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Acetylation limits 53BP1 association with damaged chromatin to promote homologous recombination
Open accessAbstract
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.
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Metadata
- Authors
- Tang, J., Cho, N. W., Cui, G., Manion, E. M., Shanbhag, N. M., Botuyan, M. V., Mer, G., & Greenberg, R. A.
- Affiliations
- University of Pennsylvania (US)
- Mayo Clinic (US)
- Corresponding author
- Greenberg, Roger A
- Venue
- Nature Structural & Molecular Biology
- Published
- 2013-02-03
- Volume
- 20
- Issue
- 3
- Pages
- 317-325
- ISSN
- 1545-9985 (ISSN-L)
- 1545-9993
- PMC
- PMC3594358
- OpenAlex
- W2060247906
- Cited by
- 521
- References
- 58
- Citations by year
- 2026: 20 · 2025: 26 · 2024: 28 · 2023: 29 · 2022: 52 · 2021: 45 · 2020: 48 · 2019: 34 · 2018: 48 · 2017: 49 · 2016: 53 · 2015: 35 · 2014: 33 · 2013: 21
- FWCI
- 21.37
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Structural & Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01CA138835, R01CA132878, R01CA174904, P50CA116201, P30CA016520)
- National Institute of General Medical Sciences (R01GM101149)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- 53BP1, BRCA1, histone H4 acetylation, H4K16 acetylation, Tip60, H4K20me2, homologous recombination, non-homologous end joining, DNA double-strand break repair, DNA repair pathway choice, Tudor domain, histone deacetylase inhibition, chromatin binding
- MeSH terms
- Tumor Suppressor p53-Binding Protein 1, ATPases Associated with Diverse Cellular Activities, Lysine Acetyltransferase 5, Acetylation, Amino Acid Sequence, Carrier Proteins, Cells, Cultured, Chromatin, Chromosomal Proteins, Non-Histone, DNA Helicases, DNA-Binding Proteins, Histone Deacetylases, Histones, Humans, Molecular Sequence Data, Magnetic Resonance Spectroscopy, Protein Conformation, BRCA1 Protein, Intracellular Signaling Peptides and Proteins, Histone Acetyltransferases, DNA Breaks, Double-Stranded, Gene Knockdown Techniques, Homologous Recombination
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