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

SummaryPR-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 CRL4Cdt2 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 CRL4Cdt2-dependent cell-cycle regulation of Set8 for the maintenance of a stable epigenetic state essential for cell viability.

Graphical AbstractFigure optionsDownload high-quality image (185 K)Download as PowerPoint slideHighlights
► CRL4-Cdt2 and PCNA promote Set8 degradation in early and mid S phase and after UV
► Disrupting Set8 degradation inhibits cellular proliferation and results in DNA damage
► Stable Set8 represses transcription of early replicating, E2F1-regulated, and histone genes
► Gene repression is due to the enrichment of H4K20me3 at the promoters of these genes