| Title: | A genome-wide synthetic dosage lethality screen reveals multiple pathways that require the functioning of ubiquitin-binding proteins Rad23 and Dsk2 |
| Author(s): | Liu C; van Dyk D; Li Y; Andrews B; Rao H; |
| Address: | "Institute of Biotechnology, Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78245, USA. liuc2@uthscsa.edu" |
| ISSN/ISBN: | 1741-7007 (Electronic) 1741-7007 (Linking) |
| Abstract: | "BACKGROUND: Ubiquitin regulates a myriad of important cellular processes through covalent attachment to its substrates. A classic role for ubiquitin is to flag proteins for destruction by the proteasome. Recent studies indicate that ubiquitin-binding proteins (e.g. Rad23, Dsk2, Rpn10) play a pivotal role in transferring ubiquitylated proteins to the proteasome. However, the specific role of these ubiquitin receptors remains poorly defined. A key to unraveling the functions of these ubiquitin receptors is to identify their cellular substrates and biological circuits they are involved in. Although many strategies have been developed for substrate isolation, the identification of physiological targets of proteolytic pathways has proven to be quite challenging. RESULTS: Using a genome-wide functional screen, we have identified 11 yeast genes that cause slower growth upon their overexpression in cells lacking two ubiquitin-binding proteins Rad23 and Dsk2. Our results suggest that proper functioning of Rad23 and Dsk2 is required for efficient pheromone response, transcription, amino acid metabolism, and DNA damage response. Two proteins identified by the screen are shown to be proteolytic substrates of Dsk2, validating the large scale synthetic dosage lethality screen as a new strategy for identifying substrates of a specific degradation pathway. CONCLUSION: In conclusion, as proof-of-concept, we show that a synthetic dosage lethality screen, which is based on the toxicity induced by gene overexpression, offers an effective, complementary method to elucidating biological functions of proteolytic pathways" |
| Keywords: | "Carrier Proteins Cell Cycle Proteins/*genetics/metabolism DNA-Binding Proteins/*genetics/metabolism *Gene Expression Regulation, Fungal *Genes, Lethal Genome Proteasome Endopeptidase Complex/metabolism Saccharomyces cerevisiae/*genetics Saccharomyces cere;" |
| Notes: | "MedlineLiu, Chang van Dyk, Dewald Li, Yue Andrews, Brenda Rao, Hai eng R01 GM078085/GM/NIGMS NIH HHS/ CAPMC/CIHR/Canada GM078085/GM/NIGMS NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't England 2009/11/17 BMC Biol. 2009 Nov 12; 7:75. doi: 10.1186/1741-7007-7-75" |
