Cell-to-cell variability and robustness in S-phase duration from genome replication kinetics

Zhang, Qing; Bassetti, Federico; Lagomarsino, Marco Cosentino

doi:10.1093/nar/gkx556

Cited by 18 publications

(29 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We also demonstrated that after transcription inhibition, S phase duration remained the same, at least after a short period ( Figure 6D). This result confirms the robustness of S phase duration, as previously suggested by other studies (47,74). Several studies have demonstrated the activation of dormant origins following replication stress to ensure the completion of DNA replication near stalled or collapsed 26 replication (6,14,(75)(76)(77).…”

Section: Discussionsupporting

confidence: 90%

“…Based on these features and considering that the precise S phase duration estimated previously ( Figure 1) is robust, as proposed for other cell types (21,47), simulations with our stochastic computational models suggest that the presence of replication-transcription conflicts might lead to an increase in origin firing, which in turn helps to maintain the robustness of the S phase duration (Figure 3, Supplementary Table S2). Analyzed together, these simulations suggest the presence of a mechanism responsible for a decrease in the mean IOD estimated under standard conditions, making the parasites fire a pool of origins greater than the minimum required to complete S phase.…”

Section: Discussionsupporting

confidence: 71%

See 1 more Smart Citation

Transcription activity contributes to the firing of non-constitutive origins in Trypanosoma brucei

Silva¹,

Cayres-Silva²,

Vitarelli³

et al. 2018

Preprint

View full text Add to dashboard Cite

The cosynthesis 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 have not yet been investigated. Here, using equations and computational analysis we demonstrated that the number of constitutive origins mapped in the Trypanosoma brucei genome is close to the minimum required to complete replication within S phase duration. However, taking into account the location of these origins in the genome, the replication in due time becomes virtually impossible, making it necessary to activate non-constitutive origins. Moreover, computational and biological assays pointed to transcription being responsible for activating non-constitutive origins. Together, our results suggest that transcription action through conflicts with replication contributes to the firing of non-constitutive origins, maintaining the robustness of S phase duration. The usage of this entire pool of origins seems to be of paramount importance for the survival of this parasite that infects million people around the world since it contributes to the maintenance of the replication of its DNA.

show abstract

Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 71%

Transcription activity contributes to the firing of non-constitutive origins in Trypanosoma brucei

Silva¹,

Cayres-Silva²,

Vitarelli³

et al. 2018

Preprint

View full text Add to dashboard Cite

show abstract

“…These apparently stochastic differences in cell-cycle durations were originally attributed exclusively to the G1 phase 13 . However, more recent studies in multiple cell types have revealed that S and G2 also contribute significant variability to total cell cycle duration 3,14,15 . Collectively, these studies have revealed that differences in cell cycle durations are an inherent property of individual cells and raise the fundamental question of how these durations are determined.Over the past 50 years, multiple models have been put forth to explain the differences in cell cycle phase durations among individual cells.…”

mentioning

confidence: 99%

Evidence that the cell cycle is a series of uncoupled, memoryless phases

Chao

Fakhreddin

Shimerov

et al. 2018

Preprint

View full text Add to dashboard Cite

The cell cycle is canonically described as a series of 4 phases: G1 (gap phase 1), S (DNA synthesis), G2 (gap phase 2), and M (mitosis). Various models have been proposed to describe the durations of each phase, including a two-state model with fixed S-G2-M duration and random G1 duration 1,2 ; a "stretched" model in which phase durations are proportional 3 ; and an inheritance model in which sister cells show correlated phase durations 2,4 . A fundamental challenge is to understand the quantitative laws that govern cell-cycle progression and to reconcile the evidence supporting these different models. Here, we used time-lapse fluorescence microscopy to quantify the durations of G1, S, G2, and M phases for thousands of individual cells from three human cell lines. We found no evidence of correlation between any pair of phase durations. Instead, each phase followed an Erlang distribution with a characteristic rate and number of steps. These observations suggest that each cell cycle phase is memoryless with respect to previous phase durations. We challenged this model by perturbing the durations of specific phases through oncogene activation, inhibition of DNA synthesis, reduced temperature, and DNA damage. Phase durations remained uncoupled in individual cells despite large changes in durations in cell populations. To explain this behavior, we propose a mathematical model in which the independence of cell-cycle phase durations arises from a large number of molecular factors that each exerts a minor influence on the rate of cell-cycle progression. The model predicts that it is possible to force correlations between phases by making large perturbations to a single factor that contributes to more than one phase duration, which we confirmed experimentally by inhibiting cyclindependent kinase 2 (CDK2). We further report that phases can show coupling under certain dysfunctional states such as in a transformed cell line with defective cell cycle checkpoints. This quantitative model of cell cycle progression explains the paradoxical observation that phase durations are both inherited and independent and suggests how cell cycle progression may be altered in disease states.The discovery that DNA synthesis occurs during a well-defined period of time between cell divisions 5 led to the development of the canonical four-stage cell cycle model comprising G1, S, G2, and M phases. It has long been known that the durations of these phases can vary considerably across cell types 6 . For example, stem cells and immune cells have relatively brief G1 durations compared to somatic cells 7-9 . Phase durations can also change under certain environmental stresses such as starvation, which lengthens G1 10 , or DNA damage, which prolongs G1 and G2 11,12 . Furthermore, examination of individual cells has revealed that phase durations vary even among clonal cells under similar environmental conditions 6 . These apparently stochastic differences in cell-cycle durations were originally attributed exclusively to the G1 phase 13 . However, more ...

show abstract

“…As functional properties, we considered the efficiency and the characteristic firing time of each individual origin and that of its closest neighboring origin along the chromosomes. We used a stochastic mathematical model to infer origin firing rates from the fit to our replication timing data and derived the efficiency and firing time of each individual origin in the 10 Lachancea genomes from running the model 14 .…”

Section: The Loss Of An Active Replication Origin Depends On Its Neigmentioning

confidence: 99%

“…Mathematical modeling of such replication timing data gives access to the stochastic firing components of each individual origin 10,[12][13][14] . First, each replication origin has a given probability of activation, named efficiency, which represents the proportion of the cells in a population in which the origin actively fires.…”

Section: Introductionmentioning

confidence: 99%

The evolution of the temporal program of genome replication

Agier

Delmas

Zhang

et al. 2017

Preprint

Self Cite

View full text Add to dashboard Cite

Comparative analyses of temporal programs of genome replication revealed either a nearly complete conservation between closely related species or a comprehensive reprogramming between distantly related species. Therefore, many important questions on the evolutionary remodeling of replication timing programs remain unanswered. To address this issue, we generated genome-wide replication timing profiles for ten yeast species from the genus Lachancea, covering a continuous evolutionary range from closely related to more divergent species. The comparative analysis of these profiles revealed that the replication program linearly evolves with increasing evolutionary divergence between these species. We found that the evolution of the timing program mainly results from a high evolutionary turnover rate of the cohort of active replication origins. We detected about one thousand evolutionary events of losses of active replication origins and gains of newborn origins since the species diverged from their last common ancestor about 80 million years ago. We show that the relocation of active replication origins is independent from synteny breakpoints, suggesting that chromosome rearrangements did not drive the evolution of the replication programs.Rather, origin gains and losses are linked both in space, along chromosomes, and in time, along the same branches of the phylogenetic tree. New origins continuously arise with on average low to medium firing efficiencies and increase in efficiency and earliness as they evolutionarily age. Yet, a subset of newborn origins emerges with high firing efficiency and origin losses occur concomitantly to their emergence and preferentially in their direct chromosomal vicinity. These key findings on the evolutionary birth, death and conservation of active replication origins provide the first description of how the temporal program of genome replication has evolved in eukaryotes.

show abstract

Cell-to-cell variability and robustness in S-phase duration from genome replication kinetics

Cited by 18 publications

References 42 publications

Transcription activity contributes to the firing of non-constitutive origins in Trypanosoma brucei

Transcription activity contributes to the firing of non-constitutive origins in Trypanosoma brucei

Evidence that the cell cycle is a series of uncoupled, memoryless phases

The evolution of the temporal program of genome replication

Contact Info

Product

Resources

About