Abstract
Histone lysine methylation is a key regulator of gene expression and heterochromatin function, but little is known as to how this modification impinges on other chromatin activities. Here we demonstrate that a previously uncharacterized SET domain protein, Set9, is responsible for H4-K20 methylation in the fission yeast Schizosaccharomyces pombe. Surprisingly, H4-K20 methylation does not have any apparent role in the regulation of gene expression or heterochromatin function. Rather, we find the modification has a role in DNA damage response. Loss of Set9 activity or mutation of H4-K20 markedly impairs cell survival after genotoxic challenge and compromises the ability of cells to maintain checkpoint mediated cell cycle arrest. Genetic experiments link Set9 to Crb2, a homolog of the mammalian checkpoint protein 53BP1, and the enzyme is required for Crb2 localization to sites of DNA damage. These results argue that H4-K20 methylation functions as a "histone mark" required for the recruitment of the checkpoint protein Crb2.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism*
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Cell Survival / genetics
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DNA Damage / genetics*
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Gene Expression Regulation, Fungal / genetics
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Genes, cdc / physiology
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Histone Methyltransferases
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Histone-Lysine N-Methyltransferase / genetics
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Histone-Lysine N-Methyltransferase / metabolism
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Histones / genetics
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Histones / metabolism*
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism
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Lysine / metabolism*
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Methylation
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Mutation / genetics
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Phosphoproteins / genetics
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Phosphoproteins / metabolism
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Protein Methyltransferases
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Protein Transport / genetics
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Schizosaccharomyces / genetics*
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Schizosaccharomyces / metabolism*
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Schizosaccharomyces pombe Proteins / genetics
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Schizosaccharomyces pombe Proteins / metabolism*
Substances
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Cell Cycle Proteins
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Crb2 protein, S pombe
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Histones
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Intracellular Signaling Peptides and Proteins
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Nuclear Proteins
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Phosphoproteins
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Schizosaccharomyces pombe Proteins
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Histone Methyltransferases
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Protein Methyltransferases
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Histone-Lysine N-Methyltransferase
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Lysine