Regulation of BRCC, a holoenzyme complex containing BRCA1 and BRCA2, by a signalosome-like subunit and its role in DNA repair

Yuanshu Dong; Mohamed Ali Hakimi; Xiaowei Chen; Easwari Kumaraswamy; Neil S. Cooch; Andrew K. Godwin; Ramin Shiekhattar

doi:10.1016/S1097-2765(03)00424-6

Regulation of BRCC, a holoenzyme complex containing BRCA1 and BRCA2, by a signalosome-like subunit and its role in DNA repair

Yuanshu Dong, Mohamed Ali Hakimi, Xiaowei Chen, Easwari Kumaraswamy, Neil S. Cooch, Andrew K. Godwin, Ramin Shiekhattar

Research output: Contribution to journal › Article › peer-review

207 Scopus citations

Abstract

We have isolated a holoenzyme complex termed BRCC containing BRCA1, BRCA2, and RAD51. BRCC not only displays increased association with p53 following DNA damage but also ubiquitinates p53 in vitro. BRCC36 and BRCC45 are novel components of the complex with sequence homology to a subunit of the signalosome and proteasome complexes. Reconstitution of a recombinant four-subunit complex containing BRCA1/BARD1/BRCC45/BRCC36 revealed an enhanced E3 ligase activity compared to that of BRCA1/BARD1 heterodimer. In vivo, depletion of BRCC36 and BRCC45 by the small interfering RNAs (siRNAs) resulted in increased sensitivity to ionizing radiation and defects in G2/M checkpoint. BRCC36 shows aberrant expression in sporadic breast tumors. These findings identify BRCC as a ubiquitin E3 ligase complex that enhances cellular survival following DNA damage.

Original language	English (US)
Pages (from-to)	1087-1099
Number of pages	13
Journal	Molecular Cell
Volume	12
Issue number	5
DOIs	https://doi.org/10.1016/S1097-2765(03)00424-6
State	Published - Nov 2003
Externally published	Yes

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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Regulation of BRCC, a holoenzyme complex containing BRCA1 and BRCA2, by a signalosome-like subunit and its role in DNA repair. / Dong, Yuanshu; Hakimi, Mohamed Ali; Chen, Xiaowei; Kumaraswamy, Easwari; Cooch, Neil S.; Godwin, Andrew K.; Shiekhattar, Ramin.

In: Molecular Cell, Vol. 12, No. 5, 11.2003, p. 1087-1099.

Research output: Contribution to journal › Article › peer-review

@article{4ea5a0ace9ce4c52875fd40429519239,

title = "Regulation of BRCC, a holoenzyme complex containing BRCA1 and BRCA2, by a signalosome-like subunit and its role in DNA repair",

abstract = "We have isolated a holoenzyme complex termed BRCC containing BRCA1, BRCA2, and RAD51. BRCC not only displays increased association with p53 following DNA damage but also ubiquitinates p53 in vitro. BRCC36 and BRCC45 are novel components of the complex with sequence homology to a subunit of the signalosome and proteasome complexes. Reconstitution of a recombinant four-subunit complex containing BRCA1/BARD1/BRCC45/BRCC36 revealed an enhanced E3 ligase activity compared to that of BRCA1/BARD1 heterodimer. In vivo, depletion of BRCC36 and BRCC45 by the small interfering RNAs (siRNAs) resulted in increased sensitivity to ionizing radiation and defects in G2/M checkpoint. BRCC36 shows aberrant expression in sporadic breast tumors. These findings identify BRCC as a ubiquitin E3 ligase complex that enhances cellular survival following DNA damage.",

author = "Yuanshu Dong and Hakimi, {Mohamed Ali} and Xiaowei Chen and Easwari Kumaraswamy and Cooch, {Neil S.} and Godwin, {Andrew K.} and Ramin Shiekhattar",

note = "Funding Information: Thanks to Drs. Joan W. Conaway for plasmids encoding E2s and Junjie Chen and David Livingston for the BARD1 antibodies. Also, many thanks to Z.Q. Pan for the gift of plasmids to BRCA1 and BARD1 and Ricard Baer for the gift of viruses encoding BRCA1 and BARD1. We thank T. Beer of the Wistar Proteomics Facility for expertise in the microcapillary HPLC/mass spectrometry. Thanks to J. Norman, D. Bochar, O. Barak, and T. Halazonetis for critical comments. Also, thanks to D. Cvetkovic for the great help in LCM. R.S. was supported by grants from NIH (CA90758-02), ACS, USAMRMC, and the Breast Cancer Research Foundation (BCRF). A.K.G. was supported in part by a grant from the NIH (Ovarian Cancer SPORE P50 CA83638) and the USAMRMC (DAMD17-01-1-0521). X.C. was supported by a postdoctoral fellowship from the Eileen-Stein Jacoby Fund. M.-A.H. was supported by a postdoctoral fellowship from the Association pour la Recherche Sur le Cancer (France). ",

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doi = "10.1016/S1097-2765(03)00424-6",

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T1 - Regulation of BRCC, a holoenzyme complex containing BRCA1 and BRCA2, by a signalosome-like subunit and its role in DNA repair

AU - Dong, Yuanshu

AU - Hakimi, Mohamed Ali

AU - Chen, Xiaowei

AU - Kumaraswamy, Easwari

AU - Cooch, Neil S.

AU - Godwin, Andrew K.

AU - Shiekhattar, Ramin

N1 - Funding Information: Thanks to Drs. Joan W. Conaway for plasmids encoding E2s and Junjie Chen and David Livingston for the BARD1 antibodies. Also, many thanks to Z.Q. Pan for the gift of plasmids to BRCA1 and BARD1 and Ricard Baer for the gift of viruses encoding BRCA1 and BARD1. We thank T. Beer of the Wistar Proteomics Facility for expertise in the microcapillary HPLC/mass spectrometry. Thanks to J. Norman, D. Bochar, O. Barak, and T. Halazonetis for critical comments. Also, thanks to D. Cvetkovic for the great help in LCM. R.S. was supported by grants from NIH (CA90758-02), ACS, USAMRMC, and the Breast Cancer Research Foundation (BCRF). A.K.G. was supported in part by a grant from the NIH (Ovarian Cancer SPORE P50 CA83638) and the USAMRMC (DAMD17-01-1-0521). X.C. was supported by a postdoctoral fellowship from the Eileen-Stein Jacoby Fund. M.-A.H. was supported by a postdoctoral fellowship from the Association pour la Recherche Sur le Cancer (France).

PY - 2003/11

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N2 - We have isolated a holoenzyme complex termed BRCC containing BRCA1, BRCA2, and RAD51. BRCC not only displays increased association with p53 following DNA damage but also ubiquitinates p53 in vitro. BRCC36 and BRCC45 are novel components of the complex with sequence homology to a subunit of the signalosome and proteasome complexes. Reconstitution of a recombinant four-subunit complex containing BRCA1/BARD1/BRCC45/BRCC36 revealed an enhanced E3 ligase activity compared to that of BRCA1/BARD1 heterodimer. In vivo, depletion of BRCC36 and BRCC45 by the small interfering RNAs (siRNAs) resulted in increased sensitivity to ionizing radiation and defects in G2/M checkpoint. BRCC36 shows aberrant expression in sporadic breast tumors. These findings identify BRCC as a ubiquitin E3 ligase complex that enhances cellular survival following DNA damage.

AB - We have isolated a holoenzyme complex termed BRCC containing BRCA1, BRCA2, and RAD51. BRCC not only displays increased association with p53 following DNA damage but also ubiquitinates p53 in vitro. BRCC36 and BRCC45 are novel components of the complex with sequence homology to a subunit of the signalosome and proteasome complexes. Reconstitution of a recombinant four-subunit complex containing BRCA1/BARD1/BRCC45/BRCC36 revealed an enhanced E3 ligase activity compared to that of BRCA1/BARD1 heterodimer. In vivo, depletion of BRCC36 and BRCC45 by the small interfering RNAs (siRNAs) resulted in increased sensitivity to ionizing radiation and defects in G2/M checkpoint. BRCC36 shows aberrant expression in sporadic breast tumors. These findings identify BRCC as a ubiquitin E3 ligase complex that enhances cellular survival following DNA damage.

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