SET8 is degraded via PCNA-coupled CRL4(CDT2) ubiquitylation in S phase and after UV irradiation

Stine Jørgensen, Morten Eskildsen, Kasper Fugger, Lisbeth Hansen, Marie Sofie Yoo Larsen, Arne Nedergaard Kousholt, Randi G Syljuåsen, Morten Beck Trelle, Ole Nørregaard Jensen, Kristian Helin, Claus Storgaard Sørensen

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    104 Citations (Scopus)

    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.
    Original languageEnglish
    JournalJournal of Cell Biology
    Volume192
    Issue number1
    Pages (from-to)43-54
    Number of pages12
    ISSN0021-9525
    DOIs
    Publication statusPublished - 10 Jan 2011

    Keywords

    • Amino Acid Sequence
    • Cell Line
    • DNA Damage
    • G1 Phase
    • Histone-Lysine N-Methyltransferase
    • Humans
    • Molecular Sequence Data
    • Nuclear Proteins
    • Proliferating Cell Nuclear Antigen
    • Protein Binding
    • Protein Processing, Post-Translational
    • S Phase
    • Ubiquitin-Protein Ligases
    • Ubiquitination
    • Ultraviolet Rays

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