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

[1] Recognition of UbcH5c and the nucleosome by the Bmi1/Ring1b ubiquitin ligase complex [J].

Bentley, Matthew L. ;

Corn, Jacob E. ;

Dong, Ken C. ;

Phung, Qui ;

Cheung, Tommy K. ;

Cochran, Andrea G. .

EMBO JOURNAL, 2011, 30 (16) :3285-3297

[2] A UbcH5/ubiquitin noncovalent complex is required for processive BRCA1-directed ubiquitination [J].

Brzovic, PS ;

Lissounov, A ;

Christensen, DE ;

Hoyt, DW ;

Klevit, RE .

MOLECULAR CELL, 2006, 21 (06) :873-880

[3] Structure of a BRCA1-BARD1 heterodimeric RING-RING complex [J].

Brzovic, PS ;

Rajagopal, P ;

Hoyt, DW ;

King, MC ;

Klevit, RE .

NATURE STRUCTURAL BIOLOGY, 2001, 8 (10) :833-837

[4] Structure and E3-ligase activity of the Ring-Ring complex of polycomb proteins Bmi1 and Ring1b [J].

Buchwald, Gretel ;

van der Stoop, Petra ;

Weichenrieder, Oliver ;

Perrakis, Anastassis ;

van Lohuizen, Maarten ;

Sixma, Titia K. .

EMBO JOURNAL, 2006, 25 (11) :2465-2474

[5] Molecular Insights into the Function of RING Finger (RNF)-containing Proteins hRNF8 and hRNF168 in Ubc13/Mms2-dependent Ubiquitylation [J].

Campbell, Stephen J. ;

Edwards, Ross A. ;

Leung, Charles C. Y. ;

Neculai, Dante ;

Hodge, Curtis D. ;

Dhe-Paganon, Sirano ;

Glover, J. N. Mark .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2012, 287 (28) :23900-23910

[6] Autoubiquitination of the BRCA1-BARD1 RING ubiquitin ligase [J].

Chen, A ;

Kleiman, FE ;

Manley, JL ;

Ouchi, T ;

Pan, ZQ .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (24) :22085-22092

[7] E2-BRCA1 RING interactions dictate synthesis of mono- or specific polyubiquitin chain linkages [J].

Christensen, Devin E. ;

Brzovic, Peter S. ;

Klevit, Rachel E. .

NATURE STRUCTURAL & MOLECULAR BIOLOGY, 2007, 14 (10) :941-948

[8] The BRCA1-RAP80 Complex Regulates DNA Repair Mechanism Utilization by Restricting End Resection [J].

Coleman, Kara A. ;

Greenberg, Roger A. .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2011, 286 (15) :13669-13680

[9] RNF168 Binds and Amplifies Ubiquitin Conjugates on Damaged Chromosomes to Allow Accumulation of Repair Proteins [J].

Doil, Carsten ;

Mailand, Niels ;

Bekker-Jensen, Simon ;

Menard, Patrice ;

Larsen, Dorthe Helena ;

Pepperkok, Rainer ;

Ellenberg, Jan ;

Panier, Stephanie ;

Durocher, Daniel ;

Bartek, Jiri ;

Lukas, Jiri ;

Lukas, Claudia .

CELL, 2009, 136 (03) :435-446

[10] A phosphorylated form of mel-18 targets the Ring1B histone H2A ubliquitin ligase to chromatin [J].

Elderkin, Sarah ;

Maertens, Goedele N. ;

Endoh, Mitsuhiro ;

Mallery, Donna L. ;

Morrice, Nick ;

Koseki, Haruhiko ;

Peters, Gordon ;

Brockdorff, Neil ;

Hiom, Kevin .

MOLECULAR CELL, 2007, 28 (01) :107-120

← 1 2 3 →