BRCA1 is a histone-H2A-specific ubiquitin ligase

Reinhard Kalb; Donna L. Mallery; Conor Larkin; Jeffrey T. J. Huang; Kevin Hiom

doi:10.1016/j.celrep.2014.07.025

BRCA1 is a histone-H2A-specific ubiquitin ligase

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

Biomarker and Drug Analysis Laboratory

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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 language	English
Pages (from-to)	999-1005
Number of pages	7
Journal	Cell Reports
Volume	8
Issue number	4
DOIs	https://doi.org/10.1016/j.celrep.2014.07.025
Publication status	Published - 21 Aug 2014

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10.1016/j.celrep.2014.07.025

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Hiom, Kevin
- Cancer Research - Professor (Teaching and Research)
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title = "BRCA1 is a histone-H2A-specific ubiquitin ligase",

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.",

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AU - Kalb, Reinhard

AU - Mallery, Donna L.

AU - Larkin, Conor

AU - Huang, Jeffrey T. J.

AU - Hiom, Kevin

PY - 2014/8/21

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N2 - 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.

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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DO - 10.1016/j.celrep.2014.07.025

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JO - Cell Reports

JF - Cell Reports

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ER -

BRCA1 is a histone-H2A-specific ubiquitin ligase

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Hiom, Kevin

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