scholarly journals The Beacon Calculus: A formal method for the flexible and concise modelling of biological systems

2019 ◽  
Author(s):  
Michael A. Boemo ◽  
Luca Cardelli ◽  
Conrad A. Nieduszynski
Keyword(s):  
Dna Replication ◽  
Open Source ◽  
Biological System ◽  
Genome Stability ◽  
Formal Method ◽  
Biological Systems ◽  
Origin Firing ◽  
Link Type ◽  
Multisite Phosphorylation ◽  
Large State Space

AbstractBiological systems are made up of components that change their actions (and interactions) over time and coordinate with other components nearby. Together with a large state space, the complexity of this behaviour can make it difficult to create concise mathematical models that can be easily extended or modified. This paper introduces the Beacon Calculus, a process algebra designed to simplify the task of modelling interacting biological components. Its breadth is demonstrated by creating models of DNA replication dynamics, the gene expression dynamics in response to DNA methylation damage, and a multisite phosphorylation switch. The flexibility of these models is shown by adapting the DNA replication model to further include two topics of interest from the literature: cooperative origin firing and replication fork barriers. The Beacon Calculus is supported with the open-source simulator bcs (https://github.com/MBoemo/bcs.git) to allow users to develop and simulate their own models.Author summarySimulating a model of a biological system can suggest ideas for future experiments and help ensure that conclusions about a mechanism are consistent with data. The Beacon Calculus is a new language that makes modelling simple by allowing users to simulate a biological system in only a few lines of code. This simplicity is critical as it allows users the freedom to come up with new ideas and rapidly test them. Models written in the Beacon Calculus are also easy to modify and extend, allowing users to add new features to the model or incorporate it into a larger biological system. We demonstrate the breadth of applications in this paper by applying the Beacon Calculus to DNA replication and DNA damage repair, both of which have implications for genome stability and cancer. We also apply it to multisite phosphorylation, which is important for cellular signalling. To enable users to create their own models, we created the open-source Beacon Calculus simulator bcs (https://github.com/MBoemo/bcs.git) which is easy to install and is well-supported by documentation and examples.

scholarly journals Modelling Biological Systems with Competitive Coherence

2012 ◽  
Vol 2012 ◽  
pp. 1-20 ◽  
Author(s):  
Vic Norris ◽  
Maurice Engel ◽  
Maurice Demarty
Keyword(s):  
Dna Replication ◽  
Biological System ◽  
Biological Systems ◽  
Input Sequence ◽  
Living Systems ◽  
Small Subset ◽  
Learning Program ◽  
Evolutionary Advantage ◽  
Over Time

Many living systems, from cells to brains to governments, are controlled by the activity of a small subset of their constituents. It has been argued that coherence is of evolutionary advantage and that this active subset of constituents results from competition between two processes, a Next process that brings about coherence over time, and a Now process that brings about coherence between the interior and the exterior of the system at a particular time. This competition has been termed competitive coherence and has been implemented in a toy-learning program in order to clarify the concept and to generate—and ultimately test—new hypotheses covering subjects as diverse as complexity, emergence, DNA replication, global mutations, dreaming, bioputing (computing using either the parts of biological system or the entire biological system), and equilibrium and nonequilibrium structures. Here, we show that a program using competitive coherence, Coco, can learn to respond to a simple input sequence 1, 2, 3, 2, 3, with responses to inputs that differ according to the position of the input in the sequence and hence require competition between both Next and Now processes.

scholarly journals On the Interplay of the DNA Replication Program and the Intra-S Phase Checkpoint Pathway

Genes ◽  
2019 ◽  
Vol 10 (2) ◽  
pp. 94 ◽  
Author(s):  
Diletta Ciardo ◽  
Arach Goldar ◽  
Kathrin Marheineke
Keyword(s):  
Dna Replication ◽  
Genome Stability ◽  
Current Knowledge ◽  
Theoretical Models ◽  
S Phase ◽  
Origin Firing ◽  
Checkpoint Pathway ◽  
M Phase ◽  
Spatio Temporal ◽  
S Phase Checkpoint

DNA replication in eukaryotes is achieved by the activation of multiple replication origins which needs to be precisely coordinated in space and time. This spatio-temporal replication program is regulated by many factors to maintain genome stability, which is frequently threatened through stresses of exogenous or endogenous origin. Intra-S phase checkpoints monitor the integrity of DNA synthesis and are activated when replication forks are stalled. Their activation leads to the stabilization of forks, to the delay of the replication program by the inhibition of late firing origins, and the delay of G2/M phase entry. In some cell cycles during early development these mechanisms are less efficient in order to allow rapid cell divisions. In this article, we will review our current knowledge of how the intra-S phase checkpoint regulates the replication program in budding yeast and metazoan models, including early embryos with rapid S phases. We sum up current models on how the checkpoint can inhibit origin firing in some genomic regions, but allow dormant origin activation in other regions. Finally, we discuss how numerical and theoretical models can be used to connect the multiple different actors into a global process and to extract general rules.

scholarly journals PARI Regulates Stalled Replication Fork Processing To Maintain Genome Stability upon Replication Stress in Mice

2017 ◽  
Vol 37 (23) ◽  
Author(s):  
Ayako L. Mochizuki ◽  
Ami Katanaya ◽  
Eri Hayashi ◽  
Mihoko Hosokawa ◽  
Emiko Moribe ◽  
...  
Keyword(s):  
Stem Cells ◽  
Dna Replication ◽  
Genome Stability ◽  
Ex Vivo ◽  
Chromosome Instability ◽  
Embryonic Stem ◽  
Replication Stress ◽  
Genotoxic Stress ◽  
Origin Firing

ABSTRACT DNA replication is frequently perturbed by intrinsic, as well as extrinsic, genotoxic stress. At damaged forks, DNA replication and repair activities require proper coordination to maintain genome integrity. We show here that PARI antirecombinase plays an essential role in modulating the initial response to replication stress in mice. PARI is functionally dormant at replisomes during normal replication, but upon replication stress, it enhances nascent-strand shortening that is regulated by RAD51 and MRE11. PARI then promotes double-strand break induction, followed by new origin firing instead of replication restart. Such PARI function is apparently obstructive to replication but is nonetheless physiologically required for chromosome stability in vivo and ex vivo. Of note, Pari-deficient embryonic stem cells exhibit spontaneous chromosome instability, which is attenuated by differentiation induction, suggesting that pluripotent stem cells have a preferential requirement for PARI that acts against endogenous replication stress. PARI is a latent modulator of stalled fork processing, which is required for stable genome inheritance under both endogenous and exogenous replication stress in mice.

scholarly journals DNA Replication Modulates R-loop Levels to Maintain Genome Stability

2017 ◽  
Author(s):  
Stephan Hamperl ◽  
Joshua Saldivar ◽  
Michael Bocek ◽  
Karlene A. Cimprich
Keyword(s):  
Dna Damage ◽  
Dna Replication ◽  
Genome Stability ◽  
Genome Instability ◽  
Loop Formation ◽  
Origin Firing ◽  
Disease States ◽  
Replication Fork Progression ◽  
Mechanistic Basis ◽  
Transcription And Replication

SummaryConflicts between transcription and replication are a potent source of DNA damage. The transcription machinery has the potential to aggravate such conflicts by generating co-transcriptional R-loops as an additional barrier to replication fork progression. Here, we investigate the influence of conflict orientation and R-loop formation on genome stability in human cells using a defined episomal system. This approach reveals that head-on (HO) and co-directional (CD) conflicts induce distinct DNA damage responses. Unexpectedly, the replisome acts as an orientation-dependent regulator of R-loop levels, reducing R-loops in the CD orientation but promoting their formation in the HO orientation. Replication stress and deregulated origin firing increase the number of HO collisions leading to genome-destabilizing R-loops. Our findings not only uncover an intrinsic function of the replisome in R-loop homeostasis, but also suggest a mechanistic basis for genome instability associated with deregulated DNA replication, which is observed in many disease states, including cancer.

scholarly journals The Amazing Acrobat: Yeast’s Histone H3K56 Juggles Several Important Roles While Maintaining Perfect Balance

Genes ◽  
2021 ◽  
Vol 12 (3) ◽  
pp. 342
Author(s):  
Lihi Gershon ◽  
Martin Kupiec
Keyword(s):  
Dna Replication ◽  
Genome Stability ◽  
Entry And Exit ◽  
Yeast Saccharomyces Cerevisiae ◽  
Cellular Processes ◽  
M Phase ◽  
Dna Replication And Repair ◽  
H3k56 Acetylation ◽  
Timely Fashion ◽  
The Many

Acetylation on lysine 56 of histone H3 of the yeast Saccharomyces cerevisiae has been implicated in many cellular processes that affect genome stability. Despite being the object of much research, the complete scope of the roles played by K56 acetylation is not fully understood even today. The acetylation is put in place at the S-phase of the cell cycle, in order to flag newly synthesized histones that are incorporated during DNA replication. The signal is removed by two redundant deacetylases, Hst3 and Hst4, at the entry to G2/M phase. Its crucial location, at the entry and exit points of the DNA into and out of the nucleosome, makes this a central modification, and dictates that if acetylation and deacetylation are not well concerted and executed in a timely fashion, severe genomic instability arises. In this review, we explore the wealth of information available on the many roles played by H3K56 acetylation and the deacetylases Hst3 and Hst4 in DNA replication and repair.

scholarly journals Regulation of DNA Replication Licensing and Re-Replication by Cdt1

2021 ◽  
Vol 22 (10) ◽  
pp. 5195
Author(s):  
Hui Zhang
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Replication ◽  
Genome Stability ◽  
E3 Ligase ◽  
S Phase ◽  
Replication Initiation ◽  
Nuclear Antigen ◽  
Repair Synthesis ◽  
Ubiquitin E3 Ligase

In eukaryotic cells, DNA replication licensing is precisely regulated to ensure that the initiation of genomic DNA replication in S phase occurs once and only once for each mitotic cell division. A key regulatory mechanism by which DNA re-replication is suppressed is the S phase-dependent proteolysis of Cdt1, an essential replication protein for licensing DNA replication origins by loading the Mcm2-7 replication helicase for DNA duplication in S phase. Cdt1 degradation is mediated by CRL4Cdt2 ubiquitin E3 ligase, which further requires Cdt1 binding to proliferating cell nuclear antigen (PCNA) through a PIP box domain in Cdt1 during DNA synthesis. Recent studies found that Cdt2, the specific subunit of CRL4Cdt2 ubiquitin E3 ligase that targets Cdt1 for degradation, also contains an evolutionarily conserved PIP box-like domain that mediates the interaction with PCNA. These findings suggest that the initiation and elongation of DNA replication or DNA damage-induced repair synthesis provide a novel mechanism by which Cdt1 and CRL4Cdt2 are both recruited onto the trimeric PCNA clamp encircling the replicating DNA strands to promote the interaction between Cdt1 and CRL4Cdt2. The proximity of PCNA-bound Cdt1 to CRL4Cdt2 facilitates the destruction of Cdt1 in response to DNA damage or after DNA replication initiation to prevent DNA re-replication in the cell cycle. CRL4Cdt2 ubiquitin E3 ligase may also regulate the degradation of other PIP box-containing proteins, such as CDK inhibitor p21 and histone methylase Set8, to regulate DNA replication licensing, cell cycle progression, DNA repair, and genome stability by directly interacting with PCNA during DNA replication and repair synthesis.

Sign in / Sign up

Export Citation Format

Share Document