Replication-Coupled Dilution of H4K20me2 Guides 53BP1 to Pre-replicative Chromatin

• DOI: 10.1016/j.celrep.2017.05.016
• Publication Date: 2017-05-31T18:17:20Z
• Authors: Stefania Pellegrino; Jone Michelena; Federico Teloni; Ralph Imhof; Matthias Altmeyer
• Keywords: DNA Replication; QH301-705.5; DNA repair; HDR; H4K20; Models, Biological; Article; Histones; 03 medical and health sciences; 1300 General Biochemistry, Genetics and Molecular Biology; Cell Line, Tumor; HR; Humans; DNA Breaks, Double-Stranded; histone methylation; Biology (General); NHEJ; 0303 health sciences; Lysine; Recombinational DNA Repair; 10226 Department of Molecular Mechanisms of Disease; 53BP1; Chromatin; 570 Life sciences; biology; chromatin; Tumor Suppressor p53-Binding Protein 1; DSB repair pathway choice; genome stability

The bivalent histone modification reader 53BP1 accumulates around DNA double-strand breaks (DSBs), where it dictates repair pathway choice decisions by limiting DNA end resection. How this function is regulated locally and across the cell cycle to channel repair reactions toward non-homologous end joining (NHEJ) in G1 and promote homology-directed repair (HDR) in S/G2 is insufficiently understood. Here, we show that the ability of 53BP1 to accumulate around DSBs declines as cells progress through S phase and reveal that the inverse relationship between 53BP1 recruitment and replicated chromatin is linked to the replication-coupled dilution of 53BP1's target mark H4K20me2. Consistently, premature maturation of post-replicative chromatin restores H4K20me2 and rescues 53BP1 accumulation on replicated chromatin. The H4K20me2-mediated chromatin association of 53BP1 thus represents an inbuilt mechanism to distinguish DSBs in pre- versus post-replicative chromatin, allowing for localized repair pathway choice decisions based on the availability of replication-generated template strands for HDR.