Karolin Klement 1 , 2 , 3 , Martijn S. Luijsterburg 4 , Jordan B. Pinder 5 , Chad S. Cena 1 , 2 , 3 , Victor Del Nero 1 , 2 , 3 , Christopher M. Wintersinger 1 , 2 , 3 , Graham Dellaire 5 , Haico van Attikum 4 , Aaron A. Goodarzi , 1 , 2 , 3
22 December 2014
Chromatin compaction mediated by CHD3.1 must be counteracted by ACF1–SNF2H and RNF20 in order to allow DNA double-strand break repair in heterochromatin of postreplicative cells.
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.