KAP-1 phosphorylation regulates CHD3 nucleosome remodeling during the DNA double-strand break response

• DOI: 10.1038/nsmb.2077
• Publication Date: 2011-06-05T17:19:09Z
• Authors: Aaron A Goodarzi; Thomas Kurka; Penelope A Jeggo
• Keywords: 0303 health sciences; DNA Repair; Morpholines; DNA Helicases; Nuclear Proteins; Cell Cycle Proteins; Ataxia Telangiectasia Mutated Proteins; Protein Serine-Threonine Kinases; Nucleosomes; DNA-Binding Proteins; Histones; Mice; 03 medical and health sciences; HEK293 Cells; Heterochromatin; NIH 3T3 Cells; Animals; Humans; DNA Breaks, Double-Stranded; Phosphorylation; HeLa Cells; Mi-2 Nucleosome Remodeling and Deacetylase Complex

KAP-1 poses a substantial barrier to DNA double-strand break (DSB) repair within heterochromatin that is alleviated by ATM-dependent KAP-1 phosphorylation (pKAP-1). Here we address the mechanistic consequences of pKAP-1 that promote heterochromatic DSB repair and chromatin relaxation. KAP-1 function involves autoSUMOylation and recruitment of nucleosome deacetylation, methylation and remodeling activities. Although heterochromatin acetylation or methylation changes were not detected, radiation-induced pKAP-1 dispersed the nucleosome remodeler CHD3 from DSBs and triggered concomitant chromatin relaxation; pKAP-1 loss reversed these effects. Depletion or inactivation of CHD3, or ablation of its interaction with KAP-1(SUMO1), bypassed pKAP-1's role in repair. Though KAP-1 SUMOylation was unaffected after irradiation, CHD3 dissociated from KAP-1(SUMO1) in a pKAP-1-dependent manner. We demonstrate that KAP-1(Ser824) phosphorylation generates a motif that directly perturbs interactions between CHD3's SUMO-interacting motif and SUMO1, dispersing CHD3 from heterochromatin DSBs and enabling repair.