Opposing ISWI- and CHD-class chromatin remodeling activities orchestrate heterochromatic DNA repair |
| |
Authors: | Karolin Klement Martijn S. Luijsterburg Jordan B. Pinder Chad S. Cena Victor Del Nero Christopher M. Wintersinger Graham Dellaire Haico van Attikum Aaron A. Goodarzi |
| |
Affiliation: | 1.Robson DNA Science Centre, Southern Alberta Cancer Research Institute; and 2.Department of Biochemistry and Molecular Biology, and 3.Department of Oncology, Cumming School of Medicine; University of Calgary, Calgary, Alberta T2N 4N1, Canada;4.Department of Human Genetics, Leiden University Medical Centre, 2333 ZC Leiden, Netherlands;5.Department of Pathology, Dalhousie University, Halifax, Nova Scotia B3H 4R2, Canada |
| |
Abstract: | 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. |
| |
Keywords: | |
|
|