BRCA1 Is a Histone-H2A-Specific Ubiquitin Ligase

• BRCA1/BARD1 is a histone-H2A-specific ubiquitin ligase
• BRCA1/BARD1 ubiquitylates histone H2A on lysines 127 and 129
• Specificity for H2A is provided within in a nucleosomal context
• Heterodimeric RING domains of BRCA1/BARD1 are sufficient for E3 function in vivo

SummaryThe 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.

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