scholarly journals Extrachromosomal Circular DNA: Current Knowledge and Implications for CNS Aging and Neurodegeneration

2020 ◽  
Vol 21 (7) ◽  
pp. 2477 ◽  
Author(s):  
Quratul Ain ◽  
Christian Schmeer ◽  
Diane Wengerodt ◽  
Otto W. Witte ◽  
Alexandra Kretz
Keyword(s):  
Dna Repair ◽  
Current Knowledge ◽  
Critical Role ◽  
Regional Distribution ◽  
Gene Copy Number ◽  
Gene Copy ◽  
Extrachromosomal Dna ◽  
Circular Dna ◽  
Age Related ◽  
Circular Dnas

Still unresolved is the question of how a lifetime accumulation of somatic gene copy number alterations impact organ functionality and aging and age-related pathologies. Such an issue appears particularly relevant in the broadly post-mitotic central nervous system (CNS), where non-replicative neurons are restricted in DNA-repair choices and are prone to accumulate DNA damage, as they remain unreplaced over a lifetime. Both DNA injuries and consecutive DNA-repair strategies are processes that can evoke extrachromosomal circular DNA species, apparently from either part of the genome. Due to their capacity to amplify gene copies and related transcripts, the individual cellular load of extrachromosomal circular DNAs will contribute to a dynamic pool of additional coding and regulatory chromatin elements. Analogous to tumor tissues, where the mosaicism of circular DNAs plays a well-characterized role in oncogene plasticity and drug resistance, we suggest involvement of the “circulome” also in the CNS. Accordingly, we summarize current knowledge on the molecular biogenesis, homeostasis and gene regulatory impacts of circular extrachromosomal DNA and propose, in light of recent discoveries, a critical role in CNS aging and neurodegeneration. Future studies will elucidate the influence of individual extrachromosomal DNA species according to their sequence complexity and regional distribution or cell-type-specific abundance.

scholarly journals Unstable amplification of two extrachromosomal elements in alpha-difluoromethylornithine-resistant Leishmania donovani.

1992 ◽  
Vol 12 (12) ◽  
pp. 5499-5507 ◽  
Author(s):  
S Hanson ◽  
S M Beverley ◽  
W Wagner ◽  
B Ullman
Keyword(s):  
Gene Amplification ◽  
Leishmania Donovani ◽  
Molecular Mechanisms ◽  
Gene Copy Number ◽  
Gene Copy ◽  
Unstable Gene ◽  
Extrachromosomal Elements ◽  
Circular Dnas ◽  
Amplification Mechanism

We describe the first example of unstable gene amplification consisting of linear extrachromosomal DNAs in drug-resistant eukaryotic cells. alpha-Difluoromethylornithine (DFMO)-resistant Leishmania donovani with an amplified ornithine decarboxylase (ODC) gene copy number contained two new extrachromosomal DNAs, both present in 10 to 20 copies. One of these was a 140-kb linear DNA (ODC140-L) on which all of the amplified copies of the odc gene were located. The second was a 70-kb circular DNA (ODC70-C) containing an inverted repeat but lacking the odc gene. Both ODC140-L and ODC70-C were derived from a preexisting wild-type chromosome, probably by a conservative amplification mechanism. Both elements were unstable in the absence of DFMO, and their disappearance coincided with a decrease in ODC activity and an increase in DFMO growth sensitivity. These results suggest the possibility that ODC70-C may play a role in DFMO resistance. These data expand the diversity of known amplification mechanisms in eukaryotes to include the simultaneous unstable amplification of both linear and circular DNAs. Further characterization of these molecules will provide insights into the molecular mechanisms underlying gene amplification, including the ability of linear amplified DNAs to acquire telomeres and the determinants of chromosomal stability.

scholarly journals Cellular Aging Characteristics and Their Association with Age-Related Disorders

Antioxidants ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 94 ◽  
Author(s):  
Magdalena Rudzińska ◽  
Alessandro Parodi ◽  
Anastasia V. Balakireva ◽  
Olga E. Chepikova ◽  
Franco M. Venanzi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cellular Senescence ◽  
Current Knowledge ◽  
Cell Metabolism ◽  
Critical Role ◽  
Cellular Aging ◽  
Molecular Signaling ◽  
Age Related ◽  
Organelle Communication ◽  
Metabolic Dysfunctions

Different molecular signaling pathways, biological processes, and intercellular communication mechanisms control longevity and are affected during cellular senescence. Recent data have suggested that organelle communication, as well as genomic and metabolic dysfunctions, contribute to this phenomenon. Oxidative stress plays a critical role by inducing structural modifications to biological molecules while affecting their function and catabolism and eventually contributing to the onset of age-related dysfunctions. In this scenario, proteins are not adequately degraded and accumulate in the cell cytoplasm as toxic aggregates, increasing cell senescence progression. In particular, carbonylation, defined as a chemical reaction that covalently and irreversibly modifies proteins with carbonyl groups, is considered to be a significant indicator of protein oxidative stress and aging. Here, we emphasize the role and dysregulation of the molecular pathways controlling cell metabolism and proteostasis, the complexity of the mechanisms that occur during aging, and their association with various age-related disorders. The last segment of the review details current knowledge on protein carbonylation as a biomarker of cellular senescence in the development of diagnostics and therapeutics for age-related dysfunctions.

scholarly journals Age-related Macular Degeneration: Current Knowledge of Zinc Metalloproteinases Involvement

2019 ◽  
Vol 20 (9) ◽  
pp. 903-918 ◽  
Author(s):  
Francesca Liva ◽  
Doretta Cuffaro ◽  
Elisa Nuti ◽  
Susanna Nencetti ◽  
Elisabetta Orlandini ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Current Knowledge ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Critical Role ◽  
The Elderly ◽  
Age Related Macular Degeneration ◽  
Tissue Inhibitors Of Metalloproteinase ◽  
Age Related ◽  
A Disintegrin And Metalloproteinase

Background: Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly with limited therapeutic options. The disease is characterized by photoreceptor loss in the macula and reduced Retinal Pigment Epithelium (RPE) function, associated with matrix degradation, cell proliferation, neovascularization and inflammation. Matrix metalloproteinases (MMPs), a disintegrin and metalloproteinases (ADAMs) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs) play a critical role in the physiology of extracellular matrix (ECM) turnover and, in turn, in ECM pathologies, such as AMD. A balance between the activities of MMPs and Tissue Inhibitors of Metalloproteinase (TIMPs) is crucial for the integrity of the ECM components; indeed, a dysregulation in the ratio of these factors produces profound changes in the ECM, including thickening and deposit formation, which eventually might lead to AMD development. Objective: This article reviews the relevance and impact of zinc metalloproteinases on the development of AMD and their roles as biomarkers and/or therapeutic targets. We illustrate some studies on several inhibitors of MMPs currently used to dissect physiological properties of MMPs. Moreover, all molecules or technologies used to control MMP and ADAM activity in AMD are analyzed. Conclusion: This study underlines the changes in the activity of MMPs expressed by RPE cells, highlights the functions of already used MMP inhibitors and consequently suggests their application as therapeutic agents for the treatment of AMD.

scholarly journals Genome instability and loss of protein homeostasis: converging paths to neurodegeneration?

Open Biology ◽  
2021 ◽  
Vol 11 (4) ◽  
Author(s):  
Anna Ainslie ◽  
Wouter Huiting ◽  
Lara Barazzuol ◽  
Steven Bergink
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Neurodegenerative Diseases ◽  
Genome Stability ◽  
Genome Instability ◽  
Copy Number Variations ◽  
Therapeutic Interventions ◽  
Gene Copy ◽  
Protein Homeostasis ◽  
Age Related

Genome instability and loss of protein homeostasis are hallmark events of age-related diseases that include neurodegeneration. Several neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis are characterized by protein aggregation, while an impaired DNA damage response (DDR) as in many genetic DNA repair disorders leads to pronounced neuropathological features. It remains unclear to what degree these cellular events interconnect with each other in the development of neurological diseases. This review highlights how the loss of protein homeostasis and genome instability influence one other. We will discuss studies that illustrate this connection. DNA damage contributes to many neurodegenerative diseases, as shown by an increased level of DNA damage in patients, possibly due to the effects of protein aggregates on chromatin, the sequestration of DNA repair proteins and novel putative DNA repair functions. Conversely, genome stability is also important for protein homeostasis. For example, gene copy number variations and the loss of key DDR components can lead to marked proteotoxic stress. An improved understanding of how protein homeostasis and genome stability are mechanistically connected is needed and promises to lead to the development of novel therapeutic interventions.

scholarly journals The eccDNA Replicon: A heritable, extra-nuclear vehicle that enables gene amplification and glyphosate resistance in Amaranthus palmeri

2020 ◽  
Author(s):  
William T. Molin ◽  
Allison Yaguchi ◽  
Mark Blenner ◽  
Christopher A. Saski
Keyword(s):  
Gene Copy Number ◽  
Gene Copy ◽  
Amaranthus Palmeri ◽  
Structural Variations ◽  
Circular Dna ◽  
Amaranthus Hypochondriacus ◽  
Gene Copy Number Variation ◽  
Number Variation ◽  
Repetitive Structure ◽  
Underlying Mechanisms

ABSTRACTGene copy number variation is a predominant mechanism by which organisms respond to selective pressures in nature, which often results in unbalanced structural variations that perpetuate as adaptations to sustain life. However, the underlying mechanisms that give rise to gene proliferation are poorly understood. Here, we show a unique result of genomic plasticity in Amaranthus palmeri, a massive, ∼400kb extrachromosomal circular DNA (eccDNA), that harbors the 5-enoylpyruvylshikimate-3-phosphate synthase (EPSPS) gene and 58 other encoded genes whose functions traverse detoxification, replication, recombination, transposition, tethering, and transport. Gene expression analysis under glyphosate stress showed transcription of 41 of the 59 genes, with high expression of EPSPS, aminotransferase, zinc-finger, and several uncharacterized proteins. The genomic architecture of the eccDNA replicon is comprised of a complex arrangement of repeat sequences and mobile genetic elements interspersed among arrays of clustered palindromes that may be crucial for stability, DNA duplication and tethering, and/or a means of nuclear integration of the adjacent and intervening sequences. Comparative analysis of orthologous genes in grain amaranth (Amaranthus hypochondriacus) and water-hemp (Amaranthus tuberculatus) suggest higher order chromatin interactions contribute to the genomic origins of the Amaranthus palmeri eccDNA replicon structure.One-sentence summaryThe eccDNA replicon is a large extra-nuclear circular DNA that is composed of a sophisticated repetitive structure, harbors the EPSPS and several other genes that are transcribed during glyphosate stress.

scholarly journals Extrachromosomal circular DNA-based amplification and transmission of herbicide resistance in crop weedAmaranthus palmeri

2018 ◽  
Vol 115 (13) ◽  
pp. 3332-3337 ◽  
Author(s):  
Dal-Hoe Koo ◽  
William T. Molin ◽  
Christopher A. Saski ◽  
Jiming Jiang ◽  
Karthik Putta ◽  
...  
Keyword(s):  
Gene Amplification ◽  
Herbicide Resistance ◽  
Germ Cells ◽  
Gene Copy Number ◽  
Gene Copy ◽  
Circular Dna ◽  
Dna Structures ◽  
Meiotic Chromosomes ◽  
Extrachromosomal Elements ◽  
Mitosis And Meiosis

Gene amplification has been observed in many bacteria and eukaryotes as a response to various selective pressures, such as antibiotics, cytotoxic drugs, pesticides, herbicides, and other stressful environmental conditions. An increase in gene copy number is often found as extrachromosomal elements that usually contain autonomously replicating extrachromosomal circular DNA molecules (eccDNAs).Amaranthus palmeri, a crop weed, can develop herbicide resistance to glyphosate [N-(phosphonomethyl) glycine] by amplification of the 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) gene, the molecular target of glyphosate. However, biological questions regarding the source of the amplifiedEPSPS, the nature of the amplified DNA structures, and mechanisms responsible for maintaining this gene amplification in cells and their inheritance remain unknown. Here, we report that amplifiedEPSPScopies in glyphosate-resistant (GR)A. palmeriare present in the form of eccDNAs with various conformations. The eccDNAs are transmitted during cell division in mitosis and meiosis to the soma and germ cells and the progeny by an as yet unknown mechanism of tethering to mitotic and meiotic chromosomes. We propose that eccDNAs are one of the components of McClintock’s postulated innate systems [McClintock B (1978)Stadler Genetics Symposium] that can rapidly produce soma variation, amplifyEPSPSgenes in the sporophyte that are transmitted to germ cells, and modulate rapid glyphosate resistance through genome plasticity and adaptive evolution.

scholarly journals Sequence characterization of eccDNA content in glyphosate sensitive and resistant Palmer amaranth from geographically distant populations

2021 ◽  
Author(s):  
Hailey Spier Camposano ◽  
Christopher A Saski ◽  
William Molin
Keyword(s):  
Ribosomal Proteins ◽  
Genome Structure ◽  
Genetic Resistance ◽  
Palmer Amaranth ◽  
Gene Copy ◽  
Circular Dna ◽  
Sequence Characterization ◽  
Epsps Gene ◽  
Repeat Content ◽  
Circular Dnas

The discovery of non-chromosomal circular DNA offers new directions in linking genome structure with function in plant biology.  Glyphosate resistance through  EPSPS  gene copy amplification in Palmer amaranth was due to an autonomously replicating extra-chromosomal circular DNA mechanism (eccDNA).  CIDER-Seq analysis of geographically distant glyphosate sensitive (GS) and resistant (GR) Palmer Amaranth ( Amaranthus palmeri ) revealed the presence of numerous small extra-chromosomal circular DNAs varying in size and with degrees of repetitive content, coding sequence, and motifs associated with autonomous replication. In GS biotypes, only a small portion of these aligned to the 399 kb eccDNA replicon, the vehicle underlying gene amplification and genetic resistance to the herbicide glyphosate. The aligned eccDNAs from GS were separated from one another by large gaps in sequence. In GR biotypes, the eccDNAs were present in both abundance and diversity to assemble into a nearly complete eccDNA replicon.  Mean sizes of eccDNAs were similar in both biotypes and were around 5kb with larger eccDNAs near 25kb.  Gene content for eccDNAs ranged from 0 to 3 with functions that include ribosomal proteins, transport, metabolism, and general stress response genetic elements. Repeat content among smaller eccDNAs indicate a potential for recombination into larger structures. Genomic hotspots were also identified in the Palmer amaranth genome with a disposition for gene focal amplifications as eccDNA. The presence of eccDNA may serve as a reservoir of genetic heterogeneity in this species and may be functionally important for survival.

scholarly journals Can diagnostic imaging help improve elder abuse detection?

2020 ◽  
Vol 93 (1110) ◽  
pp. 20190632
Author(s):  
Taryn J Rohringer ◽  
Tony E Rosen ◽  
Mihan R Lee ◽  
Pallavi Sagar ◽  
Kieran J Murphy
Keyword(s):  
Diagnostic Imaging ◽  
Elder Abuse ◽  
Current Knowledge ◽  
Critical Role ◽  
Systematic Research ◽  
Imaging Findings ◽  
Clinical Workflow ◽  
Age Related ◽  
Patterns Of Injury

Elder abuse is an underdetected, under-reported issue with severe consequences. Its detection presents unique challenges based on characteristics of this vulnerable population, including cognitive impairment, age-related deconditioning, and an increased number of co-morbidities, all of which predispose to increase vulnerability to injury. While radiologists play a critical role in detection of child abuse, this role is currently not paralleled in detection of elder abuse. We conducted a thorough review of the literature using MEDLINE to describe the current knowledge on injury patterns and injury findings seen in elder abuse, as well as barriers to and recommendations for an increased role of diagnostic imaging in elder abuse detection. Barriers limiting the role of radiologists include lack of training and paucity of rigorous systematic research delineating distinctive imaging findings for physical elder abuse. We outline the current ways in which imaging can help raise clinical suspicion for elder abuse, including inconsistencies between purported mechanism of injury and imaging findings, injury location, multiple injuries at differing stages of healing, and particular patterns of injury likely to be intentionally inflicted. We additionally outline the mechanism by which medical education and clinical workflow may be modified to increase the role for imaging and radiologist participation in detecting abuse in older adult patients, and identify potential future directions for further systematic research.

scholarly journals Circular and long non-coding RNAs and their role in ophthalmologic diseases

2018 ◽  
Author(s):  
Olga Wawrzyniak ◽  
Żaneta Zarębska ◽  
Katarzyna Rolle ◽  
Anna Gotz-Więckowska
Keyword(s):  
Current Knowledge ◽  
Critical Role ◽  
Circular Rna ◽  
Age Related Macular Degeneration ◽  
Circular Rnas ◽  
Protein Coding ◽  
Rna Molecules ◽  
Age Related ◽  
Non Coding Rnas ◽  
Transcriptional Gene Regulation

Long non-coding RNAs are >200-nucleotide-long RNA molecules which lack or have limited protein-coding potential. They can regulate protein formation through several different mechanisms. Similarly, circular RNAs are reported to play a critical role in post-transcriptional gene regulation. Changes in the expression pattern of these molecules are known to underlie various diseases, including cancer, cardiovascular, neurological and immunological disorders (Rinn & Chang, 2012; Sun & Kraus, 2015). Recent studies suggest that they are differentially expressed both in healthy ocular tissues as well as in eye pathologies, such as neovascularization, proliferative vitreoretinopathy, glaucoma, cataract, ocular malignancy or even strabismus (Li et al., 2016). Aetiology of ocular diseases is multifactorial and combines genetic and environmental factors, including epigenetic and non-coding RNAs. In addition, disorders like diabetic retinopathy or age-related macular degeneration lack biomarkers for early detection as well as effective treatment methods that would allow controlling the disease progression at its early stages. The newly discovered non-coding RNAs seem to be the ideal candidates for novel molecular markers and therapeutic strategies. In this review, we summarized the current knowledge about gene expression regulators – long non-coding and circular RNA molecules in eye diseases.

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