scholarly journals The role of chromatin at transcription-replication conflicts as a genome safeguard

2021 ◽  
Author(s):  
Aleix Bayona-Feliu ◽  
Andrés Aguilera
Keyword(s):  
Cellular Response ◽  
Replication Fork ◽  
Genome Instability ◽  
Current Knowledge ◽  
Genome Integrity ◽  
Physiological Relevance ◽  
A Genome ◽  
Dna Template ◽  
Transcription And Replication

DNA replication ensures the correct copying of the genome and the faithful transfer of the genetic information to the offspring. However, obstacles to replication fork (RF) progression cause RF stalling and compromise efficient genome duplication. Since replication uses the same DNA template as transcription, both transcription and replication must be coordinated to prevent Transcription-Replication Conflicts (TRCs) that could stall RF progression. Several factors contribute to limit the occurrence of such conflicts and their harmful impact on genome integrity. Increasing evidence indicates that chromatin homeostasis plays a key role in the cellular response to TRCs as well as in the preservation of genome integrity. Indeed, chromatin regulating enzymes are frequently mutated in cancer cells, a common characteristic of which is genome instability. Therefore, understanding the role of chromatin in TRC occurrence and resolution may help identify the molecular mechanism by which chromatin protects genome integrity, and the causes and physiological relevance of the high mutation rates of chromatin regulating factors in cancer. Here we review the current knowledge in the field, as well as the perspectives and future applications.

scholarly journals Transcription-Replication Collisions—A Series of Unfortunate Events

Biomolecules ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1249
Author(s):  
Commodore St Germain ◽  
Hongchang Zhao ◽  
Jacqueline H. Barlow
Keyword(s):  
Mammalian Cells ◽  
Replication Fork ◽  
Dna Supercoiling ◽  
Genome Integrity ◽  
High Fidelity ◽  
Chromatin Binding ◽  
Cellular Pathways ◽  
Genomic Regions ◽  
Dna Template ◽  
Transcription And Replication

Transcription-replication interactions occur when DNA replication encounters genomic regions undergoing transcription. Both replication and transcription are essential for life and use the same DNA template making conflicts unavoidable. R-loops, DNA supercoiling, DNA secondary structure, and chromatin-binding proteins are all potential obstacles for processive replication or transcription and pose an even more potent threat to genome integrity when these processes co-occur. It is critical to maintaining high fidelity and processivity of transcription and replication while navigating through a complex chromatin environment, highlighting the importance of defining cellular pathways regulating transcription-replication interaction formation, evasion, and resolution. Here we discuss how transcription influences replication fork stability, and the safeguards that have evolved to navigate transcription-replication interactions and maintain genome integrity in mammalian cells.

scholarly journals Oxidized LDLs as Signaling Molecules

Antioxidants ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1184
Author(s):  
Jean-Marc Zingg ◽  
Adelina Vlad ◽  
Roberta Ricciarelli
Keyword(s):  
Free Radicals ◽  
Cellular Response ◽  
Vascular System ◽  
Signaling Molecules ◽  
Scavenger Receptors ◽  
Physiological Relevance ◽  
Reactive Radicals ◽  
Accumulation Of Lipids

Levels of oxidized low-density lipoproteins (oxLDLs) are usually low in vivo but can increase whenever the balance between formation and scavenging of free radicals is impaired. Under normal conditions, uptake and degradation represent the physiological cellular response to oxLDL exposure. The uptake of oxLDLs is mediated by cell surface scavenger receptors that may also act as signaling molecules. Under conditions of atherosclerosis, monocytes/macrophages and vascular smooth muscle cells highly exposed to oxLDLs tend to convert to foam cells due to the intracellular accumulation of lipids. Moreover, the atherogenic process is accelerated by the increased expression of the scavenger receptors CD36, SR-BI, LOX-1, and SRA in response to high levels of oxLDL and oxidized lipids. In some respects, the effects of oxLDLs, involving cell proliferation, inflammation, apoptosis, adhesion, migration, senescence, and gene expression, can be seen as an adaptive response to the rise of free radicals in the vascular system. Unlike highly reactive radicals, circulating oxLDLs may signal to cells at more distant sites and possibly trigger a systemic antioxidant defense, thus elevating the role of oxLDLs to that of signaling molecules with physiological relevance.

scholarly journals Atypical Chemokine Receptors in Cardiovascular Disease

2019 ◽  
Vol 119 (04) ◽  
pp. 534-541 ◽  
Author(s):  
Selin Gencer ◽  
Emiel van der Vorst ◽  
Maria Aslani ◽  
Christian Weber ◽  
Yvonne Döring ◽  
...  
Keyword(s):  
G Protein ◽  
Chemokine Receptors ◽  
Cellular Response ◽  
Current Knowledge ◽  
G Protein Coupled Receptors ◽  
Signalling Pathways ◽  
Atherosclerosis Development ◽  
G Protein Coupled ◽  
Precise Role

AbstractInflammation has been well recognized as one of the main drivers of atherosclerosis development and therefore cardiovascular diseases (CVDs). It has been shown that several chemokines, small 8 to 12 kDa cytokines with chemotactic properties, play a crucial role in the pathophysiology of atherosclerosis. Chemokines classically mediate their effects by binding to G-protein-coupled receptors called chemokine receptors. In addition, chemokines can also bind to atypical chemokine receptors (ACKRs). ACKRs fail to induce G-protein-dependent signalling pathways and thus subsequent cellular response, but instead are able to internalize, scavenge or transport chemokines. In this review, we will give an overview of the current knowledge about the involvement of ACKR1–4 in CVDs and especially in atherosclerosis development. In the recent years, several studies have highlighted the importance of ACKRs in CVDs, although there are still several controversies and unexplored aspects that have to be further elucidated. A better understanding of the precise role of these atypical receptors may pave the way towards novel and improved therapeutic strategies.

scholarly journals Chromatin-associated degradation is defined by UBXN-3/FAF1 to safeguard DNA replication fork progression

2016 ◽  
Vol 7 (1) ◽  
Author(s):  
André Franz ◽  
Paul A. Pirson ◽  
Domenic Pilger ◽  
Swagata Halder ◽  
Divya Achuthankutty ◽  
...  
Keyword(s):  
Dna Replication ◽  
Dynamic Process ◽  
Metabolic Pathways ◽  
Replication Fork ◽  
Genome Instability ◽  
Genome Integrity ◽  
Substrate Selection ◽  
Replication Fork Progression ◽  
Replication Factors ◽  
Spatiotemporal Control

Abstract The coordinated activity of DNA replication factors is a highly dynamic process that involves ubiquitin-dependent regulation. In this context, the ubiquitin-directed ATPase CDC-48/p97 recently emerged as a key regulator of chromatin-associated degradation in several of the DNA metabolic pathways that assure genome integrity. However, the spatiotemporal control of distinct CDC-48/p97 substrates in the chromatin environment remained unclear. Here, we report that progression of the DNA replication fork is coordinated by UBXN-3/FAF1. UBXN-3/FAF1 binds to the licensing factor CDT-1 and additional ubiquitylated proteins, thus promoting CDC-48/p97-dependent turnover and disassembly of DNA replication factor complexes. Consequently, inactivation of UBXN-3/FAF1 stabilizes CDT-1 and CDC-45/GINS on chromatin, causing severe defects in replication fork dynamics accompanied by pronounced replication stress and eventually resulting in genome instability. Our work identifies a critical substrate selection module of CDC-48/p97 required for chromatin-associated protein degradation in both Caenorhabditis elegans and humans, which is relevant to oncogenesis and aging.

scholarly journals MRE11-RAD50-NBS1 activates Fanconi Anemia R-loop suppression at transcription-replication conflicts

2018 ◽  
Author(s):  
Emily Yun-chia Chang ◽  
James P. Wells ◽  
Shu-Huei Tsai ◽  
Yan Coulombe ◽  
Yujia A. Chan ◽  
...  
Keyword(s):  
Dna Replication ◽  
Fanconi Anemia ◽  
Replication Fork ◽  
Genome Instability ◽  
Human Cancer ◽  
Replication Stress ◽  
Maintenance Factors ◽  
Genome Wide ◽  
A Genome ◽  
Dna Replication Stress

SUMMARYEctopic R-loop accumulation causes DNA replication stress and genome instability. To avoid these outcomes, cells possess a range of anti-R-loop mechanisms, including RNaseH that degrades the RNA moiety in R-loops. To comprehensively identify anti-R-loop mechanisms, we performed a genome-wide trigenic interaction screen in yeast lacking RNH1 and RNH201. We identified >100 genes critical for fitness in the absence of RNaseH, which were enriched for DNA replication fork maintenance factors such as RAD50. We show in yeast and human cells that R-loops accumulate during RAD50 depletion. In human cancer cell models, we find that RAD50 and its partners in the MRE11-RAD50-NBS1 complex regulate R-loop-associated DNA damage and replication stress. We show that a non-nucleolytic function of MRE11 is important for R-loop suppression via activation of PCNA-ubiquitination by RAD18 and recruiting anti-R-loop helicases in the Fanconi Anemia pathway. This work establishes a novel role for MRE11-RAD50-NBS1 in directing tolerance mechanisms of transcription-replication conflicts.

scholarly journals Yeast Genome Maintenance by the Multifunctional PIF1 DNA Helicase Family

Genes ◽  
2020 ◽  
Vol 11 (2) ◽  
pp. 224 ◽  
Author(s):  
Julius Muellner ◽  
Kristina H. Schmidt
Keyword(s):  
Cellular Response ◽  
Replication Fork ◽  
Strand Break ◽  
Dna Helicase ◽  
Yeast Cells ◽  
Genome Integrity ◽  
Yeast Genome ◽  
Functional Evaluation ◽  
Cellular Functions ◽  
Yeast Homolog

The two PIF1 family helicases in Saccharomyces cerevisiae, Rrm3, and ScPif1, associate with thousands of sites throughout the genome where they perform overlapping and distinct roles in telomere length maintenance, replication through non-histone proteins and G4 structures, lagging strand replication, replication fork convergence, the repair of DNA double-strand break ends, and transposable element mobility. ScPif1 and its fission yeast homolog Pfh1 also localize to mitochondria where they protect mitochondrial genome integrity. In addition to yeast serving as a model system for the rapid functional evaluation of human Pif1 variants, yeast cells lacking Rrm3 have proven useful for elucidating the cellular response to replication fork pausing at endogenous sites. Here, we review the increasingly important cellular functions of the yeast PIF1 helicases in maintaining genome integrity, and highlight recent advances in our understanding of their roles in facilitating fork progression through replisome barriers, their functional interactions with DNA repair, and replication stress response pathways.

scholarly journals Selective Autophagy inDrosophila

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Ioannis P. Nezis
Keyword(s):  
Cellular Response ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Model Organism ◽  
Major Pathway ◽  
Selective Autophagy ◽  
Cytoplasmic Material ◽  
Evolutionarily Conserved ◽  
High Conservation

Autophagy is an evolutionarily conserved process of cellular self-eating and is a major pathway for degradation of cytoplasmic material by the lysosomal machinery. Autophagy functions as a cellular response in nutrient starvation, but it is also associated with the removal of protein aggregates and damaged organelles and therefore plays an important role in the quality control of proteins and organelles. Although it was initially believed that autophagy occurs randomly in the cell, during the last years, there is growing evidence that sequestration and degradation of cytoplasmic material by autophagy can be selective. Given the important role of autophagy and selective autophagy in several disease-related processes such as neurodegeneration, infections, and tumorigenesis, it is important to understand the molecular mechanisms of selective autophagy, especially at the organismal level.Drosophilais an excellent genetically modifiable model organism exhibiting high conservation in the autophagic machinery. However, the regulation and mechanisms of selective autophagy inDrosophilahave been largely unexplored. In this paper, I will present an overview of the current knowledge about selective autophagy inDrosophila.

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 RAD51 and mitotic function of mus81 are essential for recovery from low-dose of camptothecin in the absence of the WRN exonuclease

2019 ◽  
Vol 47 (13) ◽  
pp. 6796-6810 ◽  
Author(s):  
Francesca Antonella Aiello ◽  
Anita Palma ◽  
Eva Malacaria ◽  
Li Zheng ◽  
Judith L Campbell ◽  
...  
Keyword(s):  
Topoisomerase I ◽  
Genome Instability ◽  
Genome Integrity ◽  
Replication Forks ◽  
Wild Type ◽  
Alternative Processing ◽  
Mitotic Abnormalities ◽  
Mitotic Phosphorylation ◽  
Stalled Replication Forks

Abstract Stabilization of stalled replication forks prevents excessive fork reversal or degradation, which can undermine genome integrity. The WRN protein is unique among the other human RecQ family members to possess exonuclease activity. However, the biological role of the WRN exonuclease is poorly defined. Recently, the WRN exonuclease has been linked to protection of stalled forks from degradation. Alternative processing of perturbed forks has been associated to chemoresistance of BRCA-deficient cancer cells. Thus, we used WRN exonuclease-deficiency as a model to investigate the fate of perturbed forks undergoing degradation, but in a BRCA wild-type condition. We find that, upon treatment with clinically-relevant nanomolar doses of the Topoisomerase I inhibitor camptothecin, loss of WRN exonuclease stimulates fork inactivation and accumulation of parental gaps, which engages RAD51. Such mechanism affects reinforcement of CHK1 phosphorylation and causes persistence of RAD51 during recovery from treatment. Notably, in WRN exonuclease-deficient cells, persistence of RAD51 correlates with elevated mitotic phosphorylation of MUS81 at Ser87, which is essential to prevent excessive mitotic abnormalities. Altogether, these findings indicate that aberrant fork degradation, in the presence of a wild-type RAD51 axis, stimulates RAD51-mediated post-replicative repair and engagement of the MUS81 complex to limit genome instability and cell death.

scholarly journals PORPHYROMONAS GINGIVALIS E PERIODONTITE CRÔNICA - AVANÇOS RECENTES

2016 ◽  
Vol 7 (2) ◽  
Author(s):  
Victor Hugo Rocha Leon ◽  
Ellen Karla Nobre dos Santos-Lima ◽  
Ana Carla Montino Pimentel ◽  
Patricia Mares de Miranda ◽  
Paulo Cirino De Carvalho Filho ◽  
...  
Keyword(s):  
Porphyromonas Gingivalis ◽  
Virulence Factors ◽  
Chronic Periodontitis ◽  
Cellular Response ◽  
Current Knowledge ◽  
Periodontal Diseases ◽  
Tissue Destruction ◽  
Inflammatory State ◽  
Cell Death Mechanisms

Periodontal disease is multifactorial and it affects the tissues surrounding the teeth. Its etiology includes microrganisms as Porphyromonas gingivalis, Tannerella forsythia and Aggregatibacter actinomycetemcomitans. This work aimed to discuss the role of Porphyromonas gingivalis in chronic periodontitis. The electronic bases PubMed, BIREME and SciELO were used to search for historical aspects and studies published between 2000 and 2015, using the following descriptors in Portuguese and English: “Chronic periodontitis, Porphyromonas gingivalis” and “Virulence factors”. 205 articles were found and 24 were included. Records on periodontal diseases from the early civilization to the present day were found. Its prevalence in the world’s population remains high and several studies report the pathogenesis of the disease. P. gingivalis is able to induce humoral and cellular response in infected individuals. Studies on its escape mechanisms and virulence factors report tissue breakdown consequent to immuno-inflammatory exacerbated response in the host which may evolve into edentulism. Studies of the immune response to P. gingivalis suggest its role in perpetuation of the inflammatory state by interfering with cytokines production and cell death mechanisms in the host’s cells, resulting in tissue destruction. The current knowledge about mechanisms of infection and virulence factors of P. gingivalis indicate its role as a key component in chronic periodontitis.

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