ArticleThe Journal of biological chemistry2018
Uncoupling fork speed and origin activity to identify the primary cause of replicative stress phenotypes.
Article in The Journal of biological chemistry, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 65 citations in OpenAlex.
- Heterogeneous CRISPR/Cas9 Editing ofInternational journal of molecular sciences · 2026Article
- Article
- RNAs anchoring replication complex control initiation and firing of DNA replication.Nature communications · 2026Article
- Adaptive Replication Fork Acceleration by CDK1-Cyclin B1 Sustains Genome Duplication despite Impaired Origin Firing.bioRxiv : the preprint server for biology · 2026Article
- Multiplexed TrAEL-seq captures DNA replication dynamics in mammalian cells.Nucleic acids research · 2026Article
- Article
- CRL4Nature communications · 2025Article
- Oncogenic YAP sensitizes cells to CHK1 inhibition via CDK4/6 driven G1 acceleration.EMBO reports · 2025Article
- The DNA replication checkpoint prevents PCNA/RFC depletion to protect forks from HLTF-induced collapse in human cells.Molecular cell · 2025Article
- DNA polymerase α/primase extraction from chromatin by VCP/p97 restricts ATR activation during unperturbed DNA replication.Nature communications · 2025Article
- Embryonic stem cells maintain high origin activity and slow forks to coordinate replication with cell cycle progression.EMBO reports · 2024Article
- Review
- DNA polymerase α-primase facilitates PARP inhibitor-induced fork acceleration and protects BRCA1-deficient cells against ssDNA gaps.Nature communications · 2024Article
- PHF2 regulates genome topology and DNA replication in neural stem cells via cohesin.Nucleic acids research · 2024Article
- Paradoxical Activation of Oncogenic Signaling as a Cancer Treatment Strategy.Cancer discovery · 2024Article
- Dormant origin firing promotes head-on transcription-replication conflicts at transcription termination sites in response to BRCA2 deficiency.Nature communications · 2024Article
- RAD51 restricts DNA over-replication from re-activated origins.The EMBO journal · 2024Article
- SIN3A histone deacetylase action counteracts MUS81 to promote stalled fork stability.Cell reports · 2024Article
- Quantity and quality of minichromosome maintenance protein complexes couple replication licensing to genome integrity.Communications biology · 2024Review
- Cancer-associated FBXW7 loss is synthetic lethal with pharmacological targeting of CDC7.Molecular oncology · 2024Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
In growing cells, DNA replication precedes mitotic cell division to transmit genetic information to the next generation. The slowing or stalling of DNA replication forks at natural or exogenous obstacles causes "replicative stress" that promotes genomic instability and affects cellular fitness. Replicative stress phenotypes can be characterized at the single-molecule level with DNA combing or stretched DNA fibers, but interpreting the results obtained with these approaches is complicated by the fact that the speed of replication forks is connected to the frequency of origin activation. Primary alterations in fork speed trigger secondary responses in origins, and, conversely, primary alterations in the number of active origins induce compensatory changes in fork speed. Here, by employing interventions that temporally restrict either fork speed or origin firing while still allowing interrogation of the other variable, we report a set of experimental conditions to separate cause and effect in any manipulation that affects DNA replication dynamics. Using HeLa cells and chemical inhibition of origin activity (through a CDC7 kinase inhibitor) and of DNA synthesis (via the DNA polymerase inhibitor aphidicolin), we found that primary effects of replicative stress on velocity of replisomes (fork rate) can be readily distinguished from primary effects on origin firing. Identifying the primary cause of replicative stress in each case as demonstrated here may facilitate the design of methods to counteract replication stress in primary cells or to enhance it in cancer cells to increase their susceptibility to therapies that target DNA repair.
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