E2F1 acetylation directs p300/CBP-mediated histone acetylation at DNA double-strand breaks to facilitate repair

Swarnalatha Manickavinayaham; Renier Vélez-Cruz; Anup K Biswas; Ella Bedford; Brianna J Klein; Tatiana G Kutateladze; Bin Liu; Mark T Bedford; David G Johnson

doi:10.1038/s41467-019-12861-8

E2F1 acetylation directs p300/CBP-mediated histone acetylation at DNA double-strand breaks to facilitate repair

Nat Commun. 2019 Oct 30;10(1):4951. doi: 10.1038/s41467-019-12861-8.

Authors

Affiliations

¹ Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Science Park, Smithville, TX, 78957, USA.
² Department of Biochemistry, Midwestern University, Chicago College of Osteopathic Medicine, Downers Grove, IL, 60515, USA.
³ Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, 10032, USA.
⁴ Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO, 80045, USA.
⁵ Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Science Park, Smithville, TX, 78957, USA. djohnson@mdanderson.org.

Abstract

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Acetylation
Animals
CREB-Binding Protein / metabolism*
Cell Cycle Proteins / metabolism
DNA Breaks, Double-Stranded*
DNA Helicases / metabolism
DNA Repair / genetics
DNA-Binding Proteins / metabolism
E1A-Associated p300 Protein / metabolism*
E2F1 Transcription Factor / genetics
E2F1 Transcription Factor / metabolism*
Gene Knock-In Techniques
Histone Acetyltransferases
Histones / metabolism*
Lysine Acetyltransferase 5 / metabolism
Mice
Nuclear Proteins / metabolism
Protein Interaction Domains and Motifs
Radiation, Ionizing
Trans-Activators / metabolism
Transcription Factors / metabolism
p300-CBP Transcription Factors / metabolism

Substances

Cell Cycle Proteins
DNA-Binding Proteins
E2F1 Transcription Factor
E2f1 protein, mouse
Histones
Nijmegen breakage syndrome 1 protein, mouse
Nuclear Proteins
Trans-Activators
Transcription Factors
CREB-Binding Protein
E1A-Associated p300 Protein
Histone Acetyltransferases
Kat5 protein, mouse
Lysine Acetyltransferase 5
p300-CBP Transcription Factors
Smarca4 protein, mouse
DNA Helicases

Abstract

Publication types

MeSH terms

Substances

Grants and funding