# DNA replication stress

Source: https://onco.cc/pathways/replication-stress/  
OnCo record `replication-stress` (Pathway). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Cancers copy their DNA too fast and with broken checkpoints, so replication forks stall and collapse. They survive only by leaning on emergency repair kinases such as ATR, CHK1, and WEE1, which is why blocking those kinases can be selectively lethal.

## Summary

Oncogene activation (MYC, cyclin E, RAS) shortens G1, increases origin firing, and causes fork stalling, ssDNA gaps, and transcription-replication conflicts. ATR senses stalled forks and signals via CHK1 to slow origin firing and stabilise forks; WEE1 restrains CDK1/2. TP53-mutant and CCNE1-amplified cells depend on this axis (G1 checkpoint gone, G2/M checkpoint essential), the rationale for ATR (ceralasertib, camonsertib), CHK1, WEE1 (azenosertib), and PKMYT1 (lunresertib) inhibitors, often with PARP inhibitors or chemotherapy. Toxicity is the recurring limitation because normal proliferating tissue also uses these checkpoints.

## Fields

- Kind: Pathway
- Last checked: 2026-09-08
- Tags: mechanism
- Analogy: A photocopier running at triple speed with the paper-jam sensor removed. It keeps working only because a technician (ATR/CHK1/WEE1) constantly clears jams. Remove the technician and it destroys itself.
- Interventions: ATR inhibitors (ceralasertib, camonsertib) alone and with PARP inhibitors or IO; WEE1 (azenosertib) and PKMYT1 (lunresertib) inhibitors in CCNE1-amplified and TP53-mutant tumours; PARP inhibitors trap forks in HRD tumours (see DDR); Gemcitabine and other antimetabolites are classical replication-stress inducers

## Notes

- Leading programmes: Zou (MGH/Duke) and Cimprich (Stanford) on replication-stress signalling; ICR and Dana-Farber early-phase ATR/WEE1 programmes; NKI on CCNE1 dependencies.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Replication_stress
- Saxena & Zou, Hallmarks of DNA replication stress (Molecular Cell 2022): https://doi.org/10.1016/j.molcel.2022.05.004

## Connected records

- cancers: [Colorectal cancer](https://onco.cc/cancers/colorectal/)
- technologies: [PARP inhibitors](https://onco.cc/technologies/parp-inhibitor/), [Synthetic lethality approaches](https://onco.cc/technologies/synthetic-lethality-approaches/)
- targets: [ATR](https://onco.cc/targets/atr/), [CHEK1](https://onco.cc/targets/chek1/), [KRAS](https://onco.cc/targets/kras/), [MYC](https://onco.cc/targets/myc-gene/), [PARP](https://onco.cc/targets/parp/), [TP53](https://onco.cc/targets/tp53/), [WEE1](https://onco.cc/targets/wee1/)
- institutions: [Dana-Farber Brigham Cancer Center](https://onco.cc/institutions/dana-farber/), [Netherlands Cancer Institute (NKI-AvL)](https://onco.cc/institutions/nki/), [The Francis Crick Institute](https://onco.cc/institutions/francis-crick/), [The Institute of Cancer Research](https://onco.cc/institutions/icr-london/)
- pathways: [Base excision repair, PARP & alkylation damage](https://onco.cc/pathways/base-excision-repair-parp/), [Chromosomal instability & aneuploidy](https://onco.cc/pathways/chromosomal-instability/), [DNA damage response & homologous recombination](https://onco.cc/pathways/ddr/), [DNA replication & origin licensing](https://onco.cc/pathways/dna-replication-licensing/), [Double-strand break repair: HR versus end joining](https://onco.cc/pathways/homologous-recombination-repair/), [MYC](https://onco.cc/pathways/myc/), [p53 / RB / cell-cycle checkpoint](https://onco.cc/pathways/p53-cell-cycle/), [RNA splicing](https://onco.cc/pathways/rna-splicing/), [SWI/SNF chromatin remodelling](https://onco.cc/pathways/swi-snf-chromatin/), [Synthetic lethality: paired dependencies](https://onco.cc/pathways/synthetic-lethality-map/), [Telomere maintenance & replicative immortality](https://onco.cc/pathways/telomere-maintenance/), [The cell-cycle engine (cyclins & CDKs)](https://onco.cc/pathways/cell-cycle-engine-cdks/), [The p53 network (guardian of the genome)](https://onco.cc/pathways/p53-mdm2-axis/)
- terms: [Enabling characteristic: genome instability and mutation](https://onco.cc/terms/genome-instability-mutation/), [Synthetic lethality](https://onco.cc/terms/synthetic-lethality/)
- key papers: [Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas](https://onco.cc/key-papers/paper-palles-germline-pole-pold1-proofreading-nat-genet-2013/), [Hallmarks of DNA replication stress](https://onco.cc/key-papers/paper-saxena-mol-cell/), [Somatic POLE proofreading domain mutation, immune response, and prognosis in colorectal cancer](https://onco.cc/key-papers/paper-domingo-somatic-pole-proofreading-colorectal-lancet-gastro-2016/)
- ideas: [Attack extrachromosomal DNA, the engine of oncogene amplification](https://onco.cc/ideas/idea-ecdna-targeting/)

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