Opposing ISWI- and CHD-class chromatin remodeling activities orchestrate heterochromatic DNA repair.

Heterochromatin is a barrier to DNA repair that correlates strongly with elevated somatic mutation in cancer. CHD class II nucleosome remodeling activity (specifically CHD3.1) retained by KAP-1 increases heterochromatin compaction and impedes DNA double-strand break (DSB) repair requiring Artemis. This obstruction is alleviated by chromatin relaxation via ATM-dependent KAP-1S824 phosphorylation ...
(pKAP-1) and CHD3.1 dispersal from heterochromatic DSBs; however, how heterochromatin compaction is actually adjusted after CHD3.1 dispersal is unknown. In this paper, we demonstrate that Artemis-dependent DSB repair in heterochromatin requires ISWI (imitation switch)-class ACF1-SNF2H nucleosome remodeling. Compacted chromatin generated by CHD3.1 after DNA replication necessitates ACF1-SNF2H-mediated relaxation for DSB repair. ACF1-SNF2H requires RNF20 to bind heterochromatic DSBs, underlies RNF20-mediated chromatin relaxation, and functions downstream of pKAP-1-mediated CHD3.1 dispersal to enable DSB repair. CHD3.1 and ACF1-SNF2H display counteractive activities but similar histone affinities (via the plant homeodomains of CHD3.1 and ACF1), which we suggest necessitates a two-step dispersal and recruitment system regulating these opposing chromatin remodeling activities during DSB repair.
Mesh Terms:
Adenosine Triphosphatases, Animals, Ataxia Telangiectasia Mutated Proteins, Cell Line, Tumor, Chromatin Assembly and Disassembly, Chromosomal Proteins, Non-Histone, DNA Breaks, Double-Stranded, DNA End-Joining Repair, DNA Helicases, Heterochromatin, Histones, Mi-2 Nucleosome Remodeling and Deacetylase Complex, Mice, Molecular Sequence Data, NIH 3T3 Cells, Nuclear Proteins, Nucleosomes, Protein Binding, Protein Interaction Domains and Motifs, Transcription Factors, Ubiquitin-Protein Ligases
J. Cell Biol.
Date: Dec. 22, 2014
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