replication stress
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2022 ◽  
Vol 162 ◽  
pp. 107-117
Author(s):  
Kaylee M. Keller ◽  
Sonja Krausert ◽  
Apurva Gopisetty ◽  
Dan Luedtke ◽  
Jan Koster ◽  
...  

2022 ◽  
Vol 5 (4) ◽  
pp. e202101153
Author(s):  
Amandine Batté ◽  
Sophie C van der Horst ◽  
Mireille Tittel-Elmer ◽  
Su Ming Sun ◽  
Sushma Sharma ◽  
...  

Eukaryotic cells have evolved a replication stress response that helps to overcome stalled/collapsed replication forks and ensure proper DNA replication. The replication checkpoint protein Mrc1 plays important roles in these processes, although its functional interactions are not fully understood. Here, we show that MRC1 negatively interacts with CHL1, which encodes the helicase protein Chl1, suggesting distinct roles for these factors during the replication stress response. Indeed, whereas Mrc1 is known to facilitate the restart of stalled replication forks, we uncovered that Chl1 controls replication fork rate under replication stress conditions. Chl1 loss leads to increased RNR1 gene expression and dNTP levels at the onset of S phase likely without activating the DNA damage response. This in turn impairs the formation of RPA-coated ssDNA and subsequent checkpoint activation. Thus, the Chl1 helicase affects RPA-dependent checkpoint activation in response to replication fork arrest by ensuring proper intracellular dNTP levels, thereby controlling replication fork progression under replication stress conditions.


2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Léa Marie ◽  
Lorraine S. Symington

AbstractReplication stress and abundant repetitive sequences have emerged as primary conditions underlying genomic instability in eukaryotes. To gain insight into the mechanism of recombination between repeated sequences in the context of replication stress, we used a prokaryotic Tus/Ter barrier designed to induce transient replication fork stalling near inverted repeats in the budding yeast genome. Our study reveals that the replication fork block stimulates a unique recombination pathway dependent on Rad51 strand invasion and Rad52-Rad59 strand annealing activities, Mph1/Rad5 fork remodelers, Mre11/Exo1/Dna2 resection machineries, Rad1-Rad10 nuclease and DNA polymerase δ. Furthermore, we show recombination at stalled replication forks is limited by the Srs2 helicase and Mus81-Mms4/Yen1 nucleases. Physical analysis of the replication-associated recombinants revealed that half are associated with an inversion of sequence between the repeats. Based on our extensive genetic characterization, we propose a model for recombination of closely linked repeats that can robustly generate chromosome rearrangements.


Genes ◽  
2021 ◽  
Vol 12 (12) ◽  
pp. 2010
Author(s):  
Kamila Schirmeisen ◽  
Sarah A. E. Lambert ◽  
Karol Kramarz

DNA lesions have properties that allow them to escape their nuclear compartment to achieve DNA repair in another one. Recent studies uncovered that the replication fork, when its progression is impaired, exhibits increased mobility when changing nuclear positioning and anchors to nuclear pore complexes, where specific types of homologous recombination pathways take place. In yeast models, increasing evidence points out that nuclear positioning is regulated by small ubiquitin-like modifier (SUMO) metabolism, which is pivotal to maintaining genome integrity at sites of replication stress. Here, we review how SUMO-based pathways are instrumental to spatially segregate the subsequent steps of homologous recombination during replication fork restart. In particular, we discussed how routing towards nuclear pore complex anchorage allows distinct homologous recombination pathways to take place at halted replication forks.


2021 ◽  
Vol 12 ◽  
Author(s):  
Wei Wu ◽  
Jing Na He ◽  
Mengjiao Lan ◽  
Pumin Zhang ◽  
Wai Kit Chu

Accurate replication of the entire genome is critical for cell division and propagation. Certain regions in the genome, such as fragile sites (common fragile sites, rare fragile sites, early replicating fragile sites), rDNA and telomeres, are intrinsically difficult to replicate, especially in the presence of replication stress caused by, for example, oncogene activation during tumor development. Therefore, these regions are particularly prone to deletions and chromosome rearrangements during tumorigenesis, rendering chromosome fragility. Although, the mechanism underlying their “difficult-to-replicate” nature and genomic instability is still not fully understood, accumulating evidence suggests transcription might be a major source of endogenous replication stress (RS) leading to chromosome fragility. Here, we provide an updated overview of how transcription affects chromosome fragility. Furthermore, we will use the well characterized common fragile sites (CFSs) as a model to discuss pathways involved in offsetting transcription-induced RS at these loci with a focus on the recently discovered atypical DNA synthesis repair pathway Mitotic DNA Synthesis (MiDAS).


Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6215
Author(s):  
David King ◽  
Harriet E. D. Southgate ◽  
Saskia Roetschke ◽  
Polly Gravells ◽  
Leona Fields ◽  
...  

Despite intensive high-dose multimodal therapy, high-risk neuroblastoma (NB) confers a less than 50% survival rate. This study investigates the role of replication stress in sensitivity to inhibition of Ataxia telangiectasia and Rad3-related (ATR) in pre-clinical models of high-risk NB. Amplification of the oncogene MYCN always imparts high-risk disease and occurs in 25% of all NB. Here, we show that MYCN-induced replication stress directly increases sensitivity to the ATR inhibitors VE-821 and AZD6738. PARP inhibition with Olaparib also results in replication stress and ATR activation, and sensitises NB cells to ATR inhibition independently of MYCN status, with synergistic levels of cell death seen in MYCN expressing ATR- and PARP-inhibited cells. Mechanistically, we demonstrate that ATR inhibition increases the number of persistent stalled and collapsed replication forks, exacerbating replication stress. It also abrogates S and G2 cell cycle checkpoints leading to death during mitosis in cells treated with an ATR inhibitor combined with PARP inhibition. In summary, increased replication stress through high MYCN expression, PARP inhibition or chemotherapeutic agents results in sensitivity to ATR inhibition. Our findings provide a mechanistic rationale for the inclusion of ATR and PARP inhibitors as a potential treatment strategy for high-risk NB.


Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3455
Author(s):  
Janne J.M. van Schie ◽  
Job de Lange

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.


2021 ◽  
Author(s):  
Frances F. Diehl ◽  
Teemu P. Miettinen ◽  
Ryan Elbashir ◽  
Christopher S. Nabel ◽  
Scott R. Manalis ◽  
...  

AbstractNucleotide metabolism supports RNA synthesis and DNA replication to enable cell growth and division. Nucleotide depletion can accordingly inhibit cell growth and proliferation, but how cells sense and respond to changes in the relative levels of individual nucleotides is unclear. Moreover, the nucleotide requirement for biomass production changes over the course of the cell cycle, and how cells coordinate differential nucleotide demands with cell cycle progression is also not well understood. Here we find that excess levels of individual nucleotides can inhibit proliferation by disrupting the relative levels of nucleotide bases needed for DNA replication. The resulting purine and pyrimidine imbalances are not sensed by canonical growth regulatory pathways, causing aberrant biomass production and excessive cell growth despite inhibited proliferation. Instead, cells rely on replication stress signaling to survive during, and recover from, nucleotide imbalance during S phase. In fact, replication stress signaling is activated during unperturbed S phases and promotes nucleotide availability to support DNA replication. Together, these data reveal that imbalanced nucleotide levels are not detected until S phase, rendering cells reliant on replication stress signaling to cope with this metabolic problem, and disrupting the coordination of cell growth and division.


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