Genotoxic DNA double-strand breaks (DSBs) can be repaired by error-free homologous recombination (HR) or mutagenic non-homologous end-joining1. HR supresses tumorigenesis1, but is restricted to the S and G2 phases of the cell cycle when a sister chromatid is present2. Breast cancer type 1 susceptibility protein (BRCA1) promotes HR by antagonizing the anti-resection factor TP53-binding protein 1(53BP1) (refs. 2,3,4,5), but it remains unknown how BRCA1 function is limited to the S and G2 phases. We show that BRCA1 recruitment requires recognition of histone H4 unmethylated at lysine 20 (H4K20me0), linking DSB repair pathway choice directly to sister chromatid availability. We identify the ankyrin repeat domain of BRCA1-associated RING domain protein 1 (BARD1)—the obligate BRCA1 binding partner3—as a reader of H4K20me0 present on new histones in post-replicative chromatin6. BARD1 ankyrin repeat domain mutations disabling H4K20me0 recognition abrogate accumulation of BRCA1 at DSBs, causing aberrant build-up of 53BP1, and allowing anti-resection activity to prevail in S and G2. Consequently, BARD1 recognition of H4K20me0 is required for HR and resistance to poly (ADP-ribose) polymerase inhibitors. Collectively, this reveals that BRCA1–BARD1 monitors the replicative state of the genome to oppose 53BP1 function, routing only DSBs within sister chromatids to HR.
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The code used to analyse the mass spectrometry data is publicly available at GitHub (https://github.com/lukauskas/publications-nakamura-2018-snap-h4k20me2).
The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD009281, and are presented in Supplementary Table 1. Unprocessed images of all gels and blots (Figs. 1c,d and 5a,c and Supplementary Fig. 2h) are provided in Supplementary Fig. 5. Source data for all graphs are provided in Supplementary Table 2. All other data supporting the findings of this study are available from the corresponding authors on reasonable request.
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We thank J. Lukas for commenting on the manuscript, researchers at the Groth laboratory for fruitful discussions, R. Baer for sharing the BARD1 plasmid and BARD1-null mouse mammary carcinoma cells, M. Kanemaki for the OsTIR1 antibody, Y. Antoku for assistance with microscopy, and J. V. Johansen for help with statistical analysis. J.R.B. is funded by a Cancer Research UK Career Development Grant (C52690/A19270). Funding for T.B. was provided by the Medical Research Council (grant number MC_UP_1102/2) and European Research Council (ERC StG number 309952). S.L. was supported by a stipend from the Biotechnology and Biological Sciences Research Council. The Groth laboratory is supported by the Danish Cancer Society, Novo Nordisk Foundation, Lundbeck Foundation, European Research Council (ERC CoG number 724436), Independent Research Fund Denmark and Neye Foundation.