title: Distinct consequences of posttranslational modification by linear versus K63-linked polyubiquitin chains.
abstract: Polyubiquitin chains mediate a variety of biological processes, ranging from proteasomal targeting to inflammatory signaling and DNA repair. Their functional diversity is in part due to their ability to adopt distinct conformations, depending on how the ubiquitin moieties within the chain are linked. We have used the eukaryotic replication clamp PCNA, a natural target of lysine (K)63-linked polyubiquitylation, as a model substrate to directly compare the consequences of modification by different types of polyubiquitin chains. We show here that K63-polyubiquitylated PCNA is not subject to proteasomal degradation. In contrast, linear, noncleavable ubiquitin chains do not promote DNA damage tolerance, but function as general degradation signals. We find that a linear tetraubiquitin chain is sufficient to afford proteasomal targeting through the Cdc48-Npl4-Ufd1 complex without further modification. Although a minimum chain length of four is required for degradation, a longer chain does not further reduce the half-life of the respective substrate protein. Our results suggest that the cellular machinery responsible for recognition of ubiquitylated substrates can make subtle distinctions between highly similar forms of the polyubiquitin signal.
authors.affiliation: Cancer Research UK London Research Institute, Clare Hall Laboratories, Blanche Lane, South Mimms EN6 3LD, United Kingdom.
authors.forename: Shengkai
authors.initials: S
authors.lastname: Zhao
authors.forename: Helle D
authors.initials: HD
authors.lastname: Ulrich
mesh_terms: D015152:Blotting, Northern; D015153:Blotting, Western; D004249:DNA Damage / Q000502:physiology; D025821:Polyubiquitin / Q000378:metabolism*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D012441:Saccharomyces cerevisiae; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D018809:Proliferating Cell Nuclear Antigen; D025821:Polyubiquitin; D046988:Proteasome Endopeptidase Complex
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