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

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.
Mesh Terms:
Animals, Cell Cycle Proteins, DNA Breaks, Double-Stranded, DNA Helicases, DNA Repair, DNA-Binding Proteins, HEK293 Cells, HeLa Cells, Heterochromatin, Histones, Humans, Mice, Morpholines, NIH 3T3 Cells, Nuclear Proteins, Nucleosomes, Phosphorylation, Protein-Serine-Threonine Kinases, Pyrones, Repressor Proteins, SUMO-1 Protein, Sumoylation, Tumor Suppressor Proteins
Nat. Struct. Mol. Biol.
Date: Jul. 01, 2011
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