@article{37c016ee094f4bca9747274390fa42d6,
title = "Acetylation limits 53BP1 association with damaged chromatin to promote homologous recombination",
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.",
author = "Jiangbo Tang and Cho, {Nam Woo} and Gaofeng Cui and Manion, {Erica M.} and Shanbhag, {Niraj M.} and Botuyan, {Maria Victoria} and Georges Mer and Greenberg, {Roger A.}",
note = "Funding Information: We thank J. Wu for technical support, J. Chen (MD Anderson Cancer Center) for 53BP1−/− mouse embryonic fibroblasts, M. Jasin (Memorial Sloan-Kettering Cancer Center) for U2OS DR-GFP reporter cells, G. Stewart (University of Birmingham) for RIDDLE cells and S. Janicki (Wistar Institute) and D. Spector (Cold Spring Harbor Laboratories) for the U2OS 2-6-3 reporter cell line. We thank K.M. Miller (University of Texas) and A. Sfeir (New York University) for their critical reading of the manuscript and helpful comments. R.A.G. is supported by grant 1R01CA138835-01 from the National Cancer Institute (NCI), a Research Scholar Grant from the American Cancer Society, a Department of Defense Breast Cancer Idea Award, a UPENN–Fox Chase Cancer Center (FCCC) Specialized Program of Research Excellence (SPORE) Pilot Grant and funds from the Abramson Family Cancer Research Institute and Basser Research Center for BRCA. G.M. acknowledges support from NCI grant 1R01CA132878 and funds from the Mayo Clinic Breast Cancer SPORE NCI grant P50CA116201.",
year = "2013",
month = mar,
doi = "10.1038/nsmb.2499",
language = "English (US)",
volume = "20",
pages = "317--325",
journal = "Nature Structural and Molecular Biology",
issn = "1545-9993",
publisher = "Nature Publishing Group",
number = "3",
}