title: Global identification of modular cullin-RING ligase substrates.
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.
authors.affiliation: Division of Genetics, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Emanuele
authors.forename: Andrew E H
authors.initials: AE
authors.lastname: Elia
authors.forename: Qikai
authors.initials: Q
authors.lastname: Xu
authors.forename: Claudio R
authors.initials: CR
authors.lastname: Thoma
authors.forename: Lior
authors.initials: L
authors.lastname: Izhar
authors.forename: Yumei
authors.initials: Y
authors.lastname: Leng
authors.forename: Ailan
authors.initials: A
authors.lastname: Guo
authors.forename: Yi-Ning
authors.initials: YN
authors.lastname: Chen
authors.forename: John
authors.initials: J
authors.lastname: Rush
authors.forename: Paul Wei-Che
authors.initials: PW
authors.lastname: Hsu
authors.forename: Hsueh-Chi Sherry
authors.initials: HC
authors.lastname: Yen
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Elledge
mesh_terms: D003517:Cyclopentanes / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015894:Genome, Human; D006801:Humans; D020543:Proteome / Q000032:analysis*; D011743:Pyrimidines / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D003517:Cyclopentanes; D004791:Enzyme Inhibitors; D020543:Proteome; D011743:Pyrimidines; D044767:Ubiquitin-Protein Ligases; C539933:pevonedistat