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Nakamura, K.* ; Saredi, G.* ; Becker, J.R.* ; Foster, B. ; Nguyen, N.V.* ; Beyer, T.E.* ; Cesa, L.C.* ; Faull, P.A.* ; Lukauskas, S. ; Frimurer, T.* ; Chapman, J.R.* ; Bartke, T. ; Groth, A.*

H4K20meO recognition by BRCA1-BARD1 directs homologous recombination to sister chromatids.

Nat. Cell Biol. 21, 311-318 (2019)
Postprint DOI PMC
Open Access Green
Genotoxic DNA double-strand breaks (DSBs) can be repaired by error-free homologous recombination (HR) or mutagenic non-homologous end-joining(1). HR supresses tumorigenesis(1), but is restricted to the S and G2 phases of the cell cycle when a sister chromatid is present(2). 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 (H4K2OmeO), 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 partner(3)-as a reader of H4K2OmeO present on new histones in post-replicative chromatin(6). BARD1 ankyrin repeat domain mutations disabling H4K2OmeO 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 H4K2OmeO 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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Post-replicative Chromatin; Dna-damage; Structural Basis; Repair; 53bp1; Brca1; Suppression; Stability; Resection; Complex
ISSN (print) / ISBN 1465-7392
e-ISSN 1476-4679
Zeitschrift Nature Cell Biology
Quellenangaben Band: 21, Heft: 3, Seiten: 311-318 Artikelnummer: , Supplement: ,
Verlag Nature Publishing Group
Verlagsort Macmillan Building, 4 Crinan St, London N1 9xw, England
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Functional Epigenetics (IFE)