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Adaptive Replication Fork Acceleration by CDK1-Cyclin B1 Sustains Genome Duplication despite Impaired Origin Firing
Md Shahadat Hossain1,2, Courtney G Sansam2, Krishanu Dhar1,2
1Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104.
Biorxiv : the Preprint Server for Biology
|June 4, 2026
Summary
Cells adapt to loss of the MTBP replication factor by speeding up DNA replication forks. This CDK1-RIF1 pathway compensates for reduced origin firing, maintaining genome duplication. This plasticity is crucial for stressed cells.
Area of Science:
- Cell Biology
- Molecular Biology
- Genetics
Background:
- DNA replication requires timely origin firing and fork progression.
- MTBP is essential for initiating DNA replication.
- The mechanisms cells use to adapt to compromised replication initiation are not fully understood.
Purpose of the Study:
- To investigate the adaptive mechanisms cells employ when origin firing is reduced.
- To elucidate the role of CDK1 and RIF1 in DNA replication plasticity.
- To understand how replication fork speed compensates for impaired origin firing.
Main Methods:
- Utilized auxin-inducible degron system for MTBP depletion.
- Inhibited CDK1-Cyclin B1 and ATR pathways.
- Performed RIF1 knockdown experiments.
- Assessed DNA replication rates and fork progression.
Main Results:
- Acute MTBP depletion blocked DNA replication, but rates recovered over time.
- Recovery was dependent on CDK1-Cyclin B1 activity and involved accelerated fork progression, not restored origin firing.
- ATR inhibition and RIF1 knockdown mimicked this recovery by increasing fork speed.
- RIF1 knockdown accelerated replication independently of DDK activity.
Conclusions:
- Cells possess a CDK1-RIF1-dependent mechanism to accelerate replication fork speed.
- This adaptive response compensates for reduced origin firing, sustaining DNA synthesis.
- Replication plasticity, balancing origin firing and fork speed, is vital for genome stability, especially under stress.
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