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      Global identification of modular cullin-RING ligase substrates.

      Cell

      Cyclopentanes, pharmacology, Enzyme Inhibitors, Genome, Human, Humans, Proteome, analysis, Pyrimidines, Ubiquitin-Protein Ligases, genetics, metabolism, Ubiquitination

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          Abstract

          Cullin-RING ligases (CRLs) represent the largest E3 ubiquitin ligase family in eukaryotes, and the identification of their substrates is critical to understanding regulation of the proteome. Using genetic and pharmacologic Cullin inactivation coupled with genetic (GPS) and proteomic (QUAINT) assays, we have identified hundreds of proteins whose stabilities or ubiquitylation status are regulated by CRLs. Together, these approaches yielded many known CRL substrates as well as a multitude of previously unknown putative substrates. We demonstrate that one substrate, NUSAP1, is an SCF(Cyclin F) substrate during S and G2 phases of the cell cycle and is also degraded in response to DNA damage. This collection of regulated substrates is highly enriched for nodes in protein interaction networks, representing critical connections between regulatory pathways. This demonstrates the broad role of CRL ubiquitylation in all aspects of cellular biology and provides a set of proteins likely to be key indicators of cellular physiology. Copyright © 2011 Elsevier Inc. All rights reserved.

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          Author and article information

          Journal
          21963094
          3226719
          10.1016/j.cell.2011.09.019

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