scholarly journals Stwl Modifies Chromatin Compaction and Is Required to Maintain DNA Integrity in the Presence of Perturbed DNA Replication

2009 ◽  
Vol 20 (3) ◽  
pp. 983-994 ◽  
Author(s):  
Xia Yi ◽  
Hilda I. de Vries ◽  
Katarzyna Siudeja ◽  
Anil Rana ◽  
Willy Lemstra ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Replication ◽  
Dna Synthesis ◽  
Replication Stress ◽  
Epigenetic Mechanism ◽  
Dna Integrity ◽  
Silent Chromatin ◽  
Chromatin Compaction ◽  
Cycle Arrest ◽  
Dna Replication Stress

Hydroxyurea, a well-known DNA replication inhibitor, induces cell cycle arrest and intact checkpoint functions are required to survive DNA replication stress induced by this genotoxic agent. Perturbed DNA synthesis also results in elevated levels of DNA damage. It is unclear how organisms prevent accumulation of this type of DNA damage that coincides with hampered DNA synthesis. Here, we report the identification of stonewall (stwl) as a novel hydroxyurea-hypersensitive mutant. We demonstrate that Stwl is required to prevent accumulation of DNA damage induced by hydroxyurea; yet, Stwl is not involved in S/M checkpoint regulation. We show that Stwl is a heterochromatin-associated protein with transcription-repressing capacities. In stwl mutants, levels of trimethylated H3K27 and H3K9 (two hallmarks of silent chromatin) are decreased. Our data provide evidence for a Stwl-dependent epigenetic mechanism that is involved in the maintenance of the normal balance between euchromatin and heterochromatin and that is required to prevent accumulation of DNA damage in the presence of DNA replication stress.

scholarly journals Protective Mechanisms Against DNA Replication Stress in the Nervous System

Genes ◽  
2020 ◽  
Vol 11 (7) ◽  
pp. 730
Author(s):  
Clara Forrer Charlier ◽  
Rodrigo A. P. Martins
Keyword(s):  
Dna Damage ◽  
Nervous System ◽  
Dna Replication ◽  
Neurological Diseases ◽  
Replication Stress ◽  
Nervous System Development ◽  
Stress Generation ◽  
Genome Replication ◽  
Cns Development ◽  
Dna Replication Stress

The precise replication of DNA and the successful segregation of chromosomes are essential for the faithful transmission of genetic information during the cell cycle. Alterations in the dynamics of genome replication, also referred to as DNA replication stress, may lead to DNA damage and, consequently, mutations and chromosomal rearrangements. Extensive research has revealed that DNA replication stress drives genome instability during tumorigenesis. Over decades, genetic studies of inherited syndromes have established a connection between the mutations in genes required for proper DNA repair/DNA damage responses and neurological diseases. It is becoming clear that both the prevention and the responses to replication stress are particularly important for nervous system development and function. The accurate regulation of cell proliferation is key for the expansion of progenitor pools during central nervous system (CNS) development, adult neurogenesis, and regeneration. Moreover, DNA replication stress in glial cells regulates CNS tumorigenesis and plays a role in neurodegenerative diseases such as ataxia telangiectasia (A-T). Here, we review how replication stress generation and replication stress response (RSR) contribute to the CNS development, homeostasis, and disease. Both cell-autonomous mechanisms, as well as the evidence of RSR-mediated alterations of the cellular microenvironment in the nervous system, were discussed.

scholarly journals Protein phosphatase 2A (PP2A) promotes anaphase entry after DNA replication stress in budding yeast

2021 ◽  
Author(s):  
Cory Haluska ◽  
Fengzhi Jin ◽  
Yanchang Wang
Keyword(s):  
Cell Cycle ◽  
Dna Replication ◽  
Dna Synthesis ◽  
Protein Phosphatase ◽  
Budding Yeast ◽  
Replication Stress ◽  
S Phase ◽  
Viability Loss ◽  
Phosphatase 2A ◽  
Dna Replication Stress

DNA replication stress activates the S-phase checkpoint that arrests the cell cycle, but it is poorly understood how cells recover from this arrest. Cyclin-dependent kinase (CDK) and Protein Phosphatase 2A (PP2A) are key cell cycle regulators, and Cdc55 is a regulatory subunit of PP2A in budding yeast. We found that yeast cells lacking functional PP2ACdc55 showed slow growth in the presence of hydroxyurea (HU), a DNA synthesis inhibitor, without obvious viability loss. Moreover, PP2A mutants exhibited delayed anaphase entry and sustained levels of anaphase inhibitor Pds1 after HU treatment. A DNA damage checkpoint Chk1 phosphorylates and stabilizes Pds1. We showed that chk1Δ and mutation of the Chk1 phosphorylation sites in Pds1 largely restored efficient anaphase entry in PP2A mutants after HU treatment. In addition, deletion of SWE1 that encodes the inhibitory kinase for CDK or mutation of the Swe1 phosphorylation site in CDK ( cdc28F19) also suppressed the anaphase entry delay in PP2A mutants after HU treatment. Our genetic data suggest that Swe1/CDK acts upstream of Pds1. Surprisingly, cdc55Δ showed significant suppression to the viability loss of S-phase checkpoint mutants during DNA synthesis block. Together, our results uncover a PP2A-Swe1-CDK-Chk1-Pds1 axis that promotes recovery from DNA replication stress.

scholarly journals The deubiquitinase USP36 Regulates DNA replication stress and confers therapeutic resistance through PrimPol stabilization

2020 ◽  
Vol 48 (22) ◽  
pp. 12711-12726
Author(s):  
Yuanliang Yan ◽  
Zhijie Xu ◽  
Jinzhou Huang ◽  
Guijie Guo ◽  
Ming Gao ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Replication ◽  
Stress Response ◽  
Critical Role ◽  
Replication Stress ◽  
Regulatory Mechanisms ◽  
Therapeutic Resistance ◽  
Chemotherapy Response ◽  
Dna Replication Stress ◽  
Damage Tolerant

Abstract PrimPol has been recently identified as a DNA damage tolerant polymerase that plays an important role in replication stress response. However, the regulatory mechanisms of PrimPol are not well defined. In this study, we identify that the deubiquitinase USP36 interferes with degradation of PrimPol to regulate the replication stress response. Mechanistically, USP36 is deubiquitinated following DNA replication stress, which in turn facilitates its upregulation and interaction with PrimPol. USP36 deubiquitinates K29-linked polyubiquitination of PrimPol and increases its protein stability. Depletion of USP36 results in replication stress-related defects and elevates cell sensitivity to DNA-damage agents, such as cisplatin and olaparib. Moreover, USP36 expression positively correlates with the level of PrimPol protein and poor prognosis in patient samples. These findings indicate that the regulation of PrimPol K29-linked ubiquitination by USP36 plays a critical role in DNA replication stress and chemotherapy response.

scholarly journals Dissecting DNA damage response pathways by analysing protein localization and abundance changes during DNA replication stress

2012 ◽  
Vol 14 (9) ◽  
pp. 966-976 ◽  
Author(s):  
Johnny M. Tkach ◽  
Askar Yimit ◽  
Anna Y. Lee ◽  
Michael Riffle ◽  
Michael Costanzo ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Replication ◽  
Dna Damage Response ◽  
Protein Localization ◽  
Replication Stress ◽  
Damage Response ◽  
Dna Replication Stress

scholarly journals The activation loop residue serine 173 of S.pombe Chk1 kinase is critical for the response to DNA replication stress

2017 ◽  
Author(s):  
Naomi Coulton ◽  
Thomas Caspari
Keyword(s):  
Dna Damage ◽  
Dna Replication ◽  
Replication Stress ◽  
Genetic Alterations ◽  
Activation Loop ◽  
Replication Forks ◽  
Dna Polymerase Delta ◽  
Dna Replication Stress ◽  
Summary Statement ◽  
Chk1 Kinase

AbstractWhy the DNA damage checkpoint kinase Chk1 protects the genome of lower and higher eukaryotic cells differentially is still unclear. Mammalian Chk1 regulates replication origins, safeguards DNA replication forks and promotes fork progression. Conversely, yeast Chk1 acts only in G1 and G2. We report here that the mutation of serine 173 (S173A) in the activation loop of fission yeast Chk1 abolishes the G1-M and S-M checkpoints without affecting the G2-M arrest. Although Chk1-S173A is fully phosphorylated at serine 345 by the DNA damage sensor Rad3 (ATR) when DNA replication forks break, cells fail to stop the cell cycle. Mutant cells are uniquely sensitive to the DNA alkylation agent methyl- methanesulfate (MMS). This MMS sensitivity is genetically linked with the lagging strand DNA polymerase delta. Chk1-S173A is also unable to block mitosis when the G1 transcription factor Cdc10 is impaired. Serine 173 is equivalent to lysine 166 in human Chk1, an amino acid important for substrate specificity. We conclude that the removal of serine 173 impairs the phosphorylation of a Chk1 target that is important to protect cells from DNA replication stress.Summary statementMutation of serine-173 in the activation loop of Chk1 kinase may promote cancer as it abolishes the response to genetic alterations that arise while chromosomes are being copied.

scholarly journals DNA repair factor RAD18 and DNA polymerase Polκ confer tolerance of oncogenic DNA replication stress

2017 ◽  
Vol 216 (10) ◽  
pp. 3097-3115 ◽  
Author(s):  
Yang Yang ◽  
Yanzhe Gao ◽  
Liz Mutter-Rottmayer ◽  
Anastasia Zlatanou ◽  
Michael Durando ◽  
...  
Keyword(s):  
Dna Repair ◽  
Dna Replication ◽  
Dna Synthesis ◽  
Dna Polymerase ◽  
Replication Stress ◽  
Neoplastic Cells ◽  
Oncogenic Ras ◽  
Signaling Axis ◽  
Dna Replication Stress ◽  
Dna Repair Protein

The mechanisms by which neoplastic cells tolerate oncogene-induced DNA replication stress are poorly understood. Cyclin-dependent kinase 2 (CDK2) is a major mediator of oncogenic DNA replication stress. In this study, we show that CDK2-inducing stimuli (including Cyclin E overexpression, oncogenic RAS, and WEE1 inhibition) activate the DNA repair protein RAD18. CDK2-induced RAD18 activation required initiation of DNA synthesis and was repressed by p53. RAD18 and its effector, DNA polymerase κ (Polκ), sustained ongoing DNA synthesis in cells harboring elevated CDK2 activity. RAD18-deficient cells aberrantly accumulated single-stranded DNA (ssDNA) after CDK2 activation. In RAD18-depleted cells, the G2/M checkpoint was necessary to prevent mitotic entry with persistent ssDNA. Rad18−/− and Polκ−/− cells were highly sensitive to the WEE1 inhibitor MK-1775 (which simultaneously activates CDK2 and abrogates the G2/M checkpoint). Collectively, our results show that the RAD18–Polκ signaling axis allows tolerance of CDK2-mediated oncogenic stress and may allow neoplastic cells to breach tumorigenic barriers.

scholarly journals Harnessing DNA Replication Stress for Novel Cancer Therapy

Genes ◽  
2020 ◽  
Vol 11 (9) ◽  
pp. 990 ◽  
Author(s):  
Huanbo Zhu ◽  
Umang Swami ◽  
Ranjan Preet ◽  
Jun Zhang
Keyword(s):  
Dna Damage ◽  
Dna Replication ◽  
Cancer Therapy ◽  
Replication Stress ◽  
Replicative Stress ◽  
Combination Treatments ◽  
Damage Repair ◽  
Target Dna ◽  
Dna Replication Stress ◽  
Exogenous Factors

DNA replication is the fundamental process for accurate duplication and transfer of genetic information. Its fidelity is under constant stress from endogenous and exogenous factors which can cause perturbations that lead to DNA damage and defective replication. This can compromise genomic stability and integrity. Genomic instability is considered as one of the hallmarks of cancer. In normal cells, various checkpoints could either activate DNA repair or induce cell death/senescence. Cancer cells on the other hand potentiate DNA replicative stress, due to defective DNA damage repair mechanism and unchecked growth signaling. Though replicative stress can lead to mutagenesis and tumorigenesis, it can be harnessed paradoxically for cancer treatment. Herein, we review the mechanism and rationale to exploit replication stress for cancer therapy. We discuss both established and new approaches targeting DNA replication stress including chemotherapy, radiation, and small molecule inhibitors targeting pathways including ATR, Chk1, PARP, WEE1, MELK, NAE, TLK etc. Finally, we review combination treatments, biomarkers, and we suggest potential novel methods to target DNA replication stress to treat cancer.

scholarly journals EXTH-05. THERAPEUTIC IMPLICATIONS OF TTFIELDS INDUCED DNA DAMAGE AND REPLICATION STRESS IN NOVEL COMBINATIONS FOR CANCER TREATMENT

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi83-vi83
Author(s):  
Narasimha Kumar Karanam ◽  
Lianghao Ding ◽  
Asaithamby Aroumougame ◽  
Michael Story
Keyword(s):  
Dna Damage ◽  
Dna Replication ◽  
Replication Stress ◽  
Chemotherapeutic Agents ◽  
Parp Inhibition ◽  
Loop Formation ◽  
Repair Capacity ◽  
Therapeutic Implications ◽  
Dna Dsbs ◽  
Dna Replication Stress

Abstract TTFields are low-intensity, intermediate frequency, alternating electric fields which are applied to tumor regions using non-invasive arrays. TTFields is approved for the treatment of glioblastoma and mesothelioma with clinical trials ongoing in other cancer types. The mechanism of action for TTFields includes interference with mitosis, reduced DNA double strand break (DSB) repair capacity and the frank induction of DNA DSBs. The mechanism by which TTFields induces DNA DSBs appears to be through the enhancement of DNA replication stress with continued TTFields exposure. The induction of DNA DSBs appears to be as a result of significantly reduced expression of the DNA replication complex genes MCM6 and MCM10 as well as the Fanconi’s Anemia (FA) pathway genes. TTFields treatment increases the number of RPA foci, decreases nascent DNA length and increases R-loop formation which are markers of DNA replication stress. These results suggest that TTFields-induced replication stress is the underlying mechanism and cellular endogenous source of DNA DSB generation via replication fork collapse. The current study suggests that TTFields exposure causes a conditional vulnerability environment that renders cells more susceptible to chemotherapeutic agents that induce DNA damage and/or cause replication stress. Supporting this is the synergistic cell killing seen with TTFields exposure concomitant with cisplatin, TTFields plus concomitant PARP inhibition with or without subsequent radiation, or radiation given at the completion of a TTFields exposure. Finally, TTFields-induced mitotic aberrations and DNA damage/replication stress events, although intimately linked to one another as one can expose the other, are likely initiated independently of one another as suggested by the gene expression analysis of 47 key mitosis regulator genes. These results establish that enhanced replication stress and reduced DNA repair capacity are also major mechanisms of TTFields effects, effects for which there are therapeutic implications.

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.

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