scholarly journals Genomic Instability and Cellular Senescence: Lessons From the Budding Yeast

2021 ◽  
Vol 8 ◽  
Author(s):  
Jee Whu Lee ◽  
Eugene Boon Beng Ong
Keyword(s):  
Ribosomal Dna ◽  
Cellular Senescence ◽  
Molecular Mechanisms ◽  
Budding Yeast ◽  
Genetic Alterations ◽  
Lessons Learned ◽  
Complex Biological Process ◽  
Dna Instability ◽  
Permanent Cell ◽  
Living Organisms

Aging is a complex biological process that occurs in all living organisms. Aging is initiated by the gradual accumulation of biomolecular damage in cells leading to the loss of cellular function and ultimately death. Cellular senescence is one such pathway that leads to aging. The accumulation of nucleic acid damage and genetic alterations that activate permanent cell-cycle arrest triggers the process of senescence. Cellular senescence can result from telomere erosion and ribosomal DNA instability. In this review, we summarize the molecular mechanisms of telomere length homeostasis and ribosomal DNA stability, and describe how these mechanisms are linked to cellular senescence and longevity through lessons learned from budding yeast.

scholarly journals The epigenetic regulator SIRT7 guards against mammalian cellular senescence induced by ribosomal DNA instability

2018 ◽  
Vol 293 (28) ◽  
pp. 11242-11250 ◽  
Author(s):  
Silvana Paredes ◽  
Maria Angulo-Ibanez ◽  
Luisa Tasselli ◽  
Scott M. Carlson ◽  
Wei Zheng ◽  
...  
Keyword(s):  
Ribosomal Dna ◽  
Cellular Senescence ◽  
Dna Instability ◽  
Epigenetic Regulator

scholarly journals Adipocyte-Mineralocorticoid Receptor Alters Mitochondrial Quality Control Leading to Mitochondrial Dysfunction and Senescence of Visceral Adipose Tissue

2021 ◽  
Vol 22 (6) ◽  
pp. 2881
Author(s):  
Clara Lefranc ◽  
Malou Friederich-Persson ◽  
Fabienne Foufelle ◽  
Aurélie Nguyen Dinh Cat ◽  
Frédéric Jaisser
Keyword(s):  
Quality Control ◽  
Adipose Tissue ◽  
Mitochondrial Dysfunction ◽  
Cellular Senescence ◽  
Mineralocorticoid Receptor ◽  
Molecular Mechanisms ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Quality Control ◽  
Mitochondrial Oxidative Stress ◽  
Specific Effects

Mineralocorticoid receptor (MR) expression is increased in the adipose tissue (AT) of obese patients and animals. We previously demonstrated that adipocyte-MR overexpression in mice (Adipo-MROE mice) is associated with metabolic alterations. Moreover, we showed that MR regulates mitochondrial dysfunction and cellular senescence in the visceral AT of obese db/db mice. Our hypothesis is that adipocyte-MR overactivation triggers mitochondrial dysfunction and cellular senescence, through increased mitochondrial oxidative stress (OS). Using the Adipo-MROE mice with conditional adipocyte-MR expression, we evaluated the specific effects of adipocyte-MR on global and mitochondrial OS, as well as on OS-induced damage. Mitochondrial function was assessed by high throughput respirometry. Molecular mechanisms were probed in AT focusing on mitochondrial quality control and senescence markers. Adipo-MROE mice exhibited increased mitochondrial OS and altered mitochondrial respiration, associated with reduced biogenesis and increased fission. This was associated with OS-induced DNA-damage and AT premature senescence. In conclusion, targeted adipocyte-MR overexpression leads to an imbalance in mitochondrial dynamics and regeneration, to mitochondrial dysfunction and to ageing in visceral AT. These data bring new insights into the MR-dependent AT dysfunction in obesity.

scholarly journals WNK-SPAK/OSR1 signaling: lessons learned from an insect renal epithelium

2018 ◽  
Vol 315 (4) ◽  
pp. F903-F907 ◽  
Author(s):  
Aylin R. Rodan
Keyword(s):  
Ion Transport ◽  
Calcium Binding ◽  
Molecular Mechanisms ◽  
Extracellular Volume ◽  
Lessons Learned ◽  
Renal Epithelium ◽  
Dietary Potassium ◽  
Wnk Kinases ◽  
Cation Chloride Cotransporters

WNK [with no lysine (K)] kinases regulate renal epithelial ion transport to maintain homeostasis of electrolyte concentrations, extracellular volume, and blood pressure. The SLC12 cation-chloride cotransporters, including the sodium-potassium-2-chloride (NKCC) and sodium chloride cotransporters (NCC), are targets of WNK regulation via the intermediary kinases SPAK (Ste20-related proline/alanine-rich kinase) and OSR1 (oxidative stress response). The pathway is activated by low dietary potassium intake, resulting in increased phosphorylation and activity of NCC. Chloride regulates WNK kinases in vitro by binding to the active site and inhibiting autophosphorylation and has been proposed to modulate WNK activity in the distal convoluted tubule in response to low dietary potassium. WNK-SPAK/OSR1 regulation of NKCC-dependent ion transport is evolutionarily ancient, and it occurs in the Drosophila Malpighian (renal) tubule. Here, we review recent studies from the Drosophila tubule demonstrating cooperative roles for chloride and the scaffold protein Mo25 (mouse protein-25, also known as calcium-binding protein-39) in the regulation of WNK-SPAK/OSR1 signaling in a transporting renal epithelium. Insights gained from this genetically manipulable and physiologically accessible epithelium shed light on molecular mechanisms of regulation of the WNK-SPAK/OSR1 pathway, which is important in human health and disease.

scholarly journals Obstructive Sleep Apnea as an Acceleration Trigger of Cellular Senescence Processes through Telomere Shortening

2021 ◽  
Vol 22 (22) ◽  
pp. 12536
Author(s):  
Szymon Turkiewicz ◽  
Marta Ditmer ◽  
Marcin Sochal ◽  
Piotr Białasiewicz ◽  
Dominik Strzelecki ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Obstructive Sleep Apnea ◽  
Sleep Apnea ◽  
Circadian Clock ◽  
Chronic Inflammation ◽  
Cellular Senescence ◽  
Molecular Mechanisms ◽  
Telomere Shortening ◽  
Age Related ◽  
Obstructive Sleep

Obstructive sleep apnea (OSA) is chronic disorder which is characterized by recurrent pauses of breathing during sleep which leads to hypoxia and its two main pathological sequelae: oxidative stress and chronic inflammation. Both are also associated with cellular senescence. As OSA patients present with higher prevalence of age-related disorders, such as atrial hypertension or diabetes mellitus type 2, a relationship between OSA and accelerated aging is observable. Furthermore, it has been established that these OSA are associated with telomere shortening. This process in OSA is likely caused by increased oxidative DNA damage due to increased reactive oxygen species levels, DNA repair disruptions, hypoxia, chronic inflammation, and circadian clock disturbances. The aim of the review is to summarize study outcomes on changes in leukocyte telomere length (LTL) in OSA patients and describe possible molecular mechanisms which connect cellular senescence and the pathophysiology of OSA. The majority of OSA patients are characterized by LTL attrition due to oxidative stress, hypoxia and inflammation, which make a kind of positive feedback loop, and circadian clock disturbance.

scholarly journals Widespread alteration of protein autoinhibition in human cancers

2018 ◽  
Author(s):  
Ashwani Jha ◽  
Jennifer M. Bui ◽  
Dokyun Na ◽  
Jörg Gsponer
Keyword(s):  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Signal Propagation ◽  
Genetic Alterations ◽  
Missense Mutations ◽  
Pathway Activation ◽  
Tumorigenic Potential ◽  
Significant Enrichment ◽  
Cancer Types ◽  
Cancer Drivers

ABSTRACTAutoinhibition is a prevalent allosteric regulatory mechanism in signaling proteins as it prevents spurious pathway activation and primes for signal propagation only under appropriate inputs. Altered functioning of inhibitory allosteric switches underlies the tumorigenic potential of numerous cancer drivers. However, whether protein autoinhibition is altered generically in cancer cells remains elusive. Here, we reveal that cancer-associated missense mutations and fusion breakpoints are found with significant enrichment within inhibitory allosteric switches across all cancer types, which in the case of the fusion breakpoints is specific to cancer and not present in other diseases. Recurrently disrupted or mutated allosteric switches identify established and new cancer drivers. Cancer-specific mutations in allosteric switches are associated with distinct changes in signaling, and suggest molecular mechanisms for altered protein regulation, which in the case of ASK1, DAPK2 and EIF4G1 were supported by biophysical simulations. Our results demonstrate that autoinhibition-modulating genetic alterations are positively selected for by cancer cells, and that their study provides valuable insights into molecular mechanisms of cancer misregulation.

scholarly journals Comparative transcriptome and metabolome analyses provide new insights into the molecular mechanisms underlying taproot thickening in Panax notoginseng

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Xue-Jiao Li ◽  
Jian-Li Yang ◽  
Bing Hao ◽  
Ying-Chun Lu ◽  
Zhi-Long Qian ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Panax Notoginseng ◽  
Chinese Medicinal Herb ◽  
Developmental Factors ◽  
Expression Of Genes ◽  
Complex Biological Process ◽  
Phenylpropanoid Biosynthesis ◽  
Coordinated Expression ◽  
Major Storage Protein

Abstract Background Taproot thickening is a complex biological process that is dependent on the coordinated expression of genes controlled by both environmental and developmental factors. Panax notoginseng is an important Chinese medicinal herb that is characterized by an enlarged taproot as the main organ of saponin accumulation. However, the molecular mechanisms of taproot enlargement are poorly understood. Results A total of 29,957 differentially expressed genes (DEGs) were identified during the thickening process in the taproots of P. notoginseng. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment revealed that DEGs associated with “plant hormone signal transduction,” “starch and sucrose metabolism,” and “phenylpropanoid biosynthesis” were predominantly enriched. Further analysis identified some critical genes (e.g., RNase-like major storage protein, DA1-related protein, and Starch branching enzyme I) and metabolites (e.g., sucrose, glucose, fructose, malate, and arginine) that potentially control taproot thickening. Several aspects including hormone crosstalk, transcriptional regulation, homeostatic regulation between sugar and starch, and cell wall metabolism, were identified as important for the thickening process in the taproot of P. notoginseng. Conclusion The results provide a molecular regulatory network of taproot thickening in P. notoginseng and facilitate the further characterization of the genes responsible for taproot formation in root medicinal plants or crops.

scholarly journals Exploiting evolutionary trade-offs for posttreatment management of drug-resistant populations

2020 ◽  
Vol 117 (30) ◽  
pp. 17924-17931
Author(s):  
Sergey V. Melnikov ◽  
David L. Stevens ◽  
Xian Fu ◽  
Hui Si Kwok ◽  
Jin-Tao Zhang ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Molecular Mechanisms ◽  
Genetic Alterations ◽  
Trna Synthetase ◽  
Molecular Defect ◽  
Antibiotic Resistant ◽  
Resistance Evolution ◽  
Growth Defects ◽  
Trade Offs ◽  
Resistant Cells

Antibiotic resistance frequently evolves through fitness trade-offs in which the genetic alterations that confer resistance to a drug can also cause growth defects in resistant cells. Here, through experimental evolution in a microfluidics-based turbidostat, we demonstrate that antibiotic-resistant cells can be efficiently inhibited by amplifying the fitness costs associated with drug-resistance evolution. Using tavaborole-resistantEscherichia colias a model, we show that genetic mutations in leucyl-tRNA synthetase (that underlie tavaborole resistance) make resistant cells intolerant to norvaline, a chemical analog of leucine that is mistakenly used by tavaborole-resistant cells for protein synthesis. We then show that tavaborole-sensitive cells quickly outcompete tavaborole-resistant cells in the presence of norvaline due to the amplified cost of the molecular defect of tavaborole resistance. This finding illustrates that understanding molecular mechanisms of drug resistance allows us to effectively amplify even small evolutionary vulnerabilities of resistant cells to potentially enhance or enable adaptive therapies by accelerating posttreatment competition between resistant and susceptible cells.

scholarly journals Dissimilar Appearances Are Deceptive–Common microRNAs and Therapeutic Strategies in Liver Cancer and Melanoma

Cells ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 114
Author(s):  
Lisa Linck-Paulus ◽  
Claus Hellerbrand ◽  
Anja K. Bosserhoff ◽  
Peter Dietrich
Keyword(s):  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Therapeutic Targets ◽  
Genetic Alterations ◽  
Therapeutic Strategies ◽  
The Future ◽  
Associated Proteins ◽  
Cancer Types ◽  
Novel Therapeutic Strategies

In this review, we summarize the current knowledge on miRNAs as therapeutic targets in two cancer types that were frequently described to be driven by miRNAs—melanoma and hepatocellular carcinoma (HCC). By focusing on common microRNAs and associated pathways in these—at first sight—dissimilar cancer types, we aim at revealing similar molecular mechanisms that are evolved in microRNA-biology to drive cancer progression. Thereby, we also want to outlay potential novel therapeutic strategies. After providing a brief introduction to general miRNA biology and basic information about HCC and melanoma, this review depicts prominent examples of potent oncomiRs and tumor-suppressor miRNAs, which have been proven to drive diverse cancer types including melanoma and HCC. To develop and apply miRNA-based therapeutics for cancer treatment in the future, it is essential to understand how miRNA dysregulation evolves during malignant transformation. Therefore, we highlight important aspects such as genetic alterations, miRNA editing and transcriptional regulation based on concrete examples. Furthermore, we expand our illustration by focusing on miRNA-associated proteins as well as other regulators of miRNAs which could also provide therapeutic targets. Finally, design and delivery strategies of miRNA-associated therapeutic agents as well as potential drawbacks are discussed to address the question of how miRNAs might contribute to cancer therapy in the future.

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