H4K20me0 recognition by BRCA1-BARD1 directs homologous recombination to sister chromatids

Kyosuke Nakamura, Giulia Saredi, Jordan R. Becker, Benjamin M. Foster, Nhuong V. Nguyen, Tracey E. Beyer, Laura C. Cesa, Peter A. Faull, Saulius Lukauskas, Thomas Frimurer, J. Ross Chapman, Till Bartke (Lead / Corresponding author), Anja Groth (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

28 Citations (Scopus)

Abstract

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. 2-5), 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.

Original languageEnglish
Pages (from-to)311-318
Number of pages8
JournalNature Cell Biology
Volume21
Issue number3
DOIs
Publication statusPublished - 2019

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