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BRCA1 is a histone-H2A-specific ubiquitin ligase
Reinhard Kalb1, Donna L Mallery2, Conor Larkin3
1Division 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.
Cell Reports
|August 19, 2014
Summary
The BRCA1/BARD1 E3 ligase specifically targets histone H2A on chromatin, ubiquitylating it at specific sites. This finding clarifies the ligase
Area of Science:
- Biochemistry
- Molecular Biology
- Epigenetics
Background:
- The BRCA1/BARD1 complex functions as a heterodimeric E3 ubiquitin ligase.
- Its role in DNA damage response and chromatin silencing is known, but its specific substrate and function on chromatin remain elusive.
Purpose of the Study:
- To identify the specific substrate and chromatin-related function of the BRCA1/BARD1 E3 ligase.
Main Methods:
- In vitro and in vivo ubiquitylation assays using purified proteins and cell models.
- Site-specific mutation of histone H2A.
- Targeting of BRCA1/BARD1 RING domains to chromatin.
Main Results:
- BRCA1/BARD1 specifically ubiquitylates histone H2A at lysines 127 and 129.
- This ubiquitylation is dependent on the nucleosomal context of histone H2A.
- Targeting BRCA1/BARD1 to chromatin induces histone H2A ubiquitylation foci in vivo.
Conclusions:
- BRCA1/BARD1 is identified as a histone H2A-specific E3 ligase.
- This activity explains the ligase's localization and function within chromatin.
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