Suppression of genomic instability by SLX5 and SLX8 in Saccharomyces cerevisiae

DNA Repair (Amst). 2006 Mar 7;5(3):336-46. doi: 10.1016/j.dnarep.2005.10.010. Epub 2005 Dec 1.

Abstract

Replication forks can stall spontaneously at specific sites in the genome, and upon encountering DNA lesions resulting from chemical or radiation damage. In Saccharomyces cerevisiae proteins implicated in processing of stalled replication forks include those encoded by the SGS1, TOP3, MUS81, MMS4, SLX1, SLX4, SLX5/HEX3, and SLX8 genes. We tested the roles of these genes in suppressing gross chromosomal rearrangements (GCRs), which include translocations, large interstitial deletions, and loss of a chromosome arm with de novo telomere addition. We found that mus81, mms4, slx1, slx4, slx5, and slx8 mutants all have elevated levels of spontaneous GCRs, and that SLX5 and SLX8 are particularly critical suppressors of GCRs during normal cell cycle progression. In addition to increased GCRs, deletion of SLX5 or SLX8 resulted in increased relocalization of the DNA damage checkpoint protein Ddc2 and activation of the checkpoint kinase Rad53, indicating the accumulation of spontaneous DNA damage. Surprisingly, mutants in slx5 or slx8 were not sensitive to transient replication fork stalling induced by hydroxyurea, nor were they sensitive to replication dependent double-strand breaks induced by camptothecin. This suggested that Slx8 and Slx8 played limited roles in stabilizing, restarting, or resolving transiently stalled replication forks, but were critical for preventing the accumulation of DNA damage during normal cell cycle progression.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle Proteins / metabolism
  • Checkpoint Kinase 2
  • Chromosome Aberrations
  • DNA Damage / radiation effects
  • DNA, Fungal / genetics
  • DNA, Fungal / radiation effects
  • Genome, Fungal*
  • Genomic Instability*
  • Mutation
  • Protein-Serine-Threonine Kinases / metabolism
  • Recombination, Genetic
  • Saccharomyces cerevisiae / enzymology
  • Saccharomyces cerevisiae / genetics*
  • Saccharomyces cerevisiae Proteins / metabolism
  • Saccharomyces cerevisiae Proteins / physiology*
  • Suppression, Genetic*
  • Ultraviolet Rays

Substances

  • Cell Cycle Proteins
  • DNA, Fungal
  • Saccharomyces cerevisiae Proteins
  • Checkpoint Kinase 2
  • Protein-Serine-Threonine Kinases
  • RAD53 protein, S cerevisiae