scholarly journals The Heritability of Replication Problems

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1464
Author(s):  
Jean-Sébastien Hoffmann
Keyword(s):  
Dna Replication ◽  
Cancer Progression ◽  
Genetic Material ◽  
Replication Timing ◽  
Cellular Responses ◽  
Replication Forks ◽  
Next Generation ◽  
Checkpoint Response ◽  
Daughter Cells ◽  
The Past

The major challenge of DNA replication is to provide daughter cells with intact and fully duplicated genetic material. However, various endogenous or environmental factors can slow down or stall DNA replication forks; these replication problems are known to fuel genomic instability and associated pathology, including cancer progression. Whereas the mechanisms emphasizing the source and the cellular responses of replicative problems have attracted much consideration over the past decade, the propagation through mitosis of genome modification and its heritability in daughter cells when the stress is not strong enough to provoke a checkpoint response in G2/M was much less documented. Some recent studies addressing whether low replication stress could impact the DNA replication program of the next generation of cells made the remarkable discovery that DNA damage can indeed be transmitted to daughter cells and can be processed in the subsequent S-phase, and that the replication timing program at a subset of chromosomal domains can also be impacted in the next generation of cells. Such a progression of replication problems into mitosis and daughter cells may appear counter-intuitive, but it could offer considerable advantages by alerting the next generation of cells of potentially risky loci and offering the possibility of an adaptive mechanism to anticipate a reiteration of problems, notably for cancer cells in the context of resistance to therapy.

scholarly journals Set1-dependent H3K4 methylation becomes critical for DNA replication fork progression in response to changes in S phase dynamics in Saccharomyces cerevisiae

2020 ◽  
Author(s):  
Christophe de La Roche Saint-André ◽  
Vincent Géli
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Dna Damage ◽  
Dna Replication ◽  
Replication Fork ◽  
Genetic Material ◽  
S Phase ◽  
Replication Forks ◽  
H3k4 Methylation ◽  
Origin Firing ◽  
Phase Dynamics

AbstractDNA replication is a highly regulated process that occurs in the context of chromatin structure and is sensitive to several histone post-translational modifications. In Saccharomyces cerevisiae, the histone methylase Set1 is responsible for the transcription-dependent deposition of H3K4 methylation (H3K4me) throughout the genome. Here we show that a combination of a hypomorphic replication mutation (orc5-1) with the absence of Set1 (set1Δ) compromises the progression through S phase, and this is associated with a large increase in DNA damage. The ensuing DNA damage checkpoint activation, in addition to that of the spindle assembly checkpoint, restricts the growth of orc5-1 set1Δ. Interestingly, orc5-1 set1Δ is sensitive to the lack of RNase H activity while a reduction of histone levels is able to counterbalance the loss of Set1. We propose that the recently described Set1-dependent mitigation of transcription-replication conflicts becomes critical for growth when the replication forks accelerate due to decreased origin firing in the orc5-1 background. Furthermore, we show that an increase of reactive oxygen species (ROS) levels, likely a consequence of the elevated DNA damage, is partly responsible for the lethality in orc5-1 set1Δ.Author summaryDNA replication, that ensures the duplication of the genetic material, starts at discrete sites, termed origins, before proceeding at replication forks whose progression is carefully controlled in order to avoid conflicts with the transcription of genes. In eukaryotes, DNA replication occurs in the context of chromatin, a structure in which DNA is wrapped around proteins, called histones, that are subjected to various chemical modifications. Among them, the methylation of the lysine 4 of histone H3 (H3K4) is carried out by Set1 in Saccharomyces cerevisiae, specifically at transcribed genes. We report that, when the replication fork accelerates in response to a reduction of active origins, the absence of Set1 leads to accumulation of DNA damage. Because H3K4 methylation was recently shown to slow down replication at transcribed genes, we propose that the Set1-dependent becomes crucial to limit the occurrence of conflicts between replication and transcription caused by replication fork acceleration. In agreement with this model, stabilization of transcription-dependent structures or reduction histone levels, to limit replication fork velocity, respectively exacerbates or moderates the effect of Set1 loss. Last, but not least, we show that the oxidative stress associated to DNA damage is partly responsible for cell lethality.

scholarly journals The Human Tim/Tipin Complex Coordinates an Intra-S Checkpoint Response to UV That Slows Replication Fork Displacement

2007 ◽  
Vol 27 (8) ◽  
pp. 3131-3142 ◽  
Author(s):  
Keziban Ünsal-Kaçmaz ◽  
Paul D. Chastain ◽  
Ping-Ping Qu ◽  
Parviz Minoo ◽  
Marila Cordeiro-Stone ◽  
...  
Keyword(s):  
Dna Replication ◽  
Replication Fork ◽  
Protein A ◽  
Chain Elongation ◽  
Replication Forks ◽  
Interacting Protein ◽  
Checkpoint Response ◽  
Replication Fork Progression ◽  
Dna Chain ◽  
Interfering Rna

ABSTRACT UV-induced DNA damage stalls DNA replication forks and activates the intra-S checkpoint to inhibit replicon initiation. In response to stalled replication forks, ATR phosphorylates and activates the transducer kinase Chk1 through interactions with the mediator proteins TopBP1, Claspin, and Timeless (Tim). Murine Tim recently was shown to form a complex with Tim-interacting protein (Tipin), and a similar complex was shown to exist in human cells. Knockdown of Tipin using small interfering RNA reduced the expression of Tim and reversed the intra-S checkpoint response to UVC. Tipin interacted with replication protein A (RPA) and RPA-coated DNA, and RPA promoted the loading of Tipin onto RPA-free DNA. Immunofluorescence analysis of spread DNA fibers showed that treating HeLa cells with 2.5 J/m2 UVC not only inhibited the initiation of new replicons but also reduced the rate of chain elongation at active replication forks. The depletion of Tim and Tipin reversed the UV-induced inhibition of replicon initiation but affected the rate of DNA synthesis at replication forks in different ways. In undamaged cells depleted of Tim, the apparent rate of replication fork progression was 52% of the control. In contrast, Tipin depletion had little or no effect on fork progression in unirradiated cells but significantly attenuated the UV-induced inhibition of DNA chain elongation. Together, these findings indicate that the Tim-Tipin complex mediates the UV-induced intra-S checkpoint, Tim is needed to maintain DNA replication fork movement in the absence of damage, Tipin interacts with RPA on DNA and, in UV-damaged cells, Tipin slows DNA chain elongation in active replicons.

The DNA replication checkpoint response stabilizes stalled replication forks

Nature ◽  
2001 ◽  
Vol 412 (6846) ◽  
pp. 557-561 ◽  
Author(s):  
Massimo Lopes ◽  
Cecilia Cotta-Ramusino ◽  
Achille Pellicioli ◽  
Giordano Liberi ◽  
Paolo Plevani ◽  
...  
Keyword(s):  
Dna Replication ◽  
Replication Forks ◽  
Replication Checkpoint ◽  
Checkpoint Response ◽  
Dna Replication Checkpoint ◽  
Stalled Replication Forks

scholarly journals Mechanical Mechanisms of Chromosome Segregation

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 465
Author(s):  
Maya I. Anjur-Dietrich ◽  
Colm P. Kelleher ◽  
Daniel J. Needleman
Keyword(s):  
Cell Division ◽  
Chromosome Segregation ◽  
Genetic Material ◽  
Evolutionary Genetics ◽  
Force Generation ◽  
Coarse Grained ◽  
Subcellular Structure ◽  
Daughter Cells ◽  
The Past ◽  
The Future

Chromosome segregation—the partitioning of genetic material into two daughter cells—is one of the most crucial processes in cell division. In all Eukaryotes, chromosome segregation is driven by the spindle, a microtubule-based, self-organizing subcellular structure. Extensive research performed over the past 150 years has identified numerous commonalities and contrasts between spindles in different systems. In this review, we use simple coarse-grained models to organize and integrate previous studies of chromosome segregation. We discuss sites of force generation in spindles and fundamental mechanical principles that any understanding of chromosome segregation must be based upon. We argue that conserved sites of force generation may interact differently in different spindles, leading to distinct mechanical mechanisms of chromosome segregation. We suggest experiments to determine which mechanical mechanism is operative in a particular spindle under study. Finally, we propose that combining biophysical experiments, coarse-grained theories, and evolutionary genetics will be a productive approach to enhance our understanding of chromosome segregation in the future.

scholarly journals Stochasticity of replication fork speed plays a key role in the dynamics of DNA replication

2019 ◽  
Author(s):  
Razie Yousefi ◽  
Maga Rowicka
Keyword(s):  
Dna Replication ◽  
Replication Fork ◽  
Computational Models ◽  
Replication Timing ◽  
Temporal Organization ◽  
Yeast Cells ◽  
Replication Forks ◽  
Dna Double Strand Breaks ◽  
Timely Completion ◽  
Spatio Temporal

AbstractEukaryotic DNA replication is elaborately orchestrated to duplicate the genome timely and faithfully. Replication initiates at multiple origins from which replication forks emanate and travel bi-directionally. The complex spatio-temporal regulation of DNA replication remains incompletely understood. To study it, computational models of DNA replication have been developed in S. cerevisiae. However, in spite of the experimental evidence of replication speed stochasticity, all models assumed that replication fork speed is constant or varies only with genomic coordinates. Here, we present the first model of DNA replication assuming stochastic speed of the replication fork. Utilizing data from both wild-type and hydroxyurea-treated yeast cells, we show that our model is more accurate than models assuming constant fork speed and reconstructs dynamics of DNA replication faithfully starting both from population-wide data and data reflecting fork movement in individual cells. Completion of replication in a timely manner is a challenge due to its stochasticity; we propose an empirically derived modification to replication speed based on the distance to the approaching fork, which promotes timely completion of replication. In summary, our work discovers a key role that stochasticity of the fork speed plays in the dynamics of DNA replication. We show that without including stochasticity of fork speed it is not possible to accurately reconstruct movement of individual replication forks, measured by DNA combing.Author summaryDNA replication in eukaryotes starts from multiple sites termed replication origins. Replication timing at individual sites is stochastic, but reproducible population-wide. Complex and not yet completely understood mechanisms ensure that genome is replicated exactly once and that replication is finished in time. This complex spatio-temporal organization of DNA replication makes computational modeling a useful tool to study replication mechanisms. For simplicity, all previous models assumed constant replication fork speed. Here, we show that such models are incapable of accurately reconstructing distances travelled by individual replication forks. Therefore, we propose a model with a stochastic replication fork speed. We show that such model reproduces faithfully distances travelled by individual replication forks. Moreover, our model is simpler than previous model and thus avoids over-learning (fitting noise). We also discover how replication speed may be attuned to timely complete replication. We propose that fork speed exponentially increases with diminishing distance to the approaching fork, which we show promotes timely completion of replication. Such speed up can be e.g. explained by a synergy effect of chromatin unwinding by both forks. Our model can be used to simulate phenomena beyond replication, e.g. DNA double-strand breaks resulting from broken replication forks.

scholarly journals Comparing DNA replication programs reveals large timing shifts at centromeres of endocycling cells in maize roots

2020 ◽  
Author(s):  
Emily E. Wear ◽  
Jawon Song ◽  
Gregory J. Zynda ◽  
Leigh Mickelson-Young ◽  
Chantal LeBlanc ◽  
...  
Keyword(s):  
Cell Division ◽  
Dna Replication ◽  
Mitotic Cycle ◽  
Genetic Material ◽  
Cell Types ◽  
S Phase ◽  
Partial Replacement ◽  
Root Tips ◽  
Cell Cycles ◽  
Daughter Cells

ABSTRACTPlant cells undergo two types of cell cycles – the mitotic cycle in which DNA replication is coupled to mitosis, and the endocycle in which DNA replication occurs in the absence of cell division. To investigate DNA replication programs in these two types of cell cycles, we pulse labeled intact root tips of maize (Zea mays) with 5-ethynyl-2’-deoxyuridine (EdU) and used flow sorting of nuclei to examine DNA replication timing (RT) during the transition from a mitotic cycle to an endocycle. Here, we compare sequence-based RT profiles and found that most regions of the maize genome replicate at the same time during S phase in mitotic and endocycling cells, despite the need to replicate twice as much DNA in the endocycle. However, regions collectively corresponding to 2% of the genome displayed significant changes in timing between the two types of cell cycles. The majority of these regions are small, with a median size of 135 kb, and shift to a later RT in the endocycle. However, we found larger regions that shifted RT in centromeres of seven of the ten maize chromosomes. These regions covered the majority of the previously defined functional centromere in each case, which are ∼1–2 Mb in size in the reference genome. They replicate mainly during mid S phase in mitotic cells, but primarily in late S phase of the endocycle. Strikingly, the immediately adjacent pericentromere sequences are primarily late replicating in both cell cycles. Analysis of CENH3 enrichment levels in nuclei of different ploidies suggested that there is only a partial replacement of CENH3 nucleosomes after endocycle replication is complete. The shift to later replication of centromeres and reduced CENH3 enrichment after endocycle replication is consistent with the hypothesis that centromeres are being inactivated as their function is no longer needed.AUTHOR SUMMARYIn traditional cell division, or mitosis, a cell’s genetic material is duplicated and then split between two daughter cells. In contrast, in some specialized cell types, the DNA is duplicated a second time without an intervening division step, resulting in cells that carry twice as much DNA – a phenomenon called an endocycle, which is common during plant development. At each step, DNA replication follows an ordered program, in which highly compacted DNA is unraveled and replicated in sections at different times during the synthesis (S) phase. In plants, it is unclear whether traditional and endocycle programs are the same. Using root tips of maize, we found a small portion of the genome whose replication in the endocycle is shifted in time, usually to later in S phase. Some of these regions are scattered around the genome, and mostly coincide with active genes. However, the most prominent shifts occur in centromeres. This location is noteworthy because centromeres orchestrate the process of separating duplicated chromosomes into daughter cells, a function that is not needed in the endocycle. Our observation that centromeres replicate later in the endocycle suggests there is an important link between the time of replication and the function of centromeres.

scholarly journals Replication Stress and Consequential Instability of the Genome and Epigenome

Molecules ◽  
2019 ◽  
Vol 24 (21) ◽  
pp. 3870 ◽  
Author(s):  
Pawlos S. Tsegay ◽  
Yanhao Lai ◽  
Yuan Liu
Keyword(s):  
Dna Damage ◽  
Dna Replication ◽  
Oxidative Dna Damage ◽  
Replication Stress ◽  
Cellular Responses ◽  
Epigenetic Modifications ◽  
Daughter Cells ◽  
Dna Replication Stress ◽  
Dna Secondary Structures ◽  
The One

Cells must faithfully duplicate their DNA in the genome to pass their genetic information to the daughter cells. To maintain genomic stability and integrity, double-strand DNA has to be replicated in a strictly regulated manner, ensuring the accuracy of its copy number, integrity and epigenetic modifications. However, DNA is constantly under the attack of DNA damage, among which oxidative DNA damage is the one that most frequently occurs, and can alter the accuracy of DNA replication, integrity and epigenetic features, resulting in DNA replication stress and subsequent genome and epigenome instability. In this review, we summarize DNA damage-induced replication stress, the formation of DNA secondary structures, peculiar epigenetic modifications and cellular responses to the stress and their impact on the instability of the genome and epigenome mainly in eukaryotic cells.

The zoonotic potential of bat-borne coronaviruses

2020 ◽  
Vol 4 (4) ◽  
pp. 365-381
Author(s):  
Ny Anjara Fifi Ravelomanantsoa ◽  
Sarah Guth ◽  
Angelo Andrianiaina ◽  
Santino Andry ◽  
Anecia Gentles ◽  
...  
Keyword(s):  
Genetic Material ◽  
Field Research ◽  
Sympatric Species ◽  
Animal Origin ◽  
Mammalian Host ◽  
Past Century ◽  
The Past ◽  
Novel Host ◽  
Horseshoe Bat ◽  
Human Infections

Seven zoonoses — human infections of animal origin — have emerged from the Coronaviridae family in the past century, including three viruses responsible for significant human mortality (SARS-CoV, MERS-CoV, and SARS-CoV-2) in the past twenty years alone. These three viruses, in addition to two older CoV zoonoses (HCoV-229E and HCoV-NL63) are believed to be originally derived from wild bat reservoir species. We review the molecular biology of the bat-derived Alpha- and Betacoronavirus genera, highlighting features that contribute to their potential for cross-species emergence, including the use of well-conserved mammalian host cell machinery for cell entry and a unique capacity for adaptation to novel host environments after host switching. The adaptive capacity of coronaviruses largely results from their large genomes, which reduce the risk of deleterious mutational errors and facilitate range-expanding recombination events by offering heightened redundancy in essential genetic material. Large CoV genomes are made possible by the unique proofreading capacity encoded for their RNA-dependent polymerase. We find that bat-borne SARS-related coronaviruses in the subgenus Sarbecovirus, the source clade for SARS-CoV and SARS-CoV-2, present a particularly poignant pandemic threat, due to the extraordinary viral genetic diversity represented among several sympatric species of their horseshoe bat hosts. To date, Sarbecovirus surveillance has been almost entirely restricted to China. More vigorous field research efforts tracking the circulation of Sarbecoviruses specifically and Betacoronaviruses more generally is needed across a broader global range if we are to avoid future repeats of the COVID-19 pandemic.

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