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Cell Rep. 2014 Aug 21;8(4):999-1005. doi: 10.1016/j.celrep.2014.07.025. Epub 2014 Aug 14.

BRCA1 is a histone-H2A-specific ubiquitin ligase.

Author information

1
Division of Protein Nucleic Acid Chemistry, MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK; Department of Chromatin Research, MPI of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.
2
Division of Protein Nucleic Acid Chemistry, MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK.
3
Division of Cancer Research, Medical Research Institute, Ninewells Hospital & Medical School, Dundee DD1 9SY, Scotland.
4
Biomarker and Drug Analysis Core Facility, Medical Research Institute, Ninewells Hospital & Medical School, Dundee DD1 9SY, Scotland.
5
Division of Protein Nucleic Acid Chemistry, MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK; Division of Cancer Research, Medical Research Institute, Ninewells Hospital & Medical School, Dundee DD1 9SY, Scotland. Electronic address: k.hiom@dundee.ac.uk.

Abstract

The RING domain proteins BRCA1 and BARD1 comprise a heterodimeric ubiquitin (E3) ligase that is required for the accumulation of ubiquitin conjugates at sites of DNA damage and for silencing at DNA satellite repeat regions. Despite its links to chromatin, the substrate and underlying function of the BRCA1/BARD1 ubiquitin ligase remain unclear. Here, we show that BRCA1/BARD1 specifically ubiquitylates histone H2A in its C-terminal tail on lysines 127 and 129 in vitro and in vivo. The specificity for K127-129 is acquired only when H2A is within a nucleosomal context. Moreover, site-specific targeting of the BRCA1/BARD1 RING domains to chromatin is sufficient for H2Aub foci formation in vivo. Our data establish BRCA1/BARD1 as a histone-H2A-specific E3 ligase, helping to explain its localization and activities on chromatin in cells.

PMID:
25131202
PMCID:
PMC4382519
DOI:
10.1016/j.celrep.2014.07.025
[Indexed for MEDLINE]
Free PMC Article

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