Histone demethylase KDM5A regulates the ZMYND8-NuRD chromatin remodeler to promote DNA repair

• Published in: The Journal of cell biology Vol. 216; no. 7; pp. 1959 - 1974
• Main Authors: Gong, Fade, Clouaire, Thomas, Aguirrebengoa, Marion, Legube, Gaëlle, Miller, Kyle M
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 03-07-2017; The Rockefeller University Press
• Subjects: Binding Sites; Cell Line, Tumor; Chromatin; Chromatin - chemistry; Chromatin - enzymology; Chromatin - genetics; Chromatin Assembly and Disassembly; Damage; Deacetylation; Dealkylation; Demethylation; Deoxyribonucleic acid; DNA; DNA Breaks, Double-Stranded; DNA damage; DNA repair; Double-strand break repair; Down-Regulation; Gene silencing; HEK293 Cells; Histones - metabolism; Homologous recombination; Homology; Humans; Methylation; Mi-2 Nucleosome Remodeling and Deacetylase Complex - genetics; Mi-2 Nucleosome Remodeling and Deacetylase Complex - metabolism; Poly(ADP-ribose) Polymerases - metabolism; Protein Binding; Protein Interaction Domains and Motifs; Protein Processing, Post-Translational; Proteins; Receptors for Activated C Kinase; Receptors, Cell Surface - genetics; Receptors, Cell Surface - metabolism; Recombinational DNA Repair; Recruitment; Repair; Retinoblastoma-Binding Protein 2 - genetics; Retinoblastoma-Binding Protein 2 - metabolism; RNA Interference; Signal Transduction; Time Factors; Transcription, Genetic; Transfection; Tumor Suppressor Proteins
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.201611135

Upon DNA damage, histone modifications are dynamically reshaped to accommodate DNA damage signaling and repair within chromatin. In this study, we report the identification of the histone demethylase KDM5A as a key regulator of the bromodomain protein ZMYND8 and NuRD (nucleosome remodeling and histone deacetylation) complex in the DNA damage response. We observe KDM5A-dependent H3K4me3 demethylation within chromatin near DNA double-strand break (DSB) sites. Mechanistically, demethylation of H3K4me3 is required for ZMYND8-NuRD binding to chromatin and recruitment to DNA damage. Functionally, KDM5A deficiency results in impaired transcriptional silencing and repair of DSBs by homologous recombination. Thus, this study identifies a crucial function for KDM5A in demethylating H3K4 to allow ZMYND8-NuRD to operate within damaged chromatin to repair DSBs.