CRL4Cdt2 Regulates Cell Proliferation and Histone Gene Expression by Targeting PR-Set7/Set8 for Degradation

被引：222

作者：

Abbas, Tarek ^{[1
]}

Shibata, Etsuko ^{[1
]}

Park, Jonghoon ^{[1
]}

Jha, Sudhakar ^{[1
]}

Karnani, Neerja ^{[1
]}

Dutta, Anindya ^{[1
]}

机构：

[1] Univ Virginia, Dept Biochem & Mol Genet, Charlottesville, VA 22908 USA

来源：

MOLECULAR CELL | 2010年 / 40卷 / 01期

基金：

美国国家卫生研究院;

关键词：

DNA-DAMAGE; UBIQUITIN LIGASE; S-PHASE; METHYLATION; METHYLTRANSFERASE; REPLICATION; CHECKPOINT; LYSINE-20; PATHWAY; PCNA;

D O I：

10.1016/j.molcel.2010.09.014

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

PR-Set7/Set8 is a cell-cycle-regulated enzyme that monomethylates lysine 20 of histone H4 (H4K20). Set8 and monomethylated H4K20 are virtually undetectable during G1 and S phases of the cell cycle but increase in late S and in G2. We identify CRL4(Cdt2) as the principal E3 ubiquitin ligase responsible for Set8 proteolytic degradation in the S phase of the cell cycle, which requires Set8-PCNA interaction. Inactivation of the CRL4-Cdt2-PCNA-Set8 degradation axis results in (1) DNA damage and the induction of tumor suppressor p53 and p53-transactivated proapoptotic genes, (2) delayed progression through G2 phase of the cell cycle due to activation of the G2/M checkpoint, (3) specific repression of histone gene transcription and depletion of the histone proteins, and (4) repression of E2F1-dependent gene transcription. These results demonstrate a central role of CRL4(Cdt2)-dependent cell-cycle regulation of Set8 for the maintenance of a stable epigenetic state essential for cell viability.

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页码：9 / 21

页数：13

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