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01.11.19 Checkpoint inhibition of origin firing prevents DNA topological stress

last modified Nov 07, 2019 05:58 PM
Morafraile et al. from the Zegerman lab with UK colleagues reveal that the role of limiting the number of DNA replication initiation events is to prevent DNA topological stress, which may be relevant for cancer treatment with both topoisomerase and checkpoint inhibitors.
01.11.19 Checkpoint inhibition of origin firing prevents DNA topological stress

Excerpt from Fig 5A: Checkpoint inhibition of origin firing prevents excess catenation.

Checkpoint inhibition of origin firing prevents DNA topological stress

Morafraile EC, et al. (2019) Genes & Development Nov 1; 33 (21-22). DOI  

 

Abstract from the paper

A universal feature of DNA damage and replication stress in eukaryotes is the activation of a checkpoint-kinase response. In S-phase, the checkpoint inhibits replication initiation, yet the function of this global block to origin firing remains unknown.

To establish the physiological roles of this arm of the checkpoint, we analyzed separation of function mutants in the budding yeast Saccharomyces cerevisiae that allow global origin firing upon replication stress, despite an otherwise normal checkpoint response. Using genetic screens, we show that lack of the checkpoint-block to origin firing results in a dependence on pathways required for the resolution of topological problems. Failure to inhibit replication initiation indeed causes increased DNA catenation, resulting in DNA damage and chromosome loss. We further show that such topological stress is not only a consequence of a failed checkpoint response but also occurs in an unperturbed S-phase when too many origins fire simultaneously.

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Fig 7H from the paper: Model for the role of origin firing control in preventing topological stress.

Together we reveal that the role of limiting the number of replication initiation events is to prevent DNA topological problems, which may be relevant for the treatment of cancer with both topoisomerase and checkpoint inhibitors.

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Read more about research in the Zegerman lab.

Watch Philip Zegerman describe his research in this short YouTube video.

Studying development to understand disease

The Gurdon Institute is funded by Wellcome and Cancer Research UK to study the biology of development, and how normal growth and maintenance go wrong in cancer and other diseases.

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