Ddb1 controls genome stability and meiosis in fission yeast

Holmberg, Christian, Fleck, Oliver, Hansen, Heidi A, Liu, Cong, Slaaby, Rita, Carr, Antony M and Nielsen, Olaf (2005) Ddb1 controls genome stability and meiosis in fission yeast. Genes and Development, 19 (7). pp. 853-862. 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 ~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
Schools and Departments: School of Life Sciences > Sussex Centre for Genome Damage and Stability
Depositing User: Cong Liu
Date Deposited: 06 Feb 2012 18:42
Last Modified: 30 Nov 2012 17:00
URI: http://srodev.sussex.ac.uk/id/eprint/17867
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