BRCA1 Is a Histone-H2A-Specific Ubiquitin Ligase

被引：131

作者：

Kalb, Reinhard ^{[1
,2
]}

Mallery, Donna L. ^{[1
]}

Larkin, Conor ^{[3
]}

Huang, Jeffrey T. J. ^{[4
]}

Hiom, Kevin ^{[1
,3
]}

机构：

[1] MRC, Mol Biol Lab, Div Prot Nucl Acid Chem, Cambridge CB2 0QH, England

[2] Max Planck Inst Biochem, Dept Chromatin Res, D-82152 Martinsried, Germany

[3] Ninewells Hosp & Med Sch, Med Res Inst, Div Canc Res, Dundee DD1 9SY, Scotland

[4] Ninewells Hosp & Med Sch, Med Res Inst, Biomarker & Drug Anal Core Facil, Dundee DD1 9SY, Scotland

来源：

CELL REPORTS | 2014年 / 8卷 / 04期

基金：

英国医学研究理事会;

关键词：

RING-RING COMPLEX; HISTONE H2A; DNA-DAMAGE; BRCA1-BARD1; REPAIR; CHROMATIN; PROTEINS; NUCLEOSOME; BINDING;

D O I：

10.1016/j.celrep.2014.07.025

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：999 / 1005

页数：7

共 30 条

[21] E3 ligase activity of BRCA1 is not essential for mammalian cell viability or homology-directed repair of double-strand DNA breaks [J].

Reid, Latarsha J. ;

Shakya, Reena ;

Modi, Ami P. ;

Lokshin, Maria ;

Cheng, Jiin-Tsuey ;

Jasin, Maria ;

Baer, Richard ;

Ludwig, Thomas .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2008, 105 (52) :20876-20881

[22] Cancer-predisposing mutations within the RING domain of BRCA1: Loss of ubiquitin protein ligase activity and protection from radiation hypersensitivity [J].

Ruffner, H ;

Joazeiro, CAP ;

Hemmati, D ;

Hunter, T ;

Verma, IM .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2001, 98 (09) :5134-5139

[23] BRCA1 Tumor Suppression Depends on BRCT Phosphoprotein Binding, But Not Its E3 Ligase Activity [J].

Shakya, Reena ;

Reid, Latarsha J. ;

Reczek, Colleen R. ;

Cole, Francesca ;

Egli, Dieter ;

Lin, Chyuan-Sheng ;

deRooij, Dirk G. ;

Hirsch, Steffen ;

Ravi, Kandasamy ;

Hicks, James B. ;

Szabolcs, Matthias ;

Jasin, Maria ;

Baer, Richard ;

Ludwig, Thomas .

SCIENCE, 2011, 334 (6055) :525-528

[24] The RIDDLE Syndrome Protein Mediates a Ubiquitin-Dependent Signaling Cascade at Sites of DNA Damage [J].

Stewart, Grant S. ;

Panier, Stephanie ;

Townsend, Kelly ;

Al-Hakim, Abdallah K. ;

Kolas, Nadine K. ;

Miller, Edward S. ;

Nakada, Shinichiro ;

Ylanko, Jarkko ;

Olivarius, Signe ;

Mendez, Megan ;

Oldreive, Ceri ;

Wildenhain, Jan ;

Tagliaferro, Andrea ;

Pelletier, Laurence ;

Taubenheim, Nadine ;

Durandy, Anne ;

Byrd, Philip J. ;

Stankovic, Tatjana ;

Taylor, A. Malcolm R. ;

Durocher, Daniel .

CELL, 2009, 136 (03) :420-434

[25] SIZE-DEPENDENCE OF A STABLE HIGHER-ORDER STRUCTURE OF CHROMATIN [J].

THOMAS, JO ;

BUTLER, PJG .

JOURNAL OF MOLECULAR BIOLOGY, 1980, 144 (01) :89-93

[26]

Venkitaraman AR, 2001, J CELL SCI, V114, P3591

[27] Role of histone H2A ubiquitination in polycomb silencing [J].

Wang, HB ;

Wang, LJ ;

Erdjument-Bromage, H ;

Vidal, M ;

Tempst, P ;

Jones, RS ;

Zhang, Y .

NATURE, 2004, 431 (7010) :873-878

[28] Identification of a RING protein that can interact in vivo with the BRCA1 gene product [J].

Wu, LJC ;

Wang, ZW ;

Tsan, JT ;

Spillman, MA ;

Phung, A ;

Xu, XL ;

Yang, MCW ;

Hwang, LY ;

Bowcock, AM ;

Baer, R .

NATURE GENETICS, 1996, 14 (04) :430-440

[29] Involvement of Brca1 in S-phase and G2-phase checkpoints after ionizing irradiation [J].

Xu, B ;

Kim, ST ;

Kastan, MB .

MOLECULAR AND CELLULAR BIOLOGY, 2001, 21 (10) :3445-3450

[30] BRCA1 tumour suppression occurs via heterochromatin-mediated silencing [J].

Zhu, Quan ;

Pao, Gerald M. ;

Huynh, Alexis M. ;

Suh, Hoonkyo ;

Tonnu, Nina ;

Nederlof, Petra M. ;

Gage, Fred H. ;

Verma, Inder M. .

NATURE, 2011, 477 (7363) :179-U76

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