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

TY - JOUR

T1 - SET8 is degraded via PCNA-coupled CRL4(CDT2) ubiquitylation in S phase and after UV irradiation

AU - Jørgensen, Stine

AU - Eskildsen, Morten

AU - Fugger, Kasper

AU - Hansen, Lisbeth

AU - Larsen, Marie Sofie Yoo

AU - Kousholt, Arne Nedergaard

AU - Syljuåsen, Randi G

AU - Trelle, Morten Beck

AU - Jensen, Ole Nørregaard

AU - Helin, Kristian

AU - Sørensen, Claus Storgaard

PY - 2011/1/10

Y1 - 2011/1/10

N2 - 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.

AB - 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.

KW - Amino Acid Sequence

KW - Cell Line

KW - DNA Damage

KW - G1 Phase

KW - Histone-Lysine N-Methyltransferase

KW - Humans

KW - Molecular Sequence Data

KW - Nuclear Proteins

KW - Proliferating Cell Nuclear Antigen

KW - Protein Binding

KW - Protein Processing, Post-Translational

KW - S Phase

KW - Ubiquitin-Protein Ligases

KW - Ubiquitination

KW - Ultraviolet Rays

U2 - 10.1083/jcb.201009076

DO - 10.1083/jcb.201009076

M3 - Journal article

C2 - 21220508

SN - 0021-9525

VL - 192

SP - 43

EP - 54

JO - Journal of Cell Biology

JF - Journal of Cell Biology

IS - 1

ER -