title: SET8 is degraded via PCNA-coupled CRL4(CDT2) ubiquitylation in S phase and after UV irradiation.
abstract: The eukaryotic cell cycle is regulated by multiple ubiquitin-mediated events, such as the timely destruction of cyclins and replication licensing factors. The histone H4 methyltransferase SET8 (Pr-Set7) is required for chromosome compaction in mitosis and for maintenance of genome integrity. In this study, we show that SET8 is targeted for degradation during S phase by the CRL4(CDT2) ubiquitin ligase in a proliferating cell nuclear antigen (PCNA)-dependent manner. SET8 degradation requires a conserved degron responsible for its interaction with PCNA and recruitment to chromatin where ubiquitylation occurs. Efficient degradation of SET8 at the onset of S phase is required for the regulation of chromatin compaction status and cell cycle progression. Moreover, the turnover of SET8 is accelerated after ultraviolet irradiation dependent on the CRL4(CDT2) ubiquitin ligase and PCNA. Removal of SET8 supports the modulation of chromatin structure after DNA damage. These results demonstrate a novel regulatory mechanism, linking for the first time the ubiquitin-proteasome system with rapid degradation of a histone methyltransferase to control cell proliferation.
authors.affiliation: Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Stine
authors.initials: S
authors.lastname: Jørgensen
authors.forename: Morten
authors.initials: M
authors.lastname: Eskildsen
authors.forename: Kasper
authors.initials: K
authors.lastname: Fugger
authors.forename: Lisbeth
authors.initials: L
authors.lastname: Hansen
authors.forename: Marie Sofie Yoo
authors.initials: MS
authors.lastname: Larsen
authors.forename: Arne Nedergaard
authors.initials: AN
authors.lastname: Kousholt
authors.forename: Randi G
authors.initials: RG
authors.lastname: Syljuåsen
authors.forename: Morten Beck
authors.initials: MB
authors.lastname: Trelle
authors.forename: Ole Nørregaard
authors.initials: ON
authors.lastname: Jensen
authors.forename: Kristian
authors.initials: K
authors.lastname: Helin
authors.forename: Claus Storgaard
authors.initials: CS
authors.lastname: Sørensen
mesh_terms: D000595:Amino Acid Sequence; D002460:Cell Line; D004249:DNA Damage; D016193:G1 Phase / Q000528:radiation effects; D011495:Histone-Lysine N-Methyltransferase / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism*; D011485:Protein Binding / Q000528:radiation effects; D011499:Protein Processing, Post-Translational / Q000528:radiation effects*; D016196:S Phase / Q000528:radiation effects*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination / Q000528:radiation effects*; D014466:Ultraviolet Rays
chemical_list: C429530:DTL protein, human; D009687:Nuclear Proteins; D018809:Proliferating Cell Nuclear Antigen; D011495:Histone-Lysine N-Methyltransferase; C470730:KMT5A protein, human; D044767:Ubiquitin-Protein Ligases