Open AccessGlobal Identification of Modular Cullin-RING Ligase Substrates
Author(s) -
Michael J. Emanuele,
Andrew E. H. Elia,
Qikai Xu,
Claudio R. Thoma,
Lior Izhar,
Yumei Leng,
Ailan Guo,
Yi-Ning Chen,
A. John Rush,
Paul WeiChe Hsu,
Hsueh-Chi S. Yen,
Stephen J. Elledge
Publication year - 2011
Publication title -
cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 26.304
H-Index - 776
eISSN - 1097-4172
pISSN - 0092-8674
DOI - 10.1016/j.cell.2011.09.019
Subject(s) - cullin , biology , ubiquitin ligase , ubiquitin , ubiquitin protein ligases , microbiology and biotechnology , proteome , computational biology , f box protein , cell cycle protein , cell division control protein 4 , dna ligase , biochemistry , cell cycle , dna , cell , gene
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.
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