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

doi:10.1083/jcb.201009076

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

93 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 language	English
Journal	Journal of Cell Biology
Volume	192
Issue number	1
Pages (from-to)	43-54
Number of pages	12
ISSN	0021-9525
DOIs	https://doi.org/10.1083/jcb.201009076
Publication status	Published - 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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10.1083/jcb.201009076

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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.",

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",

author = "Stine J{\o}rgensen and Morten Eskildsen and Kasper Fugger and Lisbeth Hansen and Larsen, {Marie Sofie Yoo} and Kousholt, {Arne Nedergaard} and Sylju{\aa}sen, {Randi G} and Trelle, {Morten Beck} and Jensen, {Ole N{\o}rregaard} and Kristian Helin and S{\o}rensen, {Claus Storgaard}",

year = "2011",

month = jan,

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doi = "10.1083/jcb.201009076",

language = "English",

volume = "192",

pages = "43--54",

journal = "Journal of Cell Biology",

issn = "0021-9525",

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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 -

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

Abstract

Keywords

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