Regulation of the histone H4 monomethylase PR-Set7 by CRL4(Cdt2)-mediated PCNA-dependent degradation during DNA damage.
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.
Mesh Terms:
Animals, Biocatalysis, Cell Line, Tumor, Cullin Proteins, DNA Damage, DNA-Binding Proteins, Enzyme Activation, Enzyme Stability, Histone-Lysine N-Methyltransferase, Histones, Humans, Intracellular Signaling Peptides and Proteins, Mice, Models, Biological, Nuclear Proteins, Proliferating Cell Nuclear Antigen, Proteasome Endopeptidase Complex, Protein Binding, Protein Processing, Post-Translational, Protein Structure, Tertiary, S Phase, Signal Transduction, Ubiquitin, Ubiquitin-Protein Ligases, Ultraviolet Rays
Animals, Biocatalysis, Cell Line, Tumor, Cullin Proteins, DNA Damage, DNA-Binding Proteins, Enzyme Activation, Enzyme Stability, Histone-Lysine N-Methyltransferase, Histones, Humans, Intracellular Signaling Peptides and Proteins, Mice, Models, Biological, Nuclear Proteins, Proliferating Cell Nuclear Antigen, Proteasome Endopeptidase Complex, Protein Binding, Protein Processing, Post-Translational, Protein Structure, Tertiary, S Phase, Signal Transduction, Ubiquitin, Ubiquitin-Protein Ligases, Ultraviolet Rays
Mol. Cell
Date: Nov. 12, 2010
PubMed ID: 21035370
View in: Pubmed Google Scholar
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