Article
- The EMBO Journal (2006) 25, 2529 - 2538
- doi:10.1038/sj.emboj.7601120
Published online: 4 May 2006
Subject Categories:
Distinct functions of the ubiquitin–proteasome pathway influence nucleotide excision repair
Thomas G Gillette1, Shirong Yu2, Zheng Zhou2, Raymond Waters2, Stephen Albert Johnston1 and Simon H Reed2
- The Center for Biomedical Inventions, Medicine and Microbiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Department of Pathology, School of Medicine, Cardiff University, Cardiff, UK
Correspondence to:
Simon H Reed, Department of Pathology, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK. Tel.: +44 2920 745576; Fax: +44 2920 743496; E-mail: reedsh1@cf.ac.uk
Received 21 November 2005; Accepted 6 April 2006
Abstract
The Rad23/Rad4 nucleotide excision repair (NER) protein complex functions at an early stage of the NER reaction, possibly promoting the recognition of damaged DNA. Here we show that Rad4 protein is ubiquitinated and degraded in response to ultraviolet (UV) radiation, and identify a novel cullin-based E3 ubiquitin ligase required for this process. We also show that this novel ubiquitin ligase is required for optimal NER. Our results demonstrate that optimal NER correlates with the ubiquitination of Rad4 following UV radiation, but not its subsequent degradation. Furthermore, we show that the ubiquitin–proteasome pathway (UPP) regulates NER via two distinct mechanisms. The first occurs independently of de novo protein synthesis, and requires Rad23 and a nonproteolytic function of the 19S regulatory complex of the 26S proteasome. The second requires de novo protein synthesis, and relies on the activity of the newly identified E3 ubiquitin ligase. These studies reveal that, following UV radiation, NER is mediated by nonproteolytic activities of the UPP, via the ubiquitin-like domain of Rad23 and UV radiation-induced ubiquitination of Rad4.
Keywords:
- DNA repair,
- NER,
- proteasome,
- ubiquitin,
- yeast
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