PR-Set7–dependent lysine methylation ensures genome replication and stability through S phase
Copyright policy )PR-Set7–dependent lysine methylation ensures genome replication and stability through S phase
PR-Set7/SET8 is a histone H4–lysine 20 methyltransferase required for normal cell proliferation. However, the exact functions of this enzyme remain to be determined. In this study, we show that human PR-Set7 functions during S phase to regulate cellular proliferation. PR-Set7 associates with replication foci and maintains the bulk of H4-K20 mono- and trimethylation. Consistent with a function in chromosome dynamics during S phase, inhibition of PR-Set7 methyltransferase activity by small hairpin RNA causes a replicative stress characterized by alterations in replication fork velocity and origin firing. This stress is accompanied by massive induction of DNA strand breaks followed by a robust DNA damage response. The DNA damage response includes the activation of ataxia telangiectasia mutated and ataxia telangiectasia related kinase–mediated pathways, which, in turn, leads to p53-mediated growth arrest to avoid aberrant chromosome behavior after improper DNA replication. Collectively, these data indicate that PR-Set7–dependent lysine methylation during S phase is an essential posttranslational mechanism that ensures genome replication and stability.
DNA Replication, DNA Replication/genetics, DNA Repair, Protein-Serine-Threonine Kinases/genetics, Down-Regulation, Cell Cycle Proteins, Ataxia Telangiectasia Mutated Proteins, Protein Serine-Threonine Kinases, Tumor Suppressor Proteins/genetics, Histone-Lysine N-Methyltransferase/genetics, Protein Processing, Post-Translational/physiology, Methylation, Genomic Instability, S Phase, Histones, DNA Repair/genetics, Cell Line, Tumor, Humans, RNA, Small Interfering, Histones/genetics/metabolism, Research Articles, Cell Cycle Proteins/genetics, Lysine, Tumor Suppressor Proteins, Histone-Lysine N-Methyltransferase, Down-Regulation/genetics, DNA-Binding Proteins, S Phase/genetics, DNA Damage/genetics, Genomic Instability/genetics, Protein Processing, Post-Translational, DNA-Binding Proteins/genetics, Lysine/metabolism, DNA Damage
DNA Replication, DNA Replication/genetics, DNA Repair, Protein-Serine-Threonine Kinases/genetics, Down-Regulation, Cell Cycle Proteins, Ataxia Telangiectasia Mutated Proteins, Protein Serine-Threonine Kinases, Tumor Suppressor Proteins/genetics, Histone-Lysine N-Methyltransferase/genetics, Protein Processing, Post-Translational/physiology, Methylation, Genomic Instability, S Phase, Histones, DNA Repair/genetics, Cell Line, Tumor, Humans, RNA, Small Interfering, Histones/genetics/metabolism, Research Articles, Cell Cycle Proteins/genetics, Lysine, Tumor Suppressor Proteins, Histone-Lysine N-Methyltransferase, Down-Regulation/genetics, DNA-Binding Proteins, S Phase/genetics, DNA Damage/genetics, Genomic Instability/genetics, Protein Processing, Post-Translational, DNA-Binding Proteins/genetics, Lysine/metabolism, DNA Damage
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