CRL4(Cdt2) regulates cell proliferation and histone gene expression by targeting PR-Set7/Set8 for degradation

Mol Cell. 2010 Oct 8;40(1):9-21. doi: 10.1016/j.molcel.2010.09.014.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Apoptosis / genetics
  • Cell Cycle* / drug effects
  • Cell Cycle* / radiation effects
  • Cell Proliferation* / drug effects
  • Cell Proliferation* / radiation effects
  • Cell Survival
  • Chromatin Assembly and Disassembly* / drug effects
  • Chromatin Assembly and Disassembly* / radiation effects
  • Cullin Proteins / genetics
  • Cullin Proteins / metabolism*
  • DNA Damage
  • Down-Regulation
  • E2F1 Transcription Factor / genetics
  • E2F1 Transcription Factor / metabolism
  • Epigenesis, Genetic
  • HeLa Cells
  • Histone-Lysine N-Methyltransferase / genetics
  • Histone-Lysine N-Methyltransferase / metabolism*
  • Histones / genetics
  • Histones / metabolism*
  • Humans
  • Methylation
  • Molecular Sequence Data
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Proliferating Cell Nuclear Antigen / metabolism
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Protein Isoforms
  • Protein Processing, Post-Translational* / drug effects
  • Protein Processing, Post-Translational* / radiation effects
  • Time Factors
  • Transcription, Genetic
  • Transcriptional Activation
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • Ubiquitin-Protein Ligases
  • Ubiquitination

Substances

  • Cullin Proteins
  • DTL protein, human
  • E2F1 Transcription Factor
  • E2F1 protein, human
  • Histones
  • Nuclear Proteins
  • Proliferating Cell Nuclear Antigen
  • Protein Isoforms
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Histone-Lysine N-Methyltransferase
  • KMT5A protein, human
  • Ubiquitin-Protein Ligases