Human Molecular Genetics Advance Access originally published online on February 19, 2004
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Human Molecular Genetics, 2004, Vol. 13, No. 8 807-817
DOI: 10.1093/hmg/ddh095
Human Molecular Genetics, Vol. 13, No. 8 © Oxford University Press 2004; all rights reserved
BRCA1 : BARD1 induces the formation of conjugated ubiquitin structures, dependent on K6 of ubiquitin, in cells during DNA replication and repair
Cancer Genetics Laboratory, Department of Medical and Molecular Genetics, Division of Genetics and Development, Guy's Kings and St Thomas' School of Medicine, King's College London, 8th Floor Guy's Tower, Guy's Hospital, St Thomas' Street, London SE1 9RT, UK
Received December 4, 2003; Revised January 22, 2004; Accepted February 6, 2004
The N-terminus of the BRCA1 protein bears a RING finger domain that functions as an E3 ubiquitin ligase in vitro where it is able to catalyse the synthesis of monoubiquitin and polyubiquitin targeted proteins. This activity is greatly increased when BRCA1 is in a complex with its N-terminal binding partner BARD1. In this report we use an immunohistochemical approach to demonstrate the association of cellular BRCA1 with the end product of the ubiquitin conjugation and ligation pathway, conjugated ubiquitin. Association is apparent at DNA replication structures in S-phase and following treatment with hydroxyurea and also at sites of double strand break repair after exposure to ionizing radiation. Down-regulation of endogenous, cellular BRCA1 : BARD1 using siRNA results in abrogation of ubiquitin conjugation in these structures, suggesting that heterodimer activity is required for their formation. Conversely, ectopically expressed full-length BRCA1, but not BRCA1 bearing specific N-terminal amino acid substitutions, is able to cooperate with BARD1 to increase ubiquitin conjugation in cells. Conjugation of ubiquitin in foci is inhibited by the expression of ubiquitin bearing a lysine 6 mutation suggesting that the ubiquitin polymers formed at these sites are dependent on lysine-6 for linkage. Together these data demonstrate that BRCA1 directed ligation of ubiquitin occurs during S-phase and in response to replication stress and DNA damage and is therefore likely to be a significant aspect of BRCA1 cellular activity.
* To whom correspondence should be addressed. Tel: +44 2079555000, ext. 5585/2520; Fax: +44 2079558762; Email: joanna.morris{at}kcl.ac.uk
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  L. Postow, C. Ghenoiu, E. M. Woo, A. N. Krutchinsky, B. T. Chait, and H. Funabiki Ku80 removal from DNA through double strand break-induced ubiquitylation J. Cell Biol., August 11, 2008; 182(3): 467 - 479. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. D. Beck, S.-J. Park, Y.-J. Lee, Y. Roman, R. A. Hromas, and S.-H. Lee Human Pso4 Is a Metnase (SETMAR)-binding Partner That Regulates Metnase Function in DNA Repair J. Biol. Chem., April 4, 2008; 283(14): 9023 - 9030. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Laufer, S. V. Nandula, A. P. Modi, S. Wang, M. Jasin, V. V. V. S. Murty, T. Ludwig, and R. Baer Structural Requirements for the BARD1 Tumor Suppressor in Chromosomal Stability and Homology-directed DNA Repair J. Biol. Chem., November 23, 2007; 282(47): 34325 - 34333. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Murakawa, E. Sonoda, L. J. Barber, W. Zeng, K. Yokomori, H. Kimura, A. Niimi, A. Lehmann, G. Y. Zhao, H. Hochegger, et al. Inhibitors of the Proteasome Suppress Homologous DNA Recombination in Mammalian Cells Cancer Res., September 15, 2007; 67(18): 8536 - 8543. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. Bish and M. P. Myers Werner Helicase-interacting Protein 1 Binds Polyubiquitin via Its Zinc Finger Domain J. Biol. Chem., August 10, 2007; 282(32): 23184 - 23193. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Tembe and B. R. Henderson BARD1 Translocation to Mitochondria Correlates with Bax Oligomerization, Loss of Mitochondrial Membrane Potential, and Apoptosis J. Biol. Chem., July 13, 2007; 282(28): 20513 - 20522. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Sobhian, G. Shao, D. R. Lilli, A. C. Culhane, L. A. Moreau, B. Xia, D. M. Livingston, and R. A. Greenberg RAP80 Targets BRCA1 to Specific Ubiquitin Structures at DNA Damage Sites Science, May 25, 2007; 316(5828): 1198 - 1202. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Dreher and J. Callis Ubiquitin, Hormones and Biotic Stress in Plants Ann. Bot., May 1, 2007; 99(5): 787 - 822. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Lu, A. Amleh, J. Sun, X. Jin, S. D. McCullough, R. Baer, D. Ren, R. Li, and Y. Hu Ubiquitination and Proteasome-Mediated Degradation of BRCA1 and BARD1 during Steroidogenesis in Human Ovarian Granulosa Cells Mol. Endocrinol., March 1, 2007; 21(3): 651 - 663. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Wu, H. Nishikawa, R. Hayami, K. Sato, A. Honda, S. Aratani, T. Nakajima, M. Fukuda, and T. Ohta BRCA1 Ubiquitinates RPB8 in Response to DNA Damage Cancer Res., February 1, 2007; 67(3): 951 - 958. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Chen, A. K. Seth, and A. E. Aplin Genetic and Expression Aberrations of E3 Ubiquitin Ligases in Human Breast Cancer Mol. Cancer Res., October 1, 2006; 4(10): 695 - 707. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. E. Malone, J. R. Daling, D. R. Doody, L. Hsu, L. Bernstein, R. J. Coates, P. A. Marchbanks, M. S. Simon, J. A. McDonald, S. A. Norman, et al. Prevalence and Predictors of BRCA1 and BRCA2 Mutations in a Population-Based Study of Breast Cancer in White and Black American Women Ages 35 to 64 Years Cancer Res., August 15, 2006; 66(16): 8297 - 8308. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Yu, S. Fu, M. Lai, R. Baer, and J. Chen BRCA1 ubiquitinates its phosphorylation-dependent binding partner CtIP. Genes & Dev., July 1, 2006; 20(13): 1721 - 1726. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. E. Cohen, S. E. Pollack, and J. W. Pollard Genetic Analysis of Chromosome Pairing, Recombination, and Cell Cycle Control during First Meiotic Prophase in Mammals Endocr. Rev., June 1, 2006; 27(4): 398 - 426. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. R. Morris, L. Pangon, C. Boutell, T. Katagiri, N. H. Keep, and E. Solomon Genetic analysis of BRCA1 ubiquitin ligase activity and its relationship to breast cancer susceptibility Hum. Mol. Genet., February 15, 2006; 15(4): 599 - 606. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Simons, A. A. Horwitz, L. M. Starita, K. Griffin, R. S. Williams, J.N. M. Glover, and J. D. Parvin BRCA1 DNA-Binding Activity Is Stimulated by BARD1 Cancer Res., February 15, 2006; 66(4): 2012 - 2018. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M K Sauer and I L Andrulis Identification and characterization of missense alterations in the BRCA1 associated RING domain (BARD1) gene in breast and ovarian cancer J. Med. Genet., August 1, 2005; 42(8): 633 - 638. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Shang, G. Deng, Q. Liu, W. Guo, A. L. Haas, B. Crosas, D. Finley, and A. Taylor Lys6-modified Ubiquitin Inhibits Ubiquitin-dependent Protein Degradation J. Biol. Chem., May 27, 2005; 280(21): 20365 - 20374. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Schuchner, V. Tembe, J. A. Rodriguez, and B. R. Henderson Nuclear Targeting and Cell Cycle Regulatory Function of Human BARD1 J. Biol. Chem., March 11, 2005; 280(10): 8855 - 8861. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Hayami, K. Sato, W. Wu, T. Nishikawa, J. Hiroi, R. Ohtani-Kaneko, M. Fukuda, and T. Ohta Down-regulation of BRCA1-BARD1 Ubiquitin Ligase by CDK2 Cancer Res., January 1, 2005; 65(1): 6 - 10. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. D. Choudhury, H. Xu, and R. Baer Ubiquitination and Proteasomal Degradation of the BRCA1 Tumor Suppressor Is Regulated during Cell Cycle Progression J. Biol. Chem., August 6, 2004; 279(32): 33909 - 33918. [Abstract] [Full Text] [PDF]
|
|