BRCA1 is a histone-H2A-specific ubiquitin ligase

Reinhard Kalb, Donna L. Mallery, Conor Larkin, Jeffrey T. J. Huang, Kevin Hiom (Lead / Corresponding author)

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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.
Original languageEnglish
Pages (from-to)999-1005
Number of pages7
JournalCell Reports
Volume8
Issue number4
DOIs
Publication statusPublished - 21 Aug 2014

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Ligases
Ubiquitin
Histones
Chromatin
Ubiquitin-Protein Ligases
BRCA1 Protein
Satellite DNA
DNA Damage
DNA
Substrates

Cite this

Kalb, Reinhard ; Mallery, Donna L. ; Larkin, Conor ; Huang, Jeffrey T. J. ; Hiom, Kevin. / BRCA1 is a histone-H2A-specific ubiquitin ligase. In: Cell Reports. 2014 ; Vol. 8, No. 4. pp. 999-1005.
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BRCA1 is a histone-H2A-specific ubiquitin ligase. / Kalb, Reinhard; Mallery, Donna L.; Larkin, Conor; Huang, Jeffrey T. J.; Hiom, Kevin (Lead / Corresponding author).

In: Cell Reports, Vol. 8, No. 4, 21.08.2014, p. 999-1005.

Research output: Contribution to journalArticle

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AB - 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.

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