scholarly journals R-Loops and Its Chro-Mates: The Strange Case of Dr. Jekyll and Mr. Hyde

2021 ◽  
Vol 22 (16) ◽  
pp. 8850
Author(s):  
Sidrit Uruci ◽  
Calvin Shun Yu Lo ◽  
David Wheeler ◽  
Nitika Taneja
Keyword(s):  
Replication Fork ◽  
Potential Role ◽  
Genome Instability ◽  
Chromatin Modification ◽  
Therapeutic Interventions ◽  
Epigenetic Landscape ◽  
Physiological Processes ◽  
Stalled Fork ◽  
Chromatin Modifiers

Since their discovery, R-loops have been associated with both physiological and pathological functions that are conserved across species. R-loops are a source of replication stress and genome instability, as seen in neurodegenerative disorders and cancer. In response, cells have evolved pathways to prevent R-loop accumulation as well as to resolve them. A growing body of evidence correlates R-loop accumulation with changes in the epigenetic landscape. However, the role of chromatin modification and remodeling in R-loops homeostasis remains unclear. This review covers various mechanisms precluding R-loop accumulation and highlights the role of chromatin modifiers and remodelers in facilitating timely R-loop resolution. We also discuss the enigmatic role of RNA:DNA hybrids in facilitating DNA repair, epigenetic landscape and the potential role of replication fork preservation pathways, active fork stability and stalled fork protection pathways, in avoiding replication-transcription conflicts. Finally, we discuss the potential role of several Chro-Mates (chromatin modifiers and remodelers) in the likely differentiation between persistent/detrimental R-loops and transient/benign R-loops that assist in various physiological processes relevant for therapeutic interventions.

The GCN5: its biological functions and therapeutic potentials

2021 ◽  
Vol 135 (1) ◽  
pp. 231-257
Author(s):  
Md. Ezazul Haque ◽  
Md. Jakaria ◽  
Mahbuba Akther ◽  
Duk-Yeon Cho ◽  
In-Su Kim ◽  
...  
Keyword(s):  
Neurological Disorders ◽  
Cellular Proliferation ◽  
Chromatin Modification ◽  
Structural Features ◽  
Histone Acetyltransferases ◽  
Epigenetic Landscape ◽  
General Control ◽  
Wide Range ◽  
Lysine Acetyltransferase

Abstract General control non-depressible 5 (GCN5) or lysine acetyltransferase 2A (KAT2A) is one of the most highly studied histone acetyltransferases. It acts as both histone acetyltransferase (HAT) and lysine acetyltransferase (KAT). As an HAT it plays a pivotal role in the epigenetic landscape and chromatin modification. Besides, GCN5 regulates a wide range of biological events such as gene regulation, cellular proliferation, metabolism and inflammation. Imbalance in the GCN5 activity has been reported in many disorders such as cancer, metabolic disorders, autoimmune disorders and neurological disorders. Therefore, unravelling the role of GCN5 in different diseases progression is a prerequisite for both understanding and developing novel therapeutic agents of these diseases. In this review, we have discussed the structural features, the biological function of GCN5 and the mechanical link with the diseases associated with its imbalance. Moreover, the present GCN5 modulators and their limitations will be presented in a medicinal chemistry perspective.

scholarly journals Exosomes: A Novel Therapeutic Paradigm for Treatment of Depression

2020 ◽  
Vol 21 ◽  
Author(s):  
Shvetank Bhatt ◽  
Jovita Kanoujia ◽  
Arghya Kusum Dhar ◽  
Surendar Arumugam ◽  
Amanda K. A. Silva ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Small Rna ◽  
Potential Role ◽  
Vital Role ◽  
Physiological Processes ◽  
Treatment Of Depression ◽  
As Stress ◽  
Novel Therapeutic

Abstract: Extracellular vesicles (EVs) of endocytic origin are known as exosomes. These vesicles are released by cells and are accessible in biofluids, such as saliva, urine, and plasma. These vesicles are made up of small RNA, DNA, proteins and play a vital role in many physiological processes. In central nervous system (CNS), they participate in various physiological processes such as stress of nerve cells, communication between the cells, synaptic plasticity and neurogenesis. The role of exosomes in depression needs to be explored further. It is known that exosomes can cross blood brain barrier (BBB), which is made up of glial cells astrocytes. One of the advantages of these vescicles is that they are able to transfer macromolecules like DNA, protein, mRNAs and miRNAs to recipient cells. This review focuses on the potential role of exosomes in de-pression and their utilization as atreatmentoption or diagnostic tool of depression.

scholarly journals DNA Polymerases at the Eukaryotic Replication Fork Thirty Years after: Connection to Cancer

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3489
Author(s):  
Youri I. Pavlov ◽  
Anna S. Zhuk ◽  
Elena I. Stepchenkova
Keyword(s):  
Replication Fork ◽  
Genome Instability ◽  
Dna Polymerases ◽  
Structure And Function ◽  
The Past ◽  
New Findings ◽  
Dna Strands ◽  
Leading Strand ◽  
And Function

Recent studies on tumor genomes revealed that mutations in genes of replicative DNA polymerases cause a predisposition for cancer by increasing genome instability. The past 10 years have uncovered exciting details about the structure and function of replicative DNA polymerases and the replication fork organization. The principal idea of participation of different polymerases in specific transactions at the fork proposed by Morrison and coauthors 30 years ago and later named “division of labor,” remains standing, with an amendment of the broader role of polymerase δ in the replication of both the lagging and leading DNA strands. However, cancer-associated mutations predominantly affect the catalytic subunit of polymerase ε that participates in leading strand DNA synthesis. We analyze how new findings in the DNA replication field help elucidate the polymerase variants’ effects on cancer.

scholarly journals GRP78 in lung cancer

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Shengkai Xia ◽  
Wenzhe Duan ◽  
Wenwen Liu ◽  
Xinri Zhang ◽  
Qi Wang
Keyword(s):  
Lung Cancer ◽  
Er Stress ◽  
Potential Role ◽  
Prognostic Biomarker ◽  
Therapeutic Interventions ◽  
Comprehensive Understanding ◽  
Protein Response ◽  
First Time

AbstractGlucose-regulating protein 78 (GRP78) is a molecular chaperone in the endoplasmic reticulum (ER) that promotes folding and assembly of proteins, controls the quality of proteins, and regulates ER stress signaling through Ca2+ binding to the ER. In tumors, GRP78 is often upregulated, acting as a central stress sensor that senses and adapts to changes in the tumor microenvironment, mediating ER stress of cancer cells under various stimulations of the microenvironment to trigger the folding protein response. Increasing evidence has shown that GRP78 is closely associated with the progression and poor prognosis of lung cancer, and plays an important role in the treatment of lung cancer. Herein, we reviewed for the first time the functions and mechanisms of GRP78 in the pathological processes of lung cancer, including tumorigenesis, apoptosis, autophagy, progression, and drug resistance, giving a comprehensive understanding of the function of GRP78 in lung cancer. In addition, we also discussed the potential role of GRP78 as a prognostic biomarker and therapeutic target for lung cancer, which is conducive to improving the assessment of lung cancer and the development of new therapeutic interventions.

scholarly journals Sensing R-Loop-Associated DNA Damage to Safeguard Genome Stability

2021 ◽  
Vol 8 ◽  
Author(s):  
Carlo Rinaldi ◽  
Paolo Pizzul ◽  
Maria Pia Longhese ◽  
Diego Bonetti
Keyword(s):  
Dna Damage ◽  
Cellular Response ◽  
Genome Stability ◽  
Genome Instability ◽  
Hybrid Structure ◽  
Physiological Processes ◽  
Dna Strand ◽  
Template Dna ◽  
Dna Substrate

DNA transcription and replication are two essential physiological processes that can turn into a threat for genome integrity when they compete for the same DNA substrate. During transcription, the nascent RNA strongly binds the template DNA strand, leading to the formation of a peculiar RNA–DNA hybrid structure that displaces the non-template single-stranded DNA. This three-stranded nucleic acid transition is called R-loop. Although a programed formation of R-loops plays important physiological functions, these structures can turn into sources of DNA damage and genome instability when their homeostasis is altered. Indeed, both R-loop level and distribution in the genome are tightly controlled, and the list of factors involved in these regulatory mechanisms is continuously growing. Over the last years, our knowledge of R-loop homeostasis regulation (formation, stabilization, and resolution) has definitely increased. However, how R-loops affect genome stability and how the cellular response to their unscheduled formation is orchestrated are still not fully understood. In this review, we will report and discuss recent findings about these questions and we will focus on the role of ATM- and Rad3-related (ATR) and Ataxia–telangiectasia-mutated (ATM) kinases in the activation of an R-loop-dependent DNA damage response.

scholarly journals Protective or Harmful: The Dual Roles of Autophagy in Diabetic Retinopathy

2021 ◽  
Vol 8 ◽  
Author(s):  
Qiaoyun Gong ◽  
Haiyan Wang ◽  
Ping Yu ◽  
Tianwei Qian ◽  
Xun Xu
Keyword(s):  
Diabetic Retinopathy ◽  
Potential Role ◽  
Retinal Cell ◽  
Dual Roles ◽  
Autophagy Flux ◽  
Altered Level ◽  
Physiological Processes ◽  
Pathological Conditions ◽  
Working Age

Autophagy is a self-degradative pathway involving intracellular substance degradation and recycling. Recently, this process has attracted a great deal of attention for its fundamental effect on physiological processes in cells, tissues, and the maintenance of organismal homeostasis. Dysregulation of autophagy occurs in some diseases, including immune disease, cancer, and neurodegenerative conditions. Diabetic retinopathy (DR), as a serious microvascular complication of diabetes, is the main cause of visual loss in working-age adults worldwide. The pathogenic mechanisms of DR are thought to be associated with accumulation of oxidative stress, retinal cell apoptosis, inflammatory response, endoplasmic reticulum (ER) stress, and nutrient starvation. These factors are closely related to the regulation of autophagy under pathological conditions. Increasing evidence has demonstrated the potential role of autophagy in the progression of DR through different pathways. However, to date this role is not understood, and whether the altered level of autophagy flux protects DR, or instead aggravates the progression, needs to be explored. In this review, we explore the alterations and functions of autophagy in different retinal cells and tissues under DR conditions, and explain the mechanisms involved in DR progression. We aim to provide a basis on which DR associated stress-modulated autophagy may be understood, and to suggest novel targets for future therapeutic intervention in DR.

scholarly journals SMARCAD1 Mediated Active Replication Fork Stability Maintains Genome Integrity

2020 ◽  
Author(s):  
Calvin Shun Yu Lo ◽  
Marvin van Toorn ◽  
Vincent Gaggioli ◽  
Mariana Paes Dias ◽  
Yifan Zhu ◽  
...  
Keyword(s):  
Replication Fork ◽  
Genome Stability ◽  
Cellular Proliferation ◽  
Genome Instability ◽  
Genome Integrity ◽  
Replication Forks ◽  
Chromatin Remodeler ◽  
Active Replication ◽  
Fork Stalling ◽  
Stalled Fork

ABSTRACTStalled fork protection pathway mediated by BRCA1/2 proteins is critical for replication fork stability that has implications in tumorigenesis. However, it is unclear if additional mechanisms are required to maintain replication fork stability. We describe a novel mechanism by which the chromatin remodeler SMARCAD1 stabilizes active replication forks that is essential for resistance towards replication poisons. We find that loss of SMARCAD1 results in toxic enrichment of 53BP1 at replication forks which mediates untimely dissociation of PCNA via the PCNA-unloader, ATAD5. Faster dissociation of PCNA causes frequent fork stalling, inefficient fork restart and accumulation of single-stranded DNA resulting in genome instability. Although, loss of 53BP1 in SMARCAD1 mutants restore PCNA levels, fork restart efficiency, genome stability and tolerance to replication poisons; this requires BRCA1 mediated fork protection. Interestingly, fork protection challenged BRCA1-deficient naïve- or PARPi-resistant tumors require SMARCAD1 mediated active fork stabilization to maintain unperturbed fork progression and cellular proliferation.

Platelet Microparticles: Formation and Properties

2017 ◽  
pp. 4-13
Author(s):  
А.А. Кубатиев ◽  
Т.Г. Боровая ◽  
В.Г. Жуховицкий ◽  
С.Г. Адреевская ◽  
Н.В. Шевлягина
Keyword(s):  
Infectious Diseases ◽  
Signaling Pathways ◽  
Potential Role ◽  
Thrombus Formation ◽  
Target Cells ◽  
Physiological Processes ◽  
Phenotypic Features ◽  
Platelet Microparticles

Статья является обзорной, содержит информацию об образовании и свойствах микрочастиц тромбоцитов, их роли в физиологических процессах организма и патогенезе заболеваний. Рассматриваются механизмы ремоделирования плазмолеммы и цитоскелета тромбоцитов в ходе формирования микрочастиц, приводятся фенотипические особенности микрочастиц и их значение как молекулярных трансмиттеров и активаторов сигнальных путей в клетках-мишенях. Представлена информация об участии микрочастиц в патогенезе заболеваний, сопровождающихся тромбообразованием, в регуляции ангиогенеза и метастазировании опухолей. Рассматривается влияние микрочастиц тромбоцитов на факторы воспаления и потенциальная роль микрочастиц в патогенезе инфекционных заболеваний. This article is a review that contains information about the formation and properties of microparticles of platelets, about their role in the physiological processes of the organism and pathogenesis of the disease. Are considered: mechanisms of remodeling plasmolemma and platelet cytoskeleton during formation of microparticles, the phenotypic features of microparticles and their role as molecular transmitters and activators of signaling pathways in target cells. Presents information on the involvement of microparticles in the pathogenesis of diseases associated with thrombus formation, in the regulation of angiogenesis and metastasis of tumors. Discusses the influence of platelet microparticles on inflammation factors and the potential role of microparticles in the pathogenesis of infectious diseases.

scholarly journals Inflammation and autoimmunity in pulmonary hypertension: is there a role for endothelial adhesion molecules? (2017 Grover Conference Series)

2018 ◽  
Vol 8 (2) ◽  
pp. 204589321875759 ◽  
Author(s):  
Wolfgang M. Kuebler ◽  
Sébastien Bonnet ◽  
Arata Tabuchi
Keyword(s):  
Pulmonary Hypertension ◽  
Potential Role ◽  
Disease Process ◽  
Experimental Models ◽  
Therapeutic Interventions ◽  
Pulmonary Resistance ◽  
Resistance Vessels ◽  
Endothelial Adhesion Molecules ◽  
Inflammatory Component

While pulmonary hypertension (PH) has traditionally not been considered as a disease that is directly linked to or, potentially, even caused by inflammation, a rapidly growing body of evidence has demonstrated the accumulation of a variety of inflammatory and immune cells in PH lungs, in and around the wall of remodeled pulmonary resistance vessels and in the vicinity of plexiform lesions, respectively. Concomitantly, abundant production and release of various inflammatory mediators has been documented in both PH patients and experimental models of PH. While these findings unequivocally demonstrate an inflammatory component in PH, they have fueled an intense and presently ongoing debate as to the nature of this inflammatory aspect: is it a mere bystander of or response to the actual disease process, or is it a pathomechanistic contributor or potentially even a trigger of endothelial injury, smooth muscle hypertrophy and hyperplasia, and the resulting lung vascular remodeling? In this review, we will discuss the present evidence for an inflammatory component in PH disease with a specific focus on the potential role of the endothelium in this scenario and highlight future avenues of experimental investigation which may lead to novel therapeutic interventions.

scholarly journals Potential role of Zinc supplement in CVD and COVID-19 co-morbidity

2020 ◽  
Author(s):  
Muhammad Karim ◽  
Shahnaz Sultana ◽  
Rokaia Sultana ◽  
Mohammad Tariqur Rahman
Keyword(s):  
Viral Replication ◽  
Potential Role ◽  
Treatment Plan ◽  
Functional Expression ◽  
Therapeutic Interventions ◽  
Selective Treatment ◽  
Zinc Supplement ◽  
Co Morbidity ◽  
The Given

As far as the comorbidity is concerned, cardiovascular diseases (CVD) appear to be accounted for the highest prevalence, severity, and fatality among COVID 19 patients. A wide array of causal links connecting CVD and COVID-19 baffle the overall prognosis as well as the efficacy of the given therapeutic interventions. At the centre of this puzzle lies ACE2 that works as a receptor for the SARS-CoV-2 and functional expression of which is also needed to minimize vasoconstriction otherwise would lead to high blood pressure. Furthermore, SARS-CoV-2 infection seems to reduce the functional expression of ACE2. Given these circumstances, it might be advisable to consider a treatment plan for COVID-19 patients with CVD in an approach that would neither aggravate the vasodeleterious arm of RAAS nor compromise the vasoprotective arm of RAAS but is effective to minimize or if possible, inhibit the viral replication. A zinc supplement to the selective treatment plan, to be decided by the clinicians depending on the cardiovascular conditions of the patients, is hereafter proposed that might greatly enhance the therapeutic outcome. Notably, ACE2 is a zinc metalloenzyme and zinc is also known to inhibit viral replication.

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