An ATM-PPM1D Circuit Controls the Processing and Restart of DNA Replication Forks Article Swipe
Yiting Cao
,
Yingzheng Wang
,
Jumana Badar
,
Matous Palek
,
Khoula Jaber
,
Vítor M. Faça
,
Tengbo Huang
,
Eliz Çelik
,
Libor Macůrek
,
Marcus B. Smolka
·
YOU?
·
· 2025
· Open Access
·
· DOI: https://doi.org/10.1101/2025.05.13.652823
YOU?
·
· 2025
· Open Access
·
· DOI: https://doi.org/10.1101/2025.05.13.652823
In response to DNA replication stress, DNA damage signaling kinases inhibit origin firing and promote the remodeling and stabilization of replication forks, leading to a systemic reduction in DNA synthesis that protects genomic integrity. Little is understood about the regulatory mechanisms of replication stress recovery, including the mechanisms involved in the restart of stalled replication forks. Here, we identify the oncogenic phosphatase PPM1D/WIP1 as a critical regulator of replication fork restart. Upon recovery from replication stress, PPM1D prevents excessive MRE11-and DNA2-dependent nucleolytic degradation of stalled forks. Loss of PPM1D function leads to defects in RAD51 recruitment to chromatin and impairs RAD51-dependent fork restart. Phosphoproteomic analysis reveals that PPM1D regulates a network of ATM substrates, several of which are phosphorylated at an S/T-Q-(E/D)n motif. Strikingly, inhibition of ATM suppresses the deleterious consequences of impaired PPM1D function at replication forks, enabling timely fork restart. The dominant effect of ATM hyper-signaling in suppressing fork restart occurs, in part, through the excessive engagement of 53BP1 and consequent RAD51 antagonization. These findings uncover a new mode of ATM signaling responding to fork stalling and highlights the need for PPM1D to restrain ATM signaling and enable proper fork restart.
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Metadata
- Type
- preprint
- Language
- en
- Landing Page
- https://doi.org/10.1101/2025.05.13.652823
- https://www.biorxiv.org/content/biorxiv/early/2025/05/15/2025.05.13.652823.full.pdf
- OA Status
- green
- Cited By
- 1
- References
- 68
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4410405102
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
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https://openalex.org/W4410405102Canonical identifier for this work in OpenAlex
- DOI
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https://doi.org/10.1101/2025.05.13.652823Digital Object Identifier
- Title
-
An ATM-PPM1D Circuit Controls the Processing and Restart of DNA Replication ForksWork title
- Type
-
preprintOpenAlex work type
- Language
-
enPrimary language
- Publication year
-
2025Year of publication
- Publication date
-
2025-05-15Full publication date if available
- Authors
-
Yiting Cao, Yingzheng Wang, Jumana Badar, Matous Palek, Khoula Jaber, Vítor M. Faça, Tengbo Huang, Eliz Çelik, Libor Macůrek, Marcus B. SmolkaList of authors in order
- Landing page
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https://doi.org/10.1101/2025.05.13.652823Publisher landing page
- PDF URL
-
https://www.biorxiv.org/content/biorxiv/early/2025/05/15/2025.05.13.652823.full.pdfDirect link to full text PDF
- Open access
-
YesWhether a free full text is available
- OA status
-
greenOpen access status per OpenAlex
- OA URL
-
https://www.biorxiv.org/content/biorxiv/early/2025/05/15/2025.05.13.652823.full.pdfDirect OA link when available
- Concepts
-
Replication (statistics), Computer science, DNA replication, Parallel computing, DNA, Biology, Genetics, VirologyTop concepts (fields/topics) attached by OpenAlex
- Cited by
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1Total citation count in OpenAlex
- Citations by year (recent)
-
2025: 1Per-year citation counts (last 5 years)
- References (count)
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68Number of works referenced by this work
- Related works (count)
-
10Other works algorithmically related by OpenAlex
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