title: Ddb1 controls genome stability and meiosis in fission yeast.
abstract: The human UV-damaged DNA-binding protein Ddb1 associates with cullin 4 ubiquitin ligases implicated in nucleotide excision repair (NER). These complexes also contain the signalosome (CSN), but NER-relevant ubiquitination targets have not yet been identified. We report that fission yeast Ddb1, Cullin 4 (Pcu4), and CSN subunits Csn1 and Csn2 are required for degradation of the ribonucleotide reductase (RNR) inhibitor protein Spd1. Ddb1-deficient cells have >20-fold increased spontaneous mutation rate. This is partly dependent on the error-prone translesion DNA polymerases. Spd1 deletion substantially reduced the mutation rate, suggesting that insufficient RNR activity accounts for approximately 50% of observed mutations. Epistasis analysis indicated that Ddb1 contributed to mutation avoidance and tolerance to DNA damage in a pathway distinct from NER. Finally, we show that Ddb1/Csn1/Cullin 4-mediated Spd1 degradation becomes essential when cells differentiate into meiosis. These results suggest that Ddb1, along with Cullin 4 and the signalosome, constitute a major pathway controlling genome stability, repair, and differentiation via RNR regulation.
authors.affiliation: Department of Genetics, Institute of Molecular Biology, University of Copenhagen, DK-1353 Copenhagen K, Denmark.
authors.forename: Christian
authors.initials: C
authors.lastname: Holmberg
authors.forename: Oliver
authors.initials: O
authors.lastname: Fleck
authors.forename: Heidi A
authors.initials: HA
authors.lastname: Hansen
authors.forename: Cong
authors.initials: C
authors.lastname: Liu
authors.forename: Rita
authors.initials: R
authors.lastname: Slaaby
authors.forename: Antony M
authors.initials: AM
authors.lastname: Carr
authors.forename: Olaf
authors.initials: O
authors.lastname: Nielsen
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D044842:Cullin Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism; D042822:Genomic Instability / Q000502:physiology*; D008540:Meiosis / Q000502:physiology*; D051718:MutS Homolog 2 Protein; D009154:Mutation; D012568:Schizosaccharomyces / Q000235:genetics / Q000378:metabolism*; D029702:Schizosaccharomyces pombe Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D044842:Cullin Proteins; C091435:DDB1 protein, human; D004268:DNA-Binding Proteins; C500125:Ddb1 protein, S pombe; D005656:Fungal Proteins; C079010:SWI10 protein, S pombe; D029702:Schizosaccharomyces pombe Proteins; C102445:Spd1 protein, S pombe; D051718:MutS Homolog 2 Protein