Ddb1 controls genome stability and meiosis in fission yeast

Holmberg, C., Fleck, O., Hansen, H. A., Liu, C., Slaaby, R., Carr, A. M. and Nielsen, O. (2005) Ddb1 controls genome stability and meiosis in fission yeast. Genes and Development, 19 (7). pp. 853-62. ISSN 0890-9369

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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.

Item Type: Article
Additional Information: 0890-9369 Journal Article GDSC138
Keywords: Cell Cycle Proteins/genetics/metabolism Cullin Proteins/metabolism DNA-Binding Proteins/genetics/*metabolism Fungal Proteins/genetics/metabolism Genomic Instability/*physiology Meiosis/*physiology Mutation Research Support, Non-U.S. Gov't Schizosaccharomyces/genetics/*metabolism Schizosaccharomyces pombe Proteins/genetics/*metabolism
Depositing User: Gee Wheatley
Date Deposited: 19 Mar 2007
Last Modified: 30 Nov 2012 16:51
URI: http://srodev.sussex.ac.uk/id/eprint/945
Google Scholar:56 Citations
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