scholarly journals Mrc1 is a replication fork component whose phosphorylation in response to DNA replication stress activates Rad53

2003 ◽  
Vol 17 (14) ◽  
pp. 1755-1767 ◽  
Author(s):  
A. J. Osborn
Keyword(s):  
Dna Replication ◽  
Replication Fork ◽  
Replication Stress ◽  
Dna Replication Stress

scholarly journals DNA replication stress induced by trifluridine determines tumor cell fate according to p53 status

2019 ◽  
Author(s):  
Yuki Kataoka ◽  
Makoto Iimori ◽  
Ryo Fujisawa ◽  
Tomomi Morikawa-Ichinose ◽  
Shinichiro Niimi ◽  
...  
Keyword(s):  
Dna Replication ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Cell Fate ◽  
Replication Fork ◽  
Apoptotic Cell ◽  
Replication Stress ◽  
Dna Replication Stress ◽  
P53 Status ◽  
Fork Stalling

ABSTRACTDNA replication stress is a predominant cause of genome instability, a driver of tumorigenesis and malignant progression. Nucleoside analog-type chemotherapeutic drugs introduce DNA damage and exacerbate DNA replication stress in tumor cells. However, the mechanisms underlying tumor cytotoxicity triggered by the drugs are not fully understood. Here, we show that the fluorinated thymidine analog trifluridine (FTD), an active component of the chemotherapeutic drug trifluridine/tipiracil, delayed DNA synthesis by human replicative DNA polymerases. FTD acted as an inefficient deoxyribonucleotide triphosphate source (FTD triphosphate) and as an obstacle base (trifluorothymine) in the template DNA strand. At the cellular level, FTD decreased thymidine triphosphate in the dNTP pool and induced FTD triphosphate accumulation, resulting in replication fork stalling caused by FTD incorporation into DNA. DNA lesions involving single-stranded DNA were generated as a result of replication fork stalling, and the p53-p21 pathway was activated. Although FTD suppressed tumor cell growth irrespective of p53 status, tumor cell fate diverged at the G2/M phase transition according to p53 status; tumor cells with wild-type p53 underwent cellular senescence via mitosis skip, whereas tumor cells that lost wild-type p53 underwent apoptotic cell death via aberrant late mitosis with severely impaired separation of sister chromatids. These results suggest that DNA replication stress induced by a nucleoside analog-type chemotherapeutic drug triggers tumor cytotoxicity by determining tumor cell fate according to p53 status.SignificanceThis study identified a unique type of DNA replication stress induced by trifluridine, which directs tumor cell fate either toward cellular senescence or apoptotic cell death according to p53 status.

scholarly journals MRE11-RAD50-NBS1 activates Fanconi Anemia R-loop suppression at transcription-replication conflicts

2018 ◽  
Author(s):  
Emily Yun-chia Chang ◽  
James P. Wells ◽  
Shu-Huei Tsai ◽  
Yan Coulombe ◽  
Yujia A. Chan ◽  
...  
Keyword(s):  
Dna Replication ◽  
Fanconi Anemia ◽  
Replication Fork ◽  
Genome Instability ◽  
Human Cancer ◽  
Replication Stress ◽  
Maintenance Factors ◽  
Genome Wide ◽  
A Genome ◽  
Dna Replication Stress

SUMMARYEctopic R-loop accumulation causes DNA replication stress and genome instability. To avoid these outcomes, cells possess a range of anti-R-loop mechanisms, including RNaseH that degrades the RNA moiety in R-loops. To comprehensively identify anti-R-loop mechanisms, we performed a genome-wide trigenic interaction screen in yeast lacking RNH1 and RNH201. We identified >100 genes critical for fitness in the absence of RNaseH, which were enriched for DNA replication fork maintenance factors such as RAD50. We show in yeast and human cells that R-loops accumulate during RAD50 depletion. In human cancer cell models, we find that RAD50 and its partners in the MRE11-RAD50-NBS1 complex regulate R-loop-associated DNA damage and replication stress. We show that a non-nucleolytic function of MRE11 is important for R-loop suppression via activation of PCNA-ubiquitination by RAD18 and recruiting anti-R-loop helicases in the Fanconi Anemia pathway. This work establishes a novel role for MRE11-RAD50-NBS1 in directing tolerance mechanisms of transcription-replication conflicts.

scholarly journals Chk1 and p21 Cooperate to Prevent Apoptosis during DNA Replication Fork Stress

2006 ◽  
Vol 17 (1) ◽  
pp. 402-412 ◽  
Author(s):  
Rene Rodriguez ◽  
Mark Meuth
Keyword(s):  
Dna Replication ◽  
Cellular Response ◽  
Replication Fork ◽  
Replication Stress ◽  
S Phase ◽  
Cell Cycle Checkpoints ◽  
Primary Role ◽  
Excess Thymidine ◽  
Dna Replication Stress ◽  
Interfering Rna

Cells respond to DNA replication stress by triggering cell cycle checkpoints, repair, or death. To understand the role of the DNA damage response pathways in determining whether cells survive replication stress or become committed to death, we examined the effect of loss of these pathways on cellular response to agents that slow or arrest DNA synthesis. We show that replication inhibitors such as excess thymidine, hydroxyurea, and camptothecin are normally poor inducers of apoptosis. However, these agents become potent inducers of death in S-phase cells upon small interfering RNA-mediated depletion of the checkpoint kinase Chk1. This death response is independent of p53 and Chk2. p21-deficient cells, on the other hand, produce a more robust apoptotic response upon Chk1 depletion. p21 is normally induced only late after thymidine treatment. In Chk1-depleted cells p21 induction occurs earlier and does not require p53. Thus, Chk1 plays a primary role in the protection of cells from death induced by replication fork stress, whereas p21 mediates through its role in regulating entry into S phase. These findings are of potential importance to cancer therapy because we demonstrate that the efficacy of clinically relevant agents can be enhanced by manipulation of these signaling pathways.

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 Checkpoint proteins control morphogenetic events during DNA replication stress in Saccharomyces cerevisiae

2006 ◽  
Vol 175 (5) ◽  
pp. 729-741 ◽  
Author(s):  
Jorrit M. Enserink ◽  
Marcus B. Smolka ◽  
Huilin Zhou ◽  
Richard D. Kolodner
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Dna Replication ◽  
Cell Morphology ◽  
Replication Fork ◽  
Replication Stress ◽  
Replication Checkpoint ◽  
Checkpoint Proteins ◽  
Checkpoint Kinases ◽  
Dna Replication Checkpoint ◽  
Dna Replication Stress

In response to DNA replication stress in Saccharomyces cerevisiae, the DNA replication checkpoint maintains replication fork stability, prevents precocious chromosome segregation, and causes cells to arrest as large-budded cells. The checkpoint kinases Mec1 and Rad53 act in this checkpoint. Treatment of mec1 or rad53Δ mutants with replication inhibitors results in replication fork collapse and inappropriate partitioning of partially replicated chromosomes, leading to cell death. We describe a previously unappreciated function of various replication stress checkpoint proteins, including Rad53, in the control of cell morphology. Checkpoint mutants have aberrant cell morphology and cell walls, and show defective bud site selection. Rad53 shows genetic interactions with septin ring pathway components, and, along with other checkpoint proteins, controls the timely degradation of Swe1 during replication stress, thereby facilitating proper bud growth. Thus, checkpoint proteins play an important role in coordinating morphogenetic events with DNA replication during replication stress.

scholarly journals DNA replication stress triggers rapid DNA replication fork breakage by Artemis and XPF

PLoS Genetics ◽  
2018 ◽  
Vol 14 (7) ◽  
pp. e1007541 ◽  
Author(s):  
Rémy Bétous ◽  
Théo Goullet de Rugy ◽  
Alessandra Luiza Pelegrini ◽  
Sophie Queille ◽  
Jean-Pierre de Villartay ◽  
...  
Keyword(s):  
Dna Replication ◽  
Replication Fork ◽  
Replication Stress ◽  
Dna Replication Stress

scholarly journals SAMHD1 promotes oncogene-induced replication stress

2020 ◽  
Author(s):  
Si Min Zhang ◽  
Jose M Calderón-Montaño ◽  
Sean G Rudd
Keyword(s):  
Cell Proliferation ◽  
Dna Damage ◽  
Overall Survival ◽  
Dna Replication ◽  
Replication Fork ◽  
Potential Role ◽  
Human Fibroblasts ◽  
Replication Stress ◽  
Oncogenic Ras ◽  
Dna Replication Stress

AbstractOncogenes induce DNA replication stress in cancer cells. Although this was established more than a decade ago, we are still unravelling the molecular underpinnings of this phenomenon, which will be critical if we are to exploit this knowledge to improve cancer treatment. A key mediator of oncogene-induced replication stress is the availability of DNA precursors, which will limit ongoing DNA synthesis by cellular replicases. In this study, we identify a potential role for nucleotide catabolism in promoting replication stress induced by oncogenes. Specifically, we establish that the dNTPase SAMHD1 slows DNA replication fork speeds in human fibroblasts harbouring an oncogenic RAS allele, elevating levels of endogenous DNA damage, and ultimately limiting cell proliferation. We then show that oncogenic RAS-driven tumours express reduced SAMHD1 levels, suggesting they have overcome this tumour suppressor barrier, and that this correlates with worse overall survival for these patients.Abstract Figure

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