scholarly journals Ploidy and recombination proficiency shape the evolutionary adaptation to constitutive DNA replication stress

PLoS Genetics ◽  
2021 ◽  
Vol 17 (11) ◽  
pp. e1009875
Author(s):  
Marco Fumasoni ◽  
Andrew W. Murray
Keyword(s):  
Dna Replication ◽  
Replication Stress ◽  
Dna Damage Checkpoint ◽  
Functional Modules ◽  
Evolutionary Adaptation ◽  
Genome Maintenance ◽  
Genomic Features ◽  
Evolutionary Response ◽  
Chromatid Cohesion ◽  
Dna Replication Stress

In haploid budding yeast, evolutionary adaptation to constitutive DNA replication stress alters three genome maintenance modules: DNA replication, the DNA damage checkpoint, and sister chromatid cohesion. We asked how these trajectories depend on genomic features by comparing the adaptation in three strains: haploids, diploids, and recombination deficient haploids. In all three, adaptation happens within 1000 generations at rates that are correlated with the initial fitness defect of the ancestors. Mutations in individual genes are selected at different frequencies in populations with different genomic features, but the benefits these mutations confer are similar in the three strains, and combinations of these mutations reproduce the fitness gains of evolved populations. Despite the differences in the selected mutations, adaptation targets the same three functional modules despite differences in genomic features, revealing a common evolutionary response to constitutive DNA replication stress.

scholarly journals Genome architecture shapes evolutionary adaptation to DNA replication stress

2020 ◽  
Author(s):  
Marco Fumasoni ◽  
Andrew W. Murray
Keyword(s):  
Dna Damage ◽  
Dna Replication ◽  
Replication Stress ◽  
Selective Advantage ◽  
Genome Architecture ◽  
Dna Damage Checkpoint ◽  
Evolutionary Adaptation ◽  
Loss Of Function ◽  
Genome Maintenance ◽  
Dna Replication Stress

ABSTRACTEvolutionary adaptation to perturbations in DNA replication follows reproducible trajectories that lead to changes in three important aspects of genome maintenance: DNA replication, the DNA damage checkpoint, and sister chromatid cohesion. We asked how these trajectories depend on a population’s genome architecture by testing whether ploidy or the ability to perform homologous recombination influence the evolutionary fate of the budding yeast, Saccharomyces cerevisiae, as it adapts to constitutive DNA replication stress, a condition that characterizes many cancer cells. In all three genome architectures, adaptation happens within 1000 generations at rates that are linearly correlated with the initial fitness defect of the ancestors. Which genes are mutated depends on the frequency at which mutations occur and the selective advantage they confer. The recombination-deficient strain amplifies adaptive chromosomal regions less often, whereas the selective advantage of loss-of-function mutations, such as those that inactivate the DNA damage checkpoint, is reduced in diploids because of the presence of a second, wild-type copy of the gene. Despite these differences, selection targets the same three functional modules in all three architectures, suggesting that genome architecture controls which genes are mutated but not which modules are modified.

scholarly journals The evolutionary plasticity of chromosome metabolism allows adaptation to DNA replication stress

2019 ◽  
Author(s):  
Marco Fumasoni ◽  
Andrew W. Murray
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Dna Replication ◽  
Natural Populations ◽  
Replication Stress ◽  
Dna Damage Checkpoint ◽  
Whole Genome ◽  
Replication Forks ◽  
Evolutionary Trajectory ◽  
Chromatid Cohesion ◽  
Dna Replication Stress

AbstractChromosome metabolism is defined by the pathways that collectively maintain the genome, including chromosome replication, repair and segregation. Because aspects of these pathways are conserved, chromosome metabolism is considered resistant to evolutionary change. We used the budding yeast, Saccharomyces cerevisiae, to investigate the evolutionary plasticity of chromosome metabolism. We experimentally evolved cells constitutively experiencing DNA replication stress caused by the absence of Ctf4, a protein that coordinates the activities at replication forks. Parallel populations adapted to replication stress, over 1000 generations, by acquiring multiple, successive mutations. Whole-genome sequencing and testing candidate mutations revealed adaptive changes in three aspects of chromosome metabolism: DNA replication, DNA damage checkpoint and sister chromatid cohesion. Although no gene was mutated in every population, the same pathways were sequentially altered, defining a functionally reproducible evolutionary trajectory. We propose that this evolutionary plasticity of chromosome metabolism has important implications for genome evolution in natural populations and cancer.

scholarly journals The evolutionary plasticity of chromosome metabolism allows adaptation to constitutive DNA replication stress

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Marco Fumasoni ◽  
Andrew W Murray
Keyword(s):  
Dna Replication ◽  
Natural Populations ◽  
Replication Stress ◽  
Replication Forks ◽  
Yeast Saccharomyces Cerevisiae ◽  
Evolutionary Trajectory ◽  
Biological Features ◽  
Chromatid Cohesion ◽  
Conserved Genes ◽  
Dna Replication Stress

Many biological features are conserved and thus considered to be resistant to evolutionary change. While rapid genetic adaptation following the removal of conserved genes has been observed, we often lack a mechanistic understanding of how adaptation happens. We used the budding yeast, Saccharomyces cerevisiae, to investigate the evolutionary plasticity of chromosome metabolism, a network of evolutionary conserved modules. We experimentally evolved cells constitutively experiencing DNA replication stress caused by the absence of Ctf4, a protein that coordinates the enzymatic activities at replication forks. Parallel populations adapted to replication stress, over 1000 generations, by acquiring multiple, concerted mutations. These mutations altered conserved features of two chromosome metabolism modules, DNA replication and sister chromatid cohesion, and inactivated a third, the DNA damage checkpoint. The selected mutations define a functionally reproducible evolutionary trajectory. We suggest that the evolutionary plasticity of chromosome metabolism has implications for genome evolution in natural populations and cancer.

scholarly journals Chromatin as a Platform for Modulating the Replication Stress Response

Genes ◽  
2018 ◽  
Vol 9 (12) ◽  
pp. 622 ◽  
Author(s):  
Louis-Alexandre Fournier ◽  
Arun Kumar ◽  
Peter Stirling
Keyword(s):  
Dna Replication ◽  
Stress Response ◽  
Replication Fork ◽  
Replication Stress ◽  
Genome Maintenance ◽  
Post Translational Modifications ◽  
Nucleosome Dynamics ◽  
Dna Replication Stress ◽  
Eukaryotic Dna ◽  
Fork Stalling

Eukaryotic DNA replication occurs in the context of chromatin. Recent years have seen major advances in our understanding of histone supply, histone recycling and nascent histone incorporation during replication. Furthermore, much is now known about the roles of histone remodellers and post-translational modifications in replication. It has also become clear that nucleosome dynamics during replication play critical roles in genome maintenance and that chromatin modifiers are important for preventing DNA replication stress. An understanding of how cells deploy specific nucleosome modifiers, chaperones and remodellers directly at sites of replication fork stalling has been building more slowly. Here we will specifically discuss recent advances in understanding how chromatin composition contribute to replication fork stability and restart.

scholarly journals The Interplay of Cohesin and the Replisome at Processive and Stressed DNA Replication Forks

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3455
Author(s):  
Janne J.M. van Schie ◽  
Job de Lange
Keyword(s):  
Dna Replication ◽  
Sister Chromatid ◽  
Molecular Mechanisms ◽  
Replication Stress ◽  
Sister Chromatid Cohesion ◽  
Key Factors ◽  
Sister Chromatids ◽  
Chromatid Cohesion ◽  
Dna Replication Stress ◽  
Subsequent Stabilization

The cohesin complex facilitates faithful chromosome segregation by pairing the sister chromatids after DNA replication until mitosis. In addition, cohesin contributes to proficient and error-free DNA replication. Replisome progression and establishment of sister chromatid cohesion are intimately intertwined processes. Here, we review how the key factors in DNA replication and cohesion establishment cooperate in unperturbed conditions and during DNA replication stress. We discuss the detailed molecular mechanisms of cohesin recruitment and the entrapment of replicated sister chromatids at the replisome, the subsequent stabilization of sister chromatid cohesion via SMC3 acetylation, as well as the role and regulation of cohesin in the response to DNA replication stress.

scholarly journals Targeting DNA Replication Stress for Cancer Therapy

Genes ◽  
2016 ◽  
Vol 7 (8) ◽  
pp. 51 ◽  
Author(s):  
Jun Zhang ◽  
Qun Dai ◽  
Dongkyoo Park ◽  
Xingming Deng
Keyword(s):  
Dna Replication ◽  
Cancer Therapy ◽  
Replication Stress ◽  
Dna Replication Stress

scholarly journals Targeting the DNA replication stress phenotype of KRAS mutant cancer cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Tara Al Zubaidi ◽  
O. H. Fiete Gehrisch ◽  
Marie-Michelle Genois ◽  
Qi Liu ◽  
Shan Lu ◽  
...  
Keyword(s):  
Dna Replication ◽  
Single Molecule ◽  
Replication Stress ◽  
Proton Radiation ◽  
Wild Type ◽  
Cellular Effects ◽  
Proton Treatment ◽  
Dna Replication Stress ◽  
Fork Stalling ◽  
Mutant Cells

AbstractMutant KRAS is a common tumor driver and frequently confers resistance to anti-cancer treatments such as radiation. DNA replication stress in these tumors may constitute a therapeutic liability but is poorly understood. Here, using single-molecule DNA fiber analysis, we first characterized baseline replication stress in a panel of unperturbed isogenic and non-isogenic cancer cell lines. Correlating with the observed enhanced replication stress we found increased levels of cytosolic double-stranded DNA in KRAS mutant compared to wild-type cells. Yet, despite this phenotype replication stress-inducing agents failed to selectively impact KRAS mutant cells, which were protected by CHK1. Similarly, most exogenous stressors studied did not differentially augment cytosolic DNA accumulation in KRAS mutant compared to wild-type cells. However, we found that proton radiation was able to slow fork progression and preferentially induce fork stalling in KRAS mutant cells. Proton treatment also partly reversed the radioresistance associated with mutant KRAS. The cellular effects of protons in the presence of KRAS mutation clearly contrasted that of other drugs affecting replication, highlighting the unique nature of the underlying DNA damage caused by protons. Taken together, our findings provide insight into the replication stress response associated with mutated KRAS, which may ultimately yield novel therapeutic opportunities.

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