Translesion polymerase kappa-dependent DNA synthesis underlies replication fork recovery
- New York University School of Medicine, United States
Abstract
DNA replication stress is often defined by the slowing or stalling of replication fork progression leading to local or global DNA synthesis inhibition. Failure to resolve replication stress in a timely manner contribute towards cell cycle defects, genome instability and human disease; however, the mechanism for fork recovery remains poorly defined. Here we show that the translesion DNA polymerase (Pol) kappa, a DinB orthologue, has a unique role in both protecting and restarting stalled replication forks under conditions of nucleotide deprivation. Importantly, Pol kappa-mediated DNA synthesis during hydroxyurea (HU)-dependent fork restart is regulated by both the Fanconi Anemia (FA) pathway and PCNA polyubiquitination. Loss of Pol kappa prevents timely rescue of stalled replication forks, leading to replication-associated genomic instability, and a p53-dependent cell cycle defect. Taken together, our results identify a previously unanticipated role for Pol kappa in promoting DNA synthesis and replication stress recovery at sites of stalled forks.
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All data generated or analysed during this study are included in the manuscript and supporting files.
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Funding
National Institutes of Health (ES025166)
- Peter Tonzi
National Institutes of Health (GM108119)
- Yandong Yin
- Chelsea Wei Ting Lee
American Cancer Society (RSG-16-241-01-DMC)
- Yandong Yin
- Chelsea Wei Ting Lee
V Foundation for Cancer Research
- Eli Rothenberg
- Tony T Huang
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2018, Tonzi et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Translesion polymerase kappa-dependent DNA synthesis underlies replication fork recovery
eLife 7:e41426.
https://doi.org/10.7554/eLife.41426
