Acetylation limits 53BP1 association with damaged chromatin to promote homologous recombination

Jiangbo Tang, Nam Woo Cho, Gaofeng Cui, Erica M. Manion, Niraj M. Shanbhag, Maria Victoria Botuyan, Georges Mer, Roger A. Greenberg

Research output: Contribution to journalArticle

262 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)317-325
Number of pages9
JournalNature Structural and Molecular Biology
Volume20
Issue number3
DOIs
StatePublished - Mar 2013

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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    Tang, J., Cho, N. W., Cui, G., Manion, E. M., Shanbhag, N. M., Botuyan, M. V., Mer, G., & Greenberg, R. A. (2013). Acetylation limits 53BP1 association with damaged chromatin to promote homologous recombination. Nature Structural and Molecular Biology, 20(3), 317-325. https://doi.org/10.1038/nsmb.2499