Regulation of the histone H4 monomethylase PR-Set7 by CRL4(Cdt2)-mediated PCNA-dependent degradation during DNA damage

Mol Cell. 2010 Nov 12;40(3):364-76. doi: 10.1016/j.molcel.2010.10.011. Epub 2010 Oct 28.


The histone methyltransferase PR-Set7/Set8 is the sole enzyme that catalyzes monomethylation of histone H4 at K20 (H4K20me1). Previous reports document disparate evidence regarding PR-Set7 expression during the cell cycle, the biological relevance of PR-Set7 interaction with PCNA, and its role in the cell. We find that PR-Set7 is indeed undetectable during S phase and instead is detected during late G2, mitosis, and early G1. PR-Set7 is transiently recruited to laser-induced DNA damage sites through its interaction with PCNA, after which 53BP1 is recruited dependent on PR-Set7 catalytic activity. During the DNA damage response, PR-Set7 interaction with PCNA through a specialized "PIP degron" domain targets it for PCNA-coupled CRL4(Cdt2)-dependent proteolysis. PR-Set7 mutant in its "PIP degron" is now detectable during S phase, during which the mutant protein accumulates. Outside the chromatin context, Skp2 promotes PR-Set7 degradation as well. These findings demonstrate a stringent spatiotemporal control of PR-Set7 that is essential for preserving the genomic integrity of mammalian cells.

Publication types

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

MeSH terms

  • Animals
  • Biocatalysis / radiation effects
  • Cell Line, Tumor
  • Cullin Proteins / metabolism*
  • DNA Damage*
  • DNA-Binding Proteins / metabolism*
  • Enzyme Activation / radiation effects
  • Enzyme Stability
  • Histone-Lysine N-Methyltransferase / chemistry
  • Histone-Lysine N-Methyltransferase / metabolism*
  • Histones / metabolism*
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Mice
  • Models, Biological
  • Nuclear Proteins / metabolism*
  • Proliferating Cell Nuclear Antigen / metabolism*
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Binding / radiation effects
  • Protein Processing, Post-Translational* / radiation effects
  • Protein Structure, Tertiary
  • S Phase / radiation effects
  • Signal Transduction / radiation effects
  • Tumor Suppressor p53-Binding Protein 1
  • Ubiquitin / metabolism
  • Ubiquitin-Protein Ligases / metabolism*
  • Ultraviolet Rays


  • CUL4A protein, human
  • CUL4B protein, human
  • Cullin Proteins
  • DDB1 protein, human
  • DNA-Binding Proteins
  • DTL protein, human
  • Histones
  • Intracellular Signaling Peptides and Proteins
  • Nuclear Proteins
  • Proliferating Cell Nuclear Antigen
  • TP53BP1 protein, human
  • Tumor Suppressor p53-Binding Protein 1
  • Ubiquitin
  • Histone-Lysine N-Methyltransferase
  • KMT5A protein, human
  • Ubiquitin-Protein Ligases
  • Proteasome Endopeptidase Complex