TY - JOUR
T1 - E2F1 acetylation directs p300/CBP-mediated histone acetylation at DNA double-strand breaks to facilitate repair
AU - Manickavinayaham, Swarnalatha
AU - Vélez-Cruz, Renier
AU - Biswas, Anup K.
AU - Bedford, Ella
AU - Klein, Brianna J.
AU - Kutateladze, Tatiana G.
AU - Liu, Bin
AU - Bedford, Mark T.
AU - Johnson, David G.
N1 - Funding Information:
We thank B. Brooks and R. Deen for manuscript preparation; J. Holcomb for graphics; J. Orona and M. Portis for expert technical assistance; Ray. S for preliminary study; Lin. K for biostatistics; C. Sagum and the Protein Array and Analysis Core (supported by CPRIT RP180804) and J. Terpstra and C. Jeter of the Flow Cytometry & Cellular Imaging Core (supported by CPRIT RP170628) for assistance with IF; JJ Shen and the Next-Generation Sequencing Core (supported by CPRIT RP120348 and RP170002) for RNA-Seq; A. Multani and the Molecular Cytogenetics Facility for metaphase spreads analysis; D. Hollowell and the Transgenic Animal Core for generating knock-in mice; C. Perez of the Research Histology, Pathology and Imaging services for IHC; and Dale Weiss and colleagues in the Research Animal Support Facility for animal care. This work was supported by grants from the Cancer Prevention and Research Institute of Texas (RP140222 to D.G.J.); the National Institutes of Health (CA214723 to D.G.J., GM100907 to T.G.K. and Cancer Core Support Grant CA016672); and institutional funding from the Department of Epigenetics and Molecular Carcinogenesis, the Center for Cancer Epigenetics, and the Center for Genetics and Genomics.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - E2F1 and retinoblastoma (RB) tumor-suppressor protein not only regulate the periodic expression of genes important for cell proliferation, but also localize to DNA double-strand breaks (DSBs) to promote repair. E2F1 is acetylated in response to DNA damage but the role this plays in DNA repair is unknown. Here we demonstrate that E2F1 acetylation creates a binding motif for the bromodomains of the p300/KAT3B and CBP/KAT3A acetyltransferases and that this interaction is required for the recruitment of p300 and CBP to DSBs and the induction of histone acetylation at sites of damage. A knock-in mutation that blocks E2F1 acetylation abolishes the recruitment of p300 and CBP to DSBs and also the accumulation of other chromatin modifying activities and repair factors, including Tip60, BRG1 and NBS1, and renders mice hypersensitive to ionizing radiation (IR). These findings reveal an important role for E2F1 acetylation in orchestrating the remodeling of chromatin structure at DSBs to facilitate repair.
AB - E2F1 and retinoblastoma (RB) tumor-suppressor protein not only regulate the periodic expression of genes important for cell proliferation, but also localize to DNA double-strand breaks (DSBs) to promote repair. E2F1 is acetylated in response to DNA damage but the role this plays in DNA repair is unknown. Here we demonstrate that E2F1 acetylation creates a binding motif for the bromodomains of the p300/KAT3B and CBP/KAT3A acetyltransferases and that this interaction is required for the recruitment of p300 and CBP to DSBs and the induction of histone acetylation at sites of damage. A knock-in mutation that blocks E2F1 acetylation abolishes the recruitment of p300 and CBP to DSBs and also the accumulation of other chromatin modifying activities and repair factors, including Tip60, BRG1 and NBS1, and renders mice hypersensitive to ionizing radiation (IR). These findings reveal an important role for E2F1 acetylation in orchestrating the remodeling of chromatin structure at DSBs to facilitate repair.
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U2 - 10.1038/s41467-019-12861-8
DO - 10.1038/s41467-019-12861-8
M3 - Article
C2 - 31666529
AN - SCOPUS:85074279822
SN - 2041-1723
VL - 10
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 4951
ER -