Research Articles:
Cell Stress, Vol. 9, No. 1, pp. 201 - 215; doi: 10.15698/cst2025.10.312
Quantifying replication stress in cancer without proliferation confounding
1 Institute for Computer Science, University of Koblenz, Koblenz, Rhineland-Palatinate, Germany.
Keywords: replication stress, gene expression signatures, cell proliferation, chromosomal instability, non-homologous end-joining, mismatch repair
Received originally: 27/05/2025 Received in revised form: 08/08/2025
Accepted: 26/08/2025
Published: 28/10/2025
Correspondence:
Prof. Dr. Maik Kschischo, Institute for Computer Science, University of Koblenz, Koblenz, Rhineland-Palatinate, Germany kschischo@uni-koblenz.de
Conflict of interest statement: The authors declare no competing interests.
Please cite this article as: Philipp Jungk and Maik Kschischo (2025). Quantifying replication stress in cancer without proliferation confounding. Cell Stress 9: 201-215. doi: 10.15698/cst2025.10.312
Abstract
Replication stress (RS) is a major driver of genomic instability and cancer development through impaired DNA replication that can lead to chromo-somal instability (CIN). Although RS is mechanistically linked to CIN, its relationship with cellular proliferation is complex. Depending on the con-text, RS can either promote or suppress cell growth. Existing RS gene expression signatures overlook this complexity, relying on the overex-pression of oncogenes such as MYC, which introduces a proliferation bias. To disentangle genuine RS from confounding cell cycle and prolifer-ation transcriptional profiles, we developed and validated a novel gene expression signature that accurately predicts RS independently of onco-gene activity. This tumorigenic RS signature (TRSS) captures RS-related transcriptional changes across diverse cellular contexts, enabling a more robust and proliferation-independent measure of RS in both experimental and clinical samples. Applying our signature to patient data, we discov-ered a link between RS and the non-homologous end-joining (NHEJ) DNA repair pathway. Specifically, we observed that MSH2 and MSH6 – core components of mismatch repair – are associated with elevated RS and may indicate a shift toward NHEJ-mediated repair under stress condi-tions. Our study provides a refined approach to quantify RS and sheds light on its broader impact on DNA repair network dynamics.
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ACKNOWLEDGMENTS
The authors thank Holger Bastians and Atmika Paul for providing additional RNA sequencing data for SMAD4 knockout-induced replication stress. This work was funded by the German Research Foundation (FOR2800; Deutsche Forschungsgemeinschaft).
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Quantifying replication stress in cancer without proliferation confounding by Jungk and Kschischo is licensed under a Creative Commons Attribution 4.0 International License.
