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CDT1 acts with the replisome to remodel replication forks
Caitlin Hathaway1, Thanh Le1, Yuki Hatoyama2,3
1Department of Molecular Biosciences, University of South Florida, Tampa, FL, USA.
Science Advances
|August 12, 2026
Summary
Cellular CDT1 protein facilitates replication fork remodeling via fork reversal during replication stress. This process, crucial for DNA synthesis, is regulated by interactions with the CMG helicase and PCNA unloading.
Area of Science:
- Molecular Biology
- Cell Biology
- Genetics
Background:
- Replication forks face challenges during DNA duplication, leading to replication stress.
- Fork reversal is a critical pathway for mitigating these challenges and ensuring DNA synthesis.
Purpose of the Study:
- To investigate the role of origin licensing factor CDT1 in replication fork remodeling through fork reversal.
- To elucidate the regulatory mechanisms controlling CDT1's function during replication stress.
Main Methods:
- Characterization of replication dynamics during early origin reactivation.
- Analysis of CDT1 interaction with the CMG helicase.
- Investigation of PCNA (proliferating cell nuclear antigen) and ATAD5 roles in CDT1 regulation.
Main Results:
- CDT1 blocks fork progression without causing DNA breaks during origin reactivation.
- CDT1 mediates replication fork reversal under re-replication and genotoxic stress conditions.
- CDT1's fork remodeling function depends on its interaction with the CMG helicase.
Conclusions:
- CDT1 plays a crucial role in replication fork remodeling via fork reversal in response to replication stress.
- A regulatory mechanism involving ATAD5-mediated PCNA unloading releases CDT1 to promote fork remodeling.
- Contrary to previous notions, CDT1's function is not solely inactivated during S phase but is actively regulated during stress.
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