期刊
GENOME RESEARCH
卷 22, 期 4, 页码 791-801出版社
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gr.129213.111
关键词
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资金
- Canadian Cancer Society Research Institute
- Canadian Institutes of Health Research [MOP-102629]
- National Institutes of Health [1R01HG005853, R01HG005084, R01HG005853]
- Ontario Research Fund [GL2-01-22]
- The International Human Frontier Science Program Organization
- Hungarian Scientific Research Fund (OTKA) [PD 75261]
- Hungarian Academy of Sciences
- National Science Foundation [DBI 0953881]
A combinatorial genetic perturbation strategy was applied to interrogate the yeast kinome on a genome-wide scale. We assessed the global effects of gene overexpression or gene deletion to map an integrated genetic interaction network of synthetic dosage lethal (SDL) and loss-of-function genetic interactions (GIs) for 92 kinases, producing a meta-network of 8700 GIs enriched for pathways known to be regulated by cognate kinases. Kinases most sensitive to dosage perturbations had constitutive cell cycle or cell polarity functions under standard growth conditions. Condition-specific screens confirmed that the spectrum of kinase dosage interactions can be expanded substantially in activating conditions. An integrated network composed of systematic SDL, negative and positive loss-of-function GIs, and literature-curated kinase-substrate interactions revealed kinase-dependent regulatory motifs predictive of novel gene-specific phenotypes. Our study provides a valuable resource to unravel novel functional relationships and pathways regulated by kinases and outlines a general strategy for deciphering mutant phenotypes from large-scale GI networks.
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