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Updated: Jan 18, 2026
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Direct Restart of a Replication Fork Stalled by a Head-On RNA Polymerase
Published on: April 29, 2010
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An ATM-PPM1D Circuit Controls the Processing and Restart of DNA Replication Forks.
Yiting Cao1, Yingzheng Wang1, Jumana Badar1
1Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY, 14850, USA.
Biorxiv : the Preprint Server for Biology
|June 4, 2025
Summary
The phosphatase PPM1D/WIP1 is crucial for restarting stalled DNA replication forks after stress. It prevents excessive DNA degradation and ensures proper RAD51 recruitment, highlighting a new role in DNA repair.
Area of Science:
- Molecular Biology
- Cell Biology
- Genetics
Background:
- DNA replication stress triggers signaling pathways to protect genomic integrity.
- Mechanisms regulating replication fork restart after stress are not fully understood.
Purpose of the Study:
- To identify key regulators of replication fork restart.
- To elucidate the role of PPM1D/WIP1 in replication stress recovery.
Main Methods:
- Phosphoproteomic analysis to identify ATM substrates.
- Functional assays to assess replication fork restart and DNA repair.
- Genetic manipulation to study PPM1D/WIP1 loss-of-function.
Main Results:
- PPM1D/WIP1 prevents excessive nucleolytic degradation of stalled replication forks.
- Loss of PPM1D/WIP1 impairs RAD51 recruitment and fork restart.
- ATM signaling, via 53BP1, antagonizes RAD51 and suppresses fork restart when PPM1D is deficient.
Conclusions:
- PPM1D/WIP1 is a critical regulator of replication fork restart by restraining ATM signaling.
- ATM hyper-signaling suppresses fork restart through RAD51 antagonization.
- Targeting PPM1D or ATM may offer therapeutic strategies for DNA replication stress-related disorders.
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