title: APC/C-mediated multiple monoubiquitylation provides an alternative degradation signal for cyclin B1.
abstract: The anaphase-promoting complex or cyclosome (APC/C) initiates mitotic exit by ubiquitylating cell-cycle regulators such as cyclin B1 and securin. Lys 48-linked ubiquitin chains represent the canonical signal targeting proteins for degradation by the proteasome, but they are not required for the degradation of cyclin B1. Lys 11-linked ubiquitin chains have been implicated in degradation of APC/C substrates, but the Lys 11-chain-forming E2 UBE2S is not essential for mitotic exit, raising questions about the nature of the ubiquitin signal that targets APC/C substrates for degradation. Here we demonstrate that multiple monoubiquitylation of cyclin B1, catalysed by UBCH10 or UBC4/5, is sufficient to target cyclin B1 for destruction by the proteasome. When the number of ubiquitylatable lysines in cyclin B1 is restricted, Lys 11-linked ubiquitin polymers elaborated by UBE2S become increasingly important. We therefore explain how a substrate that contains multiple ubiquitin acceptor sites confers flexibility in the requirement for particular E2 enzymes in modulating the rate of ubiquitin-dependent proteolysis.
authors.affiliation: Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA.
authors.forename: Nevena V
authors.initials: NV
authors.lastname: Dimova
authors.forename: Nathaniel A
authors.initials: NA
authors.lastname: Hathaway
authors.forename: Byung-Hoon
authors.initials: BH
authors.lastname: Lee
authors.forename: Donald S
authors.initials: DS
authors.lastname: Kirkpatrick
authors.forename: Marie Lea
authors.initials: ML
authors.lastname: Berkowitz
authors.forename: Steven P
authors.initials: SP
authors.lastname: Gygi
authors.forename: Daniel
authors.initials: D
authors.lastname: Finley
authors.forename: Randall W
authors.initials: RW
authors.lastname: King
mesh_terms: D064173:Anaphase-Promoting Complex-Cyclosome; D000818:Animals; D002457:Cell Extracts; D019926:Cyclin B / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D015151:Immunoblotting; D008239:Lysine / Q000378:metabolism; D010063:Ovum / Q000166:cytology / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D015398:Signal Transduction; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism*; D054875:Ubiquitination; D014981:Xenopus
chemical_list: D002457:Cell Extracts; D019926:Cyclin B; D025801:Ubiquitin; C105156:UBE2C protein, human; C097310:UBE2D3 protein, human; C544962:Ube2S protein, human; D044763:Ubiquitin-Conjugating Enzymes; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome; D046988:Proteasome Endopeptidase Complex; D008239:Lysine