Molecular Cell
Volume 66, Issue 4, 18 May 2017, Pages 533-545.e5
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Article
Ctf4 Prevents Genome Rearrangements by Suppressing DNA Double-Strand Break Formation and Its End Resection at Arrested Replication Forks

https://doi.org/10.1016/j.molcel.2017.04.020Get rights and content
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Highlights

  • The Mre11-Rad50-Xrs2 complex is important for DSB repair at arrested forks

  • Homologous recombination is dispensable for DSB repair at arrested forks

  • Ctf4 is a key regulator in suppressing DSB end resection

  • Suppression of end resection is important to protect DSBs from genome rearrangements

Summary

Arrested replication forks lead to DNA double-strand breaks (DSBs), which are a major source of genome rearrangements. Yet DSB repair in the context of broken forks remains poorly understood. Here we demonstrate that DSBs that are formed at arrested forks in the budding yeast ribosomal RNA gene (rDNA) locus are normally repaired by pathways dependent on the Mre11-Rad50-Xrs2 complex but independent of HR. HR is also dispensable for DSB repair at stalled forks at tRNA genes. In contrast, in cells lacking the core replisome component Ctf4, DSBs are formed more frequently, and these DSBs undergo end resection and HR-mediated repair that is prone to rDNA hyper-amplification; this highlights Ctf4 as a key regulator of DSB end resection at arrested forks. End resection also occurs during physiological rDNA amplification even in the presence of Ctf4. Suppression of end resection is thus important for protecting DSBs at arrested forks from chromosome rearrangements.

Keywords

replication fork
replication fork barrier (RFB)
Ctf4
Rad52
genome rearrangements
homologous recombination
DNA repair
ribosomal RNA gene (rDNA)
DNA double strand break (DSB)
genome instability

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