Abstract
The pathogenic sequelae of BRCA1 mutation in human and mouse cells are mitigated by concomitant deletion of 53BP1, which binds histone H4 dimethylated at Lys20 (H4K20me2) to promote nonhomologous end joining, suggesting that a balance between BRCA1 and 53BP1 regulates DNA double strand-break (DSB) repair mechanism choice. Here we document that acetylation is a key determinant of this balance. TIP60 acetyltransferase deficiency reduced BRCA1 at DSB chromatin with commensurate increases in 53BP1, whereas HDAC inhibition yielded the opposite effect. TIP60-dependent H4 acetylation diminished 53BP1 binding to H4K20me2 in part through disruption of a salt bridge between H4K16 and Glu1551 in the 53BP1 Tudor domain. Moreover, TIP60 deficiency impaired homologous recombination and conferred sensitivity to PARP inhibition in a 53BP1-dependent manner. These findings demonstrate that acetylation in cis to H4K20me2 regulates relative BRCA1 and 53BP1 DSB chromatin occupancy to direct DNA repair mechanism.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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ATPases Associated with Diverse Cellular Activities
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Acetylation
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Amino Acid Sequence
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BRCA1 Protein / genetics
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BRCA1 Protein / metabolism*
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Carrier Proteins / genetics
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Carrier Proteins / metabolism
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Cells, Cultured
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Chromatin / genetics
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Chromatin / metabolism*
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Chromosomal Proteins, Non-Histone / genetics
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Chromosomal Proteins, Non-Histone / metabolism
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DNA Breaks, Double-Stranded
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DNA Helicases / genetics
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DNA Helicases / metabolism
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Gene Knockdown Techniques
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Histone Acetyltransferases / genetics
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Histone Acetyltransferases / metabolism
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Histone Deacetylases / metabolism
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Histones / metabolism*
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Homologous Recombination*
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Humans
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Intracellular Signaling Peptides and Proteins / chemistry*
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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 Acetyltransferase 5
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Magnetic Resonance Spectroscopy
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Molecular Sequence Data
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Protein Conformation
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Tumor Suppressor p53-Binding Protein 1
Substances
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BRCA1 Protein
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Carrier Proteins
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Chromatin
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Chromosomal Proteins, Non-Histone
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DNA-Binding Proteins
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Histones
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Intracellular Signaling Peptides and Proteins
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TP53BP1 protein, human
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Trp53bp1 protein, mouse
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Tumor Suppressor p53-Binding Protein 1
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Histone Acetyltransferases
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KAT5 protein, human
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Lysine Acetyltransferase 5
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Histone Deacetylases
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ATPases Associated with Diverse Cellular Activities
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DNA Helicases
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RUVBL1 protein, human