scholarly journals How to model DNA replication in stochastic models of synthetic genetic circuits (and why)

2021 ◽  
Author(s):  
Samuel Clamons ◽  
Richard M Murray
Keyword(s):  
Dna Replication ◽  
Stochastic Models ◽  
Mechanistic Model ◽  
Genetic Circuits ◽  
Replication Mechanism ◽  
Pathological Model ◽  
Cole1 Replication

Biocircuit modeling sometimes requires explicit tracking of a self-replicating DNA species. The most obvious, straightforward way to model a replicating DNA is structurally unstable and leads to pathological model behavior. We describe a simple, stable replication mechanism with good model behavior and show how to derive it from a mechanistic model of ColE1 replication.

scholarly journals Stability and Robustness of Unbalanced Genetic Toggle Switches in the Presence of Scarce Resources

Life ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 271
Author(s):  
Chentao Yong ◽  
Andras Gyorgy
Keyword(s):  
Cell Fate ◽  
Rational Design ◽  
Resource Competition ◽  
Dynamic Properties ◽  
Mechanistic Model ◽  
Robustness Analysis ◽  
System Level ◽  
Genetic Circuits ◽  
Scarce Resources ◽  
Genetic Systems

While the vision of synthetic biology is to create complex genetic systems in a rational fashion, system-level behaviors are often perplexing due to the context-dependent dynamics of modules. One major source of context-dependence emerges due to the limited availability of shared resources, coupling the behavior of disconnected components. Motivated by the ubiquitous role of toggle switches in genetic circuits ranging from controlling cell fate differentiation to optimizing cellular performance, here we reveal how their fundamental dynamic properties are affected by competition for scarce resources. Combining a mechanistic model with nullcline-based stability analysis and potential landscape-based robustness analysis, we uncover not only the detrimental impacts of resource competition, but also how the unbalancedness of the switch further exacerbates them. While in general both of these factors undermine the performance of the switch (by pushing the dynamics toward monostability and increased sensitivity to noise), we also demonstrate that some of the unwanted effects can be alleviated by strategically optimized resource competition. Our results provide explicit guidelines for the context-aware rational design of toggle switches to mitigate our reliance on lengthy and expensive trial-and-error processes, and can be seamlessly integrated into the computer-aided synthesis of complex genetic systems.

scholarly journals Human subtelomeric copy number gains suggest a DNA replication mechanism for formation: beyond breakage–fusion–bridge for telomere stabilization

2012 ◽  
Vol 131 (12) ◽  
pp. 1895-1910 ◽  
Author(s):  
Svetlana A. Yatsenko ◽  
Patricia Hixson ◽  
Erin K. Roney ◽  
Daryl A. Scott ◽  
Christian P. Schaaf ◽  
...  
Keyword(s):  
Dna Replication ◽  
Copy Number ◽  
Replication Mechanism

scholarly journals Transcription activity contributes to the firing of non-constitutive origins in African trypanosomes helping to maintain robustness in S-phase duration

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Marcelo S. da Silva ◽  
Gustavo R. Cayres-Silva ◽  
Marcela O. Vitarelli ◽  
Paula A. Marin ◽  
Priscila M. Hiraiwa ◽  
...  
Keyword(s):  
Dna Replication ◽  
Mechanistic Model ◽  
S Phase ◽  
Dna Lesions ◽  
Phase Duration ◽  
African Trypanosomes ◽  
Transcription Activity ◽  
Dna And Rna ◽  
Polycistronic Transcription ◽  
Dna Combing

AbstractThe co-synthesis of DNA and RNA potentially generates conflicts between replication and transcription, which can lead to genomic instability. In trypanosomatids, eukaryotic parasites that perform polycistronic transcription, this phenomenon and its consequences are still little studied. Here, we showed that the number of constitutive origins mapped in the Trypanosoma brucei genome is less than the minimum required to complete replication within S-phase duration. By the development of a mechanistic model of DNA replication considering replication-transcription conflicts and using immunofluorescence assays and DNA combing approaches, we demonstrated that the activation of non-constitutive (backup) origins are indispensable for replication to be completed within S-phase period. Together, our findings suggest that transcription activity during S phase generates R-loops, which contributes to the emergence of DNA lesions, leading to the firing of backup origins that help maintain robustness in S-phase duration. The usage of this increased pool of origins, contributing to the maintenance of DNA replication, seems to be of paramount importance for the survival of this parasite that affects million people around the world.

scholarly journals A DNA Replication Mechanism for Generating Nonrecurrent Rearrangements Associated with Genomic Disorders

Cell ◽  
2007 ◽  
Vol 131 (7) ◽  
pp. 1235-1247 ◽  
Author(s):  
Jennifer A. Lee ◽  
Claudia M.B. Carvalho ◽  
James R. Lupski
Keyword(s):  
Dna Replication ◽  
Replication Mechanism ◽  
Genomic Disorders

Adenovirus DNA Replication: Mechanism and Replication Proteins

1983 ◽  
pp. 107-122
Author(s):  
Peter C. van der Vliet ◽  
Marijke M. Kwant ◽  
Bram G. M. van Bergen ◽  
Wim van Driel
Keyword(s):  
Dna Replication ◽  
Replication Proteins ◽  
Replication Mechanism

scholarly journals Structure–Function Analysis Reveals the Singularity of Plant Mitochondrial DNA Replication Components: A Mosaic and Redundant System

Plants ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 533 ◽  
Author(s):  
Brieba
Keyword(s):  
Mitochondrial Dna ◽  
Dna Replication ◽  
Function Analysis ◽  
Plant Mitochondria ◽  
Linear Structure ◽  
Mitochondrial Rna ◽  
Replication Mechanism ◽  
Plant Mitochondrial Dna ◽  
Plastid Genomes ◽  
Mitochondrial Dna Replication

Plants are sessile organisms, and their DNA is particularly exposed to damaging agents. The integrity of plant mitochondrial and plastid genomes is necessary for cell survival. During evolution, plants have evolved mechanisms to replicate their mitochondrial genomes while minimizing the effects of DNA damaging agents. The recombinogenic character of plant mitochondrial DNA, absence of defined origins of replication, and its linear structure suggest that mitochondrial DNA replication is achieved by a recombination-dependent replication mechanism. Here, I review the mitochondrial proteins possibly involved in mitochondrial DNA replication from a structural point of view. A revision of these proteins supports the idea that mitochondrial DNA replication could be replicated by several processes. The analysis indicates that DNA replication in plant mitochondria could be achieved by a recombination-dependent replication mechanism, but also by a replisome in which primers are synthesized by three different enzymes: Mitochondrial RNA polymerase, Primase-Helicase, and Primase-Polymerase. The recombination-dependent replication model and primers synthesized by the Primase-Polymerase may be responsible for the presence of genomic rearrangements in plant mitochondria.

scholarly journals Mgs1 function at G-quadruplex structures during DNA replication

2020 ◽  
Author(s):  
Katrin Paeschke ◽  
Peter Burkovics
Keyword(s):  
Dna Replication ◽  
Genome Stability ◽  
Mechanistic Model ◽  
Regulation Of Gene Expression ◽  
Telomere Maintenance ◽  
Dna Structures ◽  
Genomic Deletions ◽  
G Quadruplex

AbstractThe coordinated action of DNA polymerases and DNA helicases is essential at genomic sites that are hard to replicate. Among these are sites that harbour G-quadruplex DNA structures (G4). G4s are stable alternative DNA structures, which have been implicated to be involved in important cellular processes like the regulation of gene expression or telomere maintenance. G4 structures were shown to hinder replication fork progression and cause genomic deletions, mutations and recombination events. Many helicases unwind G4 structures and preserve genome stability, but a detailed understanding of G4 replication and the re-start of stalled replication forks around formed G4 structures is not clear, yet. In our recent study, we identified that Mgs1 preferentially binds to G4 DNA structures in vitro and is associated with putative G4-forming chromosomal regions in vivo. Mgs1 binding to G4 motifs in vivo is partially dependent on the helicase Pif1. Pif1 is the major G4-unwinding helicase in S. cerevisiae. In the absence of Mgs1, we determined elevated gross chromosomal rearrangement (GCR) rates in yeast, similar to Pif1 deletion. Here, we highlight the recent findings and set these into context with a new mechanistic model. We propose that Mgs1's functions support DNA replication at G4-forming regions.

scholarly journals RNase/Anti-RNase Activities of the Bacterial parD Toxin-Antitoxin System

2005 ◽  
Vol 187 (9) ◽  
pp. 3151-3157 ◽  
Author(s):  
Ana J. Muñoz-Gómez ◽  
Marc Lemonnier ◽  
Sandra Santos-Sierra ◽  
Alfredo Berzal-Herranz ◽  
Ramón Díaz-Orejas
Keyword(s):  
Protein Synthesis ◽  
Dna Replication ◽  
Rna Degradation ◽  
Double Stranded Rna ◽  
Cellular Processes ◽  
Inhibition Of Protein Synthesis ◽  
Reticulocyte Lysates ◽  
The Stability ◽  
Cole1 Replication

ABSTRACT The bacterial parD toxin-antitoxin system of plasmid R1 encodes two proteins, the Kid toxin and its cognate antitoxin, Kis. Kid cleaves RNA and inhibits protein synthesis and cell growth in Escherichia coli. Here, we show that Kid promotes RNA degradation and inhibition of protein synthesis in rabbit reticulocyte lysates. These new activities of the Kid toxin were counteracted by the Kis antitoxin and were not displayed by the KidR85W variant, which is nontoxic in E. coli. Moreover, while Kid cleaved single- and double-stranded RNA with a preference for UAA or UAC triplets, KidR85W maintained this sequence preference but hardly cleaved double-stranded RNA. Kid was formerly shown to inhibit DNA replication of the ColE1 plasmid. Here we provide in vitro evidence that Kid cleaves the ColE1 RNA II primer, which is required for the initiation of ColE1 replication. In contrast, KidR85W did not affect the stability of RNA II, nor did it inhibit the in vitro replication of ColE1. Thus, the endoribonuclease and the cytotoxic and DNA replication-inhibitory activities of Kid seem tightly correlated. We propose that the spectrum of action of this toxin extends beyond the sole inhibition of protein synthesis to control a broad range of RNA-regulated cellular processes.

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