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Examination of Mitotic and Meiotic Fission Yeast Nuclear Dynamics by Fluorescence Live-cell Microscopy
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Ddb1 controls genome stability and meiosis in fission yeast

Christian Holmberg1, Oliver Fleck, Heidi A Hansen

  • 1Department of Genetics, Institute of Molecular Biology, University of Copenhagen, DK-1353 Copenhagen K, Denmark.

Genes & Development
|April 5, 2005
PubMed

Insights

The DNA-binding protein Ddb1 regulates genome stability by controlling ribonucleotide reductase inhibitor Spd1 degradation. This pathway is crucial for DNA repair, mutation avoidance, and cell differentiation.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cell Biology

Background:

  • UV-damaged DNA-binding protein 1 (Ddb1) interacts with CUL4 ubiquitin ligases and the COP9 signalosome (CSN).
  • These complexes are involved in DNA repair pathways like nucleotide excision repair (NER), but specific ubiquitination targets remain elusive.
  • The role of Ddb1 in regulating genome stability beyond NER is not fully understood.

Purpose of the Study:

  • To investigate the function of Ddb1, CUL4 (Pcu4), and CSN in fission yeast.
  • To identify the ubiquitination targets regulated by the Ddb1-Cul4-CSN complex.
  • To elucidate the role of this complex in DNA damage response, mutation avoidance, and cell differentiation.

Main Methods:

  • Genetic analysis in fission yeast (Schizosaccharomyces pombe).
  • Mutation rate assays and epistasis analysis.
  • Analysis of Spd1 protein levels and degradation.
  • Investigating the role of Ddb1-mediated Spd1 degradation during meiosis.

Main Results:

  • Fission yeast Ddb1, Pcu4, Csn1, and Csn2 are essential for the degradation of the ribonucleotide reductase inhibitor Spd1.
  • Ddb1-deficient cells exhibit a >20-fold increase in spontaneous mutation rate, partly dependent on error-prone translesion DNA polymerases.
  • Spd1 deletion significantly reduces the mutation rate in Ddb1-deficient cells, indicating insufficient RNR activity contributes to ~50% of mutations.
  • Ddb1 functions in a pathway distinct from NER for mutation avoidance and DNA damage tolerance.
  • Ddb1/Csn1/Cullin 4-mediated Spd1 degradation is critical for meiotic differentiation.

Conclusions:

  • The Ddb1-Cul4-CSN complex regulates genome stability and repair through Spd1 degradation and RNR activity control.
  • This pathway plays a significant role in preventing spontaneous mutations and tolerating DNA damage.
  • Ddb1-mediated Spd1 degradation is essential for proper cell differentiation during meiosis.

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