2005 Fiscal Year Final Research Report Summary
Mechanisms that regulate chromosomal stability through the ubiquitin lipase activity of BRCA1
| Project/Area Number |
16591280
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
General surgery
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| Research Institution | St.Marianna University School of Medicine |
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Principal Investigator |
OHTA Tomohiko St.Marianna University School of Medicine, Department of Surgery, Associate Professor, 医学部, 助教授 (60233136)
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| Project Period (FY) |
2004 – 2005
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| Keywords | BRCA1 / BARD1 / familial breast cancer / ubiquitin ligase / RPB8 / RING finger / nucleophosmin |
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| Research Abstract |
I have discovered in 2001 that BRCA1 constituted a RING heterodimer type ubiquitin ligase with BARD1. In this study I further investigated the substrates of BRCA1 to elacidate how the activity contributed the BRCA1's ability to maintain the chromosomal stability. I identified several substrates by our original screen methods. Among them I have investigated nucleophosmin/B23 (NPM) in 2004. BRCA1-BARD1 interacted with and polyubiquitinated NPM in vivo and in vitro. The polyubiquitination was non-traditional Lys-6-linked type, and therefore NPM was not degraded by the modification and instead stabilized. BRCA1-BARD1 and NPM were co-localized over the chromosomal surface during mitosis when NPM was actually ubiquitinated in vivo. I propose the lack of NPM ubiquitination could be the basis of centrosome hyper amplification and aneuploidy caused by BRCA1 deficiency. I next analyzed another candidate substrate, RPB8, in 2005. BRCA1-BARD1 interacted with and polyubiquitinated RPB8 in vivo and in vitro. The ubiquitination of RPB8 was observed 10 minutes after UV irradiation in HeLa cells stably expressing FLAG-tagged RPB8, and this ubiquitination was abolished by BRCA1 knockdown by siRNA. Interestingly HeLa cells stably expressing ubiquitin-resistant RPB8 mutant exhibited UV hypersensitivity. The results suggested that BRCA1 regulates chromosomal stability by transcription-coupled DNA repair through ubiquitination of RPB8.
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Research Products
(14 results)
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[Journal Article] A FancD2-monoubiquitin fusion reveals hidden functions of Fanconi anemia core complex in DNA repair.2005
Author(s)
Matsushita N, Kitao H, Ishiai M, Nagashima N, Hirano S, Okawa K, Ohta T, Yu DS, McHugh PJ, Hickson ID, Venkitaraman AR, Kurumizaka H, Takata M.
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Journal Title
Mol Cell. 19(6)
Pages: 841-847
Description
「研究成果報告書概要(欧文)」より
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