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Dhh1 regulates the G1/S-checkpoint following DNA damage or BRCA1 expression in yeast

T J Westmoreland1, J A Olson, W Y Saito

  • 1Duke University Medical Center, Durham, North Carolina 27710, USA.

The Journal of Surgical Research
|August 29, 2003
PubMed
Abstract

Insights

Identifying genes that interact with the tumor suppressor BRCA1 is crucial. We found that deleting CCR4 or DHH1 in yeast suppressed BRCA1 lethality, suggesting a role for their human ortholog, DDX6, in DNA damage response.

Area of Science:

  • Genetics
  • Molecular Biology
  • Cell Cycle Regulation

Background:

  • The tumor suppressor BRCA1 is essential for maintaining genomic stability.
  • Heterologous expression of BRCA1 in Saccharomyces cerevisiae leads to lethality.
  • Identifying BRCA1-interacting genes can reveal new therapeutic targets.

Purpose of the Study:

  • To identify novel BRCA1-interacting genes by screening for yeast deletion mutants that suppress BRCA1-induced lethality.
  • To investigate the role of conserved gene deletions in mitigating BRCA1 toxicity.

Main Methods:

  • A collection of 4746 nonessential yeast gene deletion strains were screened for ionizing radiation (IR) sensitivity.
  • 130 radiation-sensitive strains were further screened for suppression of G1 arrest and lethality caused by GAL::BRCA1 expression.
  • BRCA1 expression levels and degradation rates were assessed in deletion strains.

Main Results:

  • Deletions of CCR4 or DHH1, core components of the CCR4-NOT transcription complex, rescued BRCA1-induced lethality.
  • BRCA1 was rapidly degraded in CCR4 or DHH1 deletion strains, not due to promoter downregulation.
  • Strains with CCR4 or DHH1 deletions exhibited defects in the G1 to S phase checkpoint transition, leading to reduced viability after DNA damage or nitrogen starvation.
  • The human ortholog of DHH1 (DDX6) partially rescued lethality in dhh1Delta strains.

Conclusions:

  • BRCA1 may interact with the conserved DDX6 protein to regulate the G1/S checkpoint.
  • This interaction is crucial for activating the G1/S checkpoint arrest following DNA damage, promoting genomic stability.
  • DDX6, a human ortholog of DHH1, plays a role in DNA damage response and checkpoint control.

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