with ATRA for 24 h and 72 h, respectively. Based on experimental transcriptomic data, we performed hierarchical modeling and determined cyclin-dependent kinase 6 (CDK6), tumor necrosis factor alpha (TNF-alpha), and transcriptional repressor CUX1 as the key regulators of the molecular response to the ATRA treatment in HL-60, NB4, and K562 cell lines, respectively. Mapping the data of TMT-based mass-spectrometric profiling on the modeling schemes, we determined CDK6 expression at the proteome level and its down-regulation at the transcriptome and proteome levels in cells treated with ATRA for 72 h. The combination of therapy with a CDK6 inhibitor (palbociclib) and ATRA (tretinoin) could be an alternative approach for the treatment of acute myeloid leukemia (AML).

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Section: Discussionmentioning

confidence: 99%

Systems Biology for Drug Target Discovery in Acute Myeloid Leukemia

Novikova,

Tolstova,

Kurbatov

et al. 2024

IJMS

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“…The cellular DNA-damage response (DDR) involves cell cycle arrest and growth inhibition, activation of DNA repair mechanisms and ultimately programmed cell death if the DNA damage is irreparable. Post-transcriptional regulatory mechanisms, involving alterations of mRNA translation/ turnover, are increasingly found to be involved in the genotoxic stress response (Mohanan et al, 2021). The tumor suppressor protein p53 (TP53) is the key regulator of the DDR (Abuetabh et al, 2022).…”

Section: Genotoxic Stress Regulates Localization Expression and Degra...mentioning

confidence: 99%

Fates and functions of RNA‐binding proteins under stress

Goswami,

Nag,

Ray

2023

WIREs RNA

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Exposure to stress activates a well‐orchestrated set of changes in gene expression programs that allow the cell to cope with and adapt to the stress, or undergo programmed cell death. RNA–protein interactions, mediating all aspects of post‐transcriptional regulation of gene expression, play crucial roles in cellular stress responses. RNA‐binding proteins (RBPs), which interact with sequence/structural elements in RNAs to control the steps of RNA metabolism, have therefore emerged as central regulators of post‐transcriptional responses to stress. Following exposure to a variety of stresses, the dynamic alterations in the RNA‐protein interactome enable cells to respond to intracellular or extracellular perturbations by causing changes in mRNA splicing, polyadenylation, stability, translation, and localization. As RBPs play a central role in determining the cellular proteome both qualitatively and quantitatively, it has become increasingly evident that their abundance, availability, and functions are also highly regulated in response to stress. Exposure to stress initiates a series of signaling cascades that converge on post‐translational modifications (PTMs) of RBPs, resulting in changes in their subcellular localization, association with stress granules, extracellular export, proteasomal degradation, and RNA‐binding activities. These alterations in the fate and function of RBPs directly impact their post‐transcriptional regulatory roles in cells under stress. Adopting the ubiquitous RBP HuR as a prototype, three scenarios illustrating the changes in nuclear‐cytoplasmic localization, RNA‐binding activity, export and degradation of HuR in response to inflammation, genotoxic stress, and heat shock depict the complex and interlinked regulatory mechanisms that control the fate and functions of RBPs under stress.This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein‐RNA Interactions: Functional Implications

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“…Genotoxic stress in mammalian cells is defined as a situation that initiates DNA damage compromising the cell's genomic integrity leading to replication and transcription arrest [1] and underlies many pathological conditions including cellular senescence [2][3][4][5], cancer [6][7][8][9] and cardiovascular diseases [10][11][12][13][14]. Recent experimental data suggest that the genotoxic stress in vitro induced by alkylating mutagen mitomycin C (MMC) is associated with the proinflammatory activation of primary human endothelial cells and the endothelial-to-mesenchymal transition [15][16][17], the key pathways underlying endothelial disfunction [18]-an initial stage of atherosclerosis [19,20], a leading cause of cardiovascular morbidity and mortality worldwide [21,22].…”

Section: Introductionmentioning

confidence: 99%

Proteomic Profiling of Endothelial Cells Exposed to Mitomycin C: Key Proteins and Pathways Underlying Genotoxic Stress-Induced Endothelial Dysfunction

Sinitsky,

Repkin,

Sinitskaya

et al. 2024

IJMS

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Mitomycin C (MMC)-induced genotoxic stress can be considered to be a novel trigger of endothelial dysfunction and atherosclerosis—a leading cause of cardiovascular morbidity and mortality worldwide. Given the increasing genotoxic load on the human organism, the decryption of the molecular pathways underlying genotoxic stress-induced endothelial dysfunction could improve our understanding of the role of genotoxic stress in atherogenesis. Here, we performed a proteomic profiling of human coronary artery endothelial cells (HCAECs) and human internal thoracic endothelial cells (HITAECs) in vitro that were exposed to MMC to identify the biochemical pathways and proteins underlying genotoxic stress-induced endothelial dysfunction. We denoted 198 and 71 unique, differentially expressed proteins (DEPs) in the MMC-treated HCAECs and HITAECs, respectively; only 4 DEPs were identified in both the HCAECs and HITAECs. In the MMC-treated HCAECs, 44.5% of the DEPs were upregulated and 55.5% of the DEPs were downregulated, while in HITAECs, these percentages were 72% and 28%, respectively. The denoted DEPs are involved in the processes of nucleotides and RNA metabolism, vesicle-mediated transport, post-translation protein modification, cell cycle control, the transport of small molecules, transcription and signal transduction. The obtained results could improve our understanding of the fundamental basis of atherogenesis and help in the justification of genotoxic stress as a risk factor for atherosclerosis.

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Genotoxic stress response: What is the role of cytoplasmic mRNA fate?

Cited by 9 publications

References 131 publications

Systems Biology for Drug Target Discovery in Acute Myeloid Leukemia

Systems Biology for Drug Target Discovery in Acute Myeloid Leukemia

Fates and functions of RNA‐binding proteins under stress

Proteomic Profiling of Endothelial Cells Exposed to Mitomycin C: Key Proteins and Pathways Underlying Genotoxic Stress-Induced Endothelial Dysfunction

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