scholarly journals On the wrong DNA track: Molecular mechanisms of repeat-mediated genome instability

2020 ◽  
Vol 295 (13) ◽  
pp. 4134-4170 ◽  
Author(s):  
Alexandra N. Khristich ◽  
Sergei M. Mirkin
Keyword(s):  
Molecular Mechanisms ◽  
Tandem Repeats ◽  
Genome Instability ◽  
Current Knowledge ◽  
Model Systems ◽  
Dna Repeats ◽  
Repeat Instability ◽  
Repeat Expansions ◽  
Induced Mutagenesis ◽  
Simple Tandem Repeats

Expansions of simple tandem repeats are responsible for almost 50 human diseases, the majority of which are severe, degenerative, and not currently treatable or preventable. In this review, we first describe the molecular mechanisms of repeat-induced toxicity, which is the connecting link between repeat expansions and pathology. We then survey alternative DNA structures that are formed by expandable repeats and review the evidence that formation of these structures is at the core of repeat instability. Next, we describe the consequences of the presence of long structure-forming repeats at the molecular level: somatic and intergenerational instability, fragility, and repeat-induced mutagenesis. We discuss the reasons for gender bias in intergenerational repeat instability and the tissue specificity of somatic repeat instability. We also review the known pathways in which DNA replication, transcription, DNA repair, and chromatin state interact and thereby promote repeat instability. We then discuss possible reasons for the persistence of disease-causing DNA repeats in the genome. We describe evidence suggesting that these repeats are a payoff for the advantages of having abundant simple-sequence repeats for eukaryotic genome function and evolvability. Finally, we discuss two unresolved fundamental questions: (i) why does repeat behavior differ between model systems and human pedigrees, and (ii) can we use current knowledge on repeat instability mechanisms to cure repeat expansion diseases?

scholarly journals Comparative Genomics and Molecular Dynamics of DNA Repeats in Eukaryotes

2008 ◽  
Vol 72 (4) ◽  
pp. 686-727 ◽  
Author(s):  
Guy-Franck Richard ◽  
Alix Kerrest ◽  
Bernard Dujon
Keyword(s):  
Molecular Mechanisms ◽  
Tandem Repeats ◽  
Current Knowledge ◽  
Biological Properties ◽  
Repeated Sequences ◽  
Trna Genes ◽  
Dna Repeats ◽  
Dna Repeat ◽  
Eukaryotic Genomes ◽  
Dispersed Repeats

SUMMARY Repeated elements can be widely abundant in eukaryotic genomes, composing more than 50% of the human genome, for example. It is possible to classify repeated sequences into two large families, “tandem repeats” and “dispersed repeats.” Each of these two families can be itself divided into subfamilies. Dispersed repeats contain transposons, tRNA genes, and gene paralogues, whereas tandem repeats contain gene tandems, ribosomal DNA repeat arrays, and satellite DNA, itself subdivided into satellites, minisatellites, and microsatellites. Remarkably, the molecular mechanisms that create and propagate dispersed and tandem repeats are specific to each class and usually do not overlap. In the present review, we have chosen in the first section to describe the nature and distribution of dispersed and tandem repeats in eukaryotic genomes in the light of complete (or nearly complete) available genome sequences. In the second part, we focus on the molecular mechanisms responsible for the fast evolution of two specific classes of tandem repeats: minisatellites and microsatellites. Given that a growing number of human neurological disorders involve the expansion of a particular class of microsatellites, called trinucleotide repeats, a large part of the recent experimental work on microsatellites has focused on these particular repeats, and thus we also review the current knowledge in this area. Finally, we propose a unified definition for mini- and microsatellites that takes into account their biological properties and try to point out new directions that should be explored in a near future on our road to understanding the genetics of repeated sequences.

scholarly journals Intragenic repeat expansions control yeast chronological aging

2019 ◽  
Author(s):  
Benjamin P Barré ◽  
Johan Hallin ◽  
Jia-Xing Yue ◽  
Karl Persson ◽  
Ekaterina Mikhalev ◽  
...  
Keyword(s):  
Life Span ◽  
Calorie Restriction ◽  
Molecular Mechanisms ◽  
Tandem Repeats ◽  
Repeat Expansion ◽  
Yeast Cells ◽  
Chronological Aging ◽  
Cellular Life ◽  
Chronological Life Span ◽  
Repeat Expansions

ABSTRACTAging varies among individuals due to both genetics and environment but the underlying molecular mechanisms remain largely unknown. Using a highly recombinedSaccharomyces cerevisiaepopulation, we found 30 distinct Quantitative Trait Loci (QTLs) that control chronological life span (CLS) in calorie rich and calorie restricted environments, and under rapamycin exposure. Calorie restriction and rapamycin extended life span in virtually all genotypes, but through different genetic variants. We tracked the two major QTLs to massive expansions of intragenic tandem repeats in the cell wall glycoproteinsFLO11andHPF1, which caused a dramatic life span shortening. Life span impairment by N-terminalHPF1repeat expansion was partially buffered by rapamycin but not by calorie restriction. TheHPF1repeat expansion shifted yeast cells from a sedentary to a buoyant state, thereby increasing their exposure to surrounding oxygen. The higher oxygenation perturbed methionine, lipid, and purine metabolism, which likely explains the life span shortening. We conclude that fast evolving intragenic repeat expansions can fundamentally change the relationship between cells and their environment with profound effects on cellular life style and longevity.

Investigating the Biological and Molecular Mechanisms Underpinning the Engraftment/Selection Advantage Conferred to Hematopoietic Stem Cells by HOXB4.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2101-2101
Author(s):  
Michael D. Milsom ◽  
Laura Hollins ◽  
Dorothy Gagen ◽  
Lorna B. Woolford ◽  
Leslie J. Fairbairn
Keyword(s):  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Cellular Transformation ◽  
Model Systems ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Increased Risk ◽  
Vitro Analysis

Abstract We have recently demonstrated that co-expression of HOXB4 enables the enhanced delivery of HSC harbouring a second therapeutic trans-gene. Nonetheless, it is of great importance to elaborate the current knowledge about the mechanism of HOXB4 action in order to both evaluate the safety implications of its use in a clinical strategy, and to gain greater insight into the regulation of HSC self-renewal/expansion. To these ends we have performed an extensive in vitro analysis of the consequences of HOXB4 overexpression in primary murine BMC and in a murine multipotent myeloid progenitor cell line (FDCP-mix). We demonstrate for the first time in murine cells, that ectopic HOXB4 reduces the responsiveness of murine hematopoietic cells to differentiation stimuli. Furthermore, by performing a detailed investigation into the kinetics of FDCP-mix differentiation, we reveal that HOXB4 overexpression results in a specific differentiation delay as opposed to an outright block. We propose that an analogous delay is in operation in repopulating cells in order that the shift to increased assymetrical self-renewal, a requirement for stem cell expansion, is achieved. Notwithstanding this, it is clear that any perturbation in differentiation constitutes an increased risk of cellular transformation if this technology were transferred to a clinical setting. In order to further define the repercussions of ectopic HOXB4 delivery, we have developed a retroviral vector which encodes an activatable version of HOXB4. We have shown that this vector is able to mediate an in vitro differentiation delay in primary murine BMC and FDCP-mix as well as enable enhanced engraftment of BMC in vivo, both dependent upon the addition of the estrogen analogue; tamoxifen. Using this system, we are currently examining the effect of ectopic HOXB4 on the transcriptome of FDCP-mix cells, in addition to performing an in depth study into the biological mechanisms affected by HOXB4 overexpression in BMC in vivo. We envisage that these model systems will be particularly amenable to the manipulation required for target gene identification/validation.

scholarly journals Pyroglutamate Aβ cascade as drug target in Alzheimer’s disease

2021 ◽  
Author(s):  
Thomas A. Bayer
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Models ◽  
Drug Target ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Passive Immunization ◽  
Model Systems ◽  
Preclinical Model

AbstractOne of the central aims in Alzheimer’s disease (AD) research is the identification of clinically relevant drug targets. A plethora of potential molecular targets work very well in preclinical model systems both in vitro and in vivo in AD mouse models. However, the lack of translation into clinical settings in the AD field is a challenging endeavor. Although it is long known that N-terminally truncated and pyroglutamate-modified Abeta (AβpE3) peptides are abundantly present in the brain of AD patients, form stable and soluble low-molecular weight oligomers, and induce neurodegeneration in AD mouse models, their potential as drug target has not been generally accepted in the past. This situation has dramatically changed with the report that passive immunization with donanemab, an AβpE3-specific antibody, cleared aymloid plaques and stabilized cognitive deficits in a group of patients with mild AD in a phase II trial. This review summarizes the current knowledge on the molecular mechanisms of generation of AβpE, its biochemical properties, and the intervention points as a drug target in AD.

scholarly journals The Startling Role of Mismatch Repair in Trinucleotide Repeat Expansions

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1019
Author(s):  
Guy-Franck Richard
Keyword(s):  
Mismatch Repair ◽  
Developmental Disorders ◽  
Molecular Mechanisms ◽  
Trinucleotide Repeat ◽  
Model Systems ◽  
Mismatched Dna ◽  
Repeat Expansions ◽  
Dna Strand

Trinucleotide repeats are a peculiar class of microsatellites whose expansions are responsible for approximately 30 human neurological or developmental disorders. The molecular mechanisms responsible for these expansions in humans are not totally understood, but experiments in model systems such as yeast, transgenic mice, and human cells have brought evidence that the mismatch repair machinery is involved in generating these expansions. The present review summarizes, in the first part, the role of mismatch repair in detecting and fixing the DNA strand slippage occurring during microsatellite replication. In the second part, key molecular differences between normal microsatellites and those that show a bias toward expansions are extensively presented. The effect of mismatch repair mutants on microsatellite expansions is detailed in model systems, and in vitro experiments on mismatched DNA substrates are described. Finally, a model presenting the possible roles of the mismatch repair machinery in microsatellite expansions is proposed.

Bacillus subtilis – Arabidopsis thaliana: a model interaction system for studying the role of volatile organic compounds in the interchange between plants and bacteria

Botany ◽  
2019 ◽  
Vol 97 (12) ◽  
pp. 661-669
Author(s):  
Fei Li ◽  
Min Tang ◽  
Xiaoxin Tang ◽  
Wei Sun ◽  
Jiyi Gong ◽  
...  
Keyword(s):  
Arabidopsis Thaliana ◽  
Bacillus Subtilis ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Model System ◽  
Model Systems ◽  
Model Interaction ◽  
Volatile Organic ◽  
Ecological Importance

Plant–bacteria interactions are known to play important physiological roles in plant growth. Determining the mechanisms behind these interactions has paramount agricultural and ecological importance. Therefore, it is essential to study Plant–bacteria interactions and determine the relevant molecular mechanisms by using model systems. This review summarizes the current knowledge regarding plant–bacteria interactions based on the Arabidopsis thaliana – Bacillus subtilis model system, and highlights future areas for research.

scholarly journals Complex chromatin motions for DNA repair

2020 ◽  
Author(s):  
Irene Chiolo ◽  
Judith Miné-Hattab
Keyword(s):  
Dna Damage ◽  
Analytical Methods ◽  
Molecular Mechanisms ◽  
Genome Instability ◽  
Model Systems ◽  
Genome Integrity ◽  
Local Motion ◽  
Nuclear Dynamics ◽  
Repair Pathways ◽  
Different Time Scales

A number of studies across different model systems revealed that chromatin undergoes significant changes in dynamics in response to DNA damage. These include local motion changes at damage sites, increased nuclear exploration of both damaged and undamaged loci, and directed motions to new nuclear locations associated with certain repair pathways. These studies also revealed the need for new analytical methods to identify directed motions in a context of mixed trajectories, and the importance of investigating nuclear dynamics over different time scales to identify diffusion regimes. Here we provide an overview of the current understanding of this field, including imaging and analytical methods developed to investigate nuclear dynamics in different contexts. These dynamics are essential for genome integrity. Identifying the molecular mechanisms responsible for these movements is key to understanding how their misregulation contributes to cancer and other genome instability disorders.

Structural biology of plasmid partition: uncovering the molecular mechanisms of DNA segregation

2008 ◽  
Vol 412 (1) ◽  
pp. 1-18 ◽  
Author(s):  
Maria A. Schumacher
Keyword(s):  
Dna Binding ◽  
Binding Proteins ◽  
Molecular Mechanisms ◽  
Tandem Repeats ◽  
Binding Protein ◽  
Higher Order ◽  
Atomic Level ◽  
Model Systems ◽  
Dna Segregation ◽  
Plasmid Partition

DNA segregation or partition is an essential process that ensures stable genome transmission. In prokaryotes, partition is best understood for plasmids, which serve as tractable model systems to study the mechanistic underpinnings of DNA segregation at a detailed atomic level owing to their simplicity. Specifically, plasmid partition requires only three elements: a centromere-like DNA site and two proteins: a motor protein, generally an ATPase, and a centromere-binding protein. In the first step of the partition process, multiple centromere-binding proteins bind co-operatively to the centromere, which typically consists of several tandem repeats, to form a higher-order nucleoprotein complex called the partition complex. The partition complex recruits the ATPase to form the segrosome and somehow activates the ATPase for DNA separation. Two major families of plasmid par systems have been delineated based on whether they utilize ATPase proteins with deviant Walker-type motifs or actin-like folds. In contrast, the centromere-binding proteins show little sequence homology even within a given family. Recent structural studies, however, have revealed that these centromere-binding proteins appear to belong to one of two major structural groups: those that employ helix–turn–helix DNA-binding motifs or those with ribbon–helix–helix DNA-binding domains. The first structure of a higher-order partition complex was recently revealed by the structure of pSK41 centromere-binding protein, ParR, bound to its centromere site. This structure showed that multiple ParR ribbon–helix–helix motifs bind symmetrically to the tandem centromere repeats to form a large superhelical structure with dimensions suitable for capture of the filaments formed by the actinlike ATPases. Surprisingly, recent data indicate that the deviant Walker ATPase proteins also form polymer-like structures, suggesting that, although the par families harbour what initially appeared to be structurally and functionally divergent proteins, they actually utilize similar mechanisms of DNA segregation. Thus, in the present review, the known Par protein and Par–protein complex structures are discussed with regard to their functions in DNA segregation in an attempt to begin to define, at a detailed atomic level, the molecular mechanisms involved in plasmid segregation.

Mesophyll conductance: the leaf corridors for photosynthesis

2020 ◽  
Vol 48 (2) ◽  
pp. 429-439 ◽  
Author(s):  
Jorge Gago ◽  
Danilo M. Daloso ◽  
Marc Carriquí ◽  
Miquel Nadal ◽  
Melanie Morales ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Main Role ◽  
Mesophyll Conductance ◽  
Future Studies ◽  
Cell Structures ◽  
Leaf Tissues ◽  
Change Framework ◽  
Chloroplast Stroma

Besides stomata, the photosynthetic CO2 pathway also involves the transport of CO2 from the sub-stomatal air spaces inside to the carboxylation sites in the chloroplast stroma, where Rubisco is located. This pathway is far to be a simple and direct way, formed by series of consecutive barriers that the CO2 should cross to be finally assimilated in photosynthesis, known as the mesophyll conductance (gm). Therefore, the gm reflects the pathway through different air, water and biophysical barriers within the leaf tissues and cell structures. Currently, it is known that gm can impose the same level of limitation (or even higher depending of the conditions) to photosynthesis than the wider known stomata or biochemistry. In this mini-review, we are focused on each of the gm determinants to summarize the current knowledge on the mechanisms driving gm from anatomical to metabolic and biochemical perspectives. Special attention deserve the latest studies demonstrating the importance of the molecular mechanisms driving anatomical traits as cell wall and the chloroplast surface exposed to the mesophyll airspaces (Sc/S) that significantly constrain gm. However, even considering these recent discoveries, still is poorly understood the mechanisms about signaling pathways linking the environment a/biotic stressors with gm responses. Thus, considering the main role of gm as a major driver of the CO2 availability at the carboxylation sites, future studies into these aspects will help us to understand photosynthesis responses in a global change framework.

Noncoding RNAs in Medicinal Plants and Their Regulatory Roles in Bioactive Compound Production

2020 ◽  
Vol 21 ◽  
Author(s):  
Caili Li ◽  
Meizhen Wang ◽  
Xiaoxiao Qiu ◽  
Hong Zhou ◽  
Shanfa Lu
Keyword(s):  
Medicinal Plants ◽  
Current Knowledge ◽  
Salvia Miltiorrhiza ◽  
Noncoding Rnas ◽  
Bioactive Compound ◽  
Research Field ◽  
Model Systems ◽  
Small Interfering Rnas ◽  
Regulatory Pathways ◽  
Regulatory Modules

Background: Noncoding RNAs (ncRNAs), such as microRNAs (miRNAs), small interfering RNAs (siRNAs) and long noncoding RNAs (lncRNAs), play significant regulatory roles in plant development and secondary metabolism and are involved in plant response to biotic and abiotic stresses. They have been intensively studied in model systems and crops for approximately two decades and massive amount of information have been obtained. However, for medicinal plants, ncRNAs, particularly their regulatory roles in bioactive compound biosynthesis, are just emerging as a hot research field. Objective: This review aims to summarize current knowledge on herbal ncRNAs and their regulatory roles in bioactive compound production. Results and Conclusion: So far, scientists have identified thousands of miRNA candidates from over 50 medicinal plant species and 11794 lncRNAs from Salvia miltiorrhiza, Panax ginseng, and Digitalis purpurea. Among them, more than 30 miRNAs and five lncRNAs have been predicted to regulate bioactive compound production. The regulation may achieve through various regulatory modules and pathways, such as the miR397-LAC module, the miR12112-PPO module, the miR156-SPL module, the miR828-MYB module, the miR858-MYB module, and other siRNA and lncRNA regulatory pathways. Further functional analysis of herbal ncRNAs will provide useful information for quality and quantity improvement of medicinal plants.

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