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DNA damage responses that enhance resilience to replication stress

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Abstract

During duplication of the genome, eukaryotic cells may experience various exogenous and endogenous replication stresses that impede progression of DNA replication along chromosomes. Chemical alterations in template DNA, imbalances of deoxynucleotide pools, repetitive sequences, tight DNA–protein complexes, and conflict with transcription can negatively affect the replication machineries. If not properly resolved, stalled replication forks can cause chromosome breaks leading to genomic instability and tumor development. Replication stress is enhanced in cancer cells due, for example, to the loss of DNA repair genes or replication–transcription conflict caused by activation of oncogenic pathways. To prevent these serious consequences, cells are equipped with diverse mechanisms that enhance the resilience of replication machineries to replication stresses. This review describes DNA damage responses activated at stressed replication forks and summarizes current knowledge on the pathways that promote faithful chromosome replication and protect chromosome integrity, including ATR-dependent replication checkpoint signaling, DNA cross-link repair, and SLX4-mediated responses to tight DNA–protein complexes that act as barriers. This review also focuses on the relevance of replication stress responses to selective cancer chemotherapies.

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Acknowledgements

We apologize to our colleagues whose work we were unable to cite due to space limitations. We thank members of the Fujita lab for helpful discussions and comments on the manuscript.

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  1. Kazumasa Yoshida

    Present address: Department of Cell Biology, Faculty of Medicine, Fukuoka University, Fukuoka, 814-0180, Japan

  2. Kazumasa Yoshida

    Present address: Central Research Institute for Advanced Molecular Medicine, Fukuoka University, Fukuoka, 814-0180, Japan

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  1. Department of Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan

    Kazumasa Yoshida & Masatoshi Fujita

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Yoshida, K., Fujita, M. DNA damage responses that enhance resilience to replication stress. Cell. Mol. Life Sci. 78, 6763–6773 (2021). https://doi.org/10.1007/s00018-021-03926-3

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