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RAD51 restricts DNA over-replication from re-activated origins
Sergio Muñoz1, Elena Blanco-Romero1, Daniel González-Acosta1,2
1DNA Replication Group, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro 3, 28029, Madrid, Spain.
The EMBO Journal
|February 15, 2024
Summary
Genome stability is maintained by RAD51, which limits DNA re-replication after origin reactivation. FBH1 enhances re-replication, while RAD51 prevents it by slowing replication forks and promoting DNA repair.
Area of Science:
- Cell Biology
- Molecular Biology
- Genetics
Background:
- Eukaryotic cells possess mechanisms to prevent DNA over-replication and maintain genomic stability.
- These mechanisms typically restrict origin licensing proteins to prevent re-activation of already-used origins.
- The study investigates additional controls that restrict DNA re-replication following origin re-activation.
Purpose of the Study:
- To identify factors that limit or enhance DNA re-replication upon origin re-activation.
- To understand the molecular mechanisms underlying the control of re-replication in eukaryotic cells.
Main Methods:
- Genetic screening in cells engineered to re-activate origins.
- Analysis of the roles of RAD51 and FBH1 in controlling re-replication.
- Investigation of replication fork dynamics and DNA repair pathways.
Main Results:
- RAD51 limits re-replication, while FBH1 (a RAD51 antagonist) enhances it.
- Chromatin-bound RAD51 slows re-replication forks, inducing fork reversal.
- PRIMPOL-mediated re-initiation creates ssDNA gaps, facilitating MRE11 exonuclease activity to eliminate re-duplicated DNA.
Conclusions:
- A safeguard mechanism involving RAD51 protects genome stability against origin re-activation.
- In RAD51 absence, re-replication forks progress extensively, compromising genomic integrity.
- This study reveals novel controls over DNA replication and genome stability.
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