Hydroxyurea-Stalled Replication Forks Become Progressively Inactivated and Require Two Different RAD51-Mediated Pathways for Restart and Repair

By E. Petermann, M. Orta, N. Issaeva, N. Schultz, Thomas Helleday. Molecules and Cells, 2010

840 citations recorded by the source corpus.

Summary Faithful DNA replication is essential to all life. Hydroxyurea (HU) depletes the cells of dNTPs, which initially results in stalled replication forks that, after prolonged treatment, collapse into DSBs. Here, we report that stalled replication forks are efficiently restarted in a RAD51-dependent process that does not trigger homologous recombination (HR). The XRCC3 protein, which is required for RAD51 foci formation, is also required for replication restart of HU-stalled forks, suggesting that RAD51-mediated strand invasion supports fork restart. In contrast, replication forks collapsed by prolonged replication blocks do not restart, and global replication is rescued by new origin firing. We find that RAD51-dependent HR is triggered for repair of collapsed replication forks, without apparent restart. In conclusion, our data suggest that restart of stalled replication forks and HR repair of collapsed replication forks require two distinct RAD51-mediated pathways.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/82ea6e524e646bfa3a1aceb6819c56845efaf32c

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In Molecular Biology

1. J. Bartek
2. J. Lukas
3. T. Halazonetis
4. Morgane Macheret
5. C. Lukas
6. Thomas Helleday
7. Thomas J. Deerinck
8. A. Fischer

Citations in the corpus

• DNA replication stress as a hallmark of cancer. (2015, background): “Although stalled and collapsed forks are clearly distinct entities, forks that have stalled for more than a few hours tend to collapse (70).”
• Chk1 promotes replication fork progression by controlling replication initiation (2010, background): “Chk1 stabilizes replication forks stalled by replication inhibitors independently of its role in promoting homologous recombination (6, 14, 33).”
• Catastrophic nuclear envelope collapse in cancer cell micronuclei (2013, background): “To assess levels of DNA damage, we looked for foci of g-H2AX, a modified histone found at sites of DNA double-stranded breaks (DSBs) (Ciccia and Elledge, 2010).”
• ATR prohibits replication catastrophe by preventing global exhaustion of RPA. (2013, positive): “However, it is also evident from these studies that replication fork breakage is a delayed response that develops only over many hours (Petermann et al., 2010).”
• The underlying mechanism for the PARP and BRCA synthetic lethality: Clearing up the misunderstandings (2011, background): “A similar function has also been demonstrated for several proteins involved in HR, e.g. RAD51, BLM, XRCC3 and FANCM (Davies et al., 2007; Petermann and Helleday, 2010; Petermann et al., 2010; Schwab et al., 2010).”