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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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.

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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