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Ctf4 Prevents Genome Rearrangements by Suppressing DNA Double-Strand Break Formation and Its End Resection at

Mariko Sasaki1, Takehiko Kobayashi1

  • 1Laboratory of Genome Regeneration, Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.

Molecular Cell
|May 20, 2017
PubMed

Insights

DNA double-strand breaks (DSBs) at arrested replication forks are repaired by Mre11-Rad50-Xrs2 pathways. Suppressing end resection protects against genome rearrangements, highlighting Ctf4

Area of Science:

  • Molecular Biology
  • Genetics
  • DNA Repair

Background:

  • Arrested replication forks generate DNA double-strand breaks (DSBs), a key driver of genome instability.
  • The mechanisms of DSB repair at stalled replication forks are not fully elucidated.

Purpose of the Study:

  • Investigate DSB repair pathways at arrested forks in budding yeast.
  • Determine the role of Ctf4 in regulating DSB processing and genome stability at the ribosomal DNA (rDNA) locus.

Main Methods:

  • Utilized budding yeast (Saccharomyces cerevisiae) as a model system.
  • Employ genetic analyses to study DSB formation and repair in wild-type and mutant strains.
  • Investigated DNA double-strand break repair pathways, including homologous recombination (HR) and Mre11-Rad50-Xrs2 complex.

Main Results:

  • DSBs at arrested forks in the rDNA locus are repaired via Mre11-Rad50-Xrs2-dependent, HR-independent pathways.
  • Cells lacking Ctf4 exhibit increased DSBs that undergo HR-mediated repair, leading to rDNA hyper-amplification.
  • End resection occurs during physiological rDNA amplification and is suppressed to prevent rearrangements.

Conclusions:

  • Ctf4 is a critical regulator of DSB end resection at arrested forks.
  • Suppression of end resection is essential for preventing chromosome rearrangements at DSBs associated with arrested forks.
Keywords:
Ctf4DNA double strand break (DSB)DNA repairRad52genome instabilitygenome rearrangementshomologous recombinationreplication forkreplication fork barrier (RFB)ribosomal RNA gene (rDNA)

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