Dept. Cancer Biology
|Professor||Natsuko Chiba, M.D., Ph.D.|
|Assistant Professor||Yuki YOSHINO, M.D., Ph.D.|
|Technical Assistant||Satoko Aoki|
|Secretarial Assistant||Yukiko Komiya|
Germline mutations in Breast cancer associated gene 1 (BRCA1) predispose women to breast and ovarian cancers. BRCA1 is involved in many cellular processes, including DNA repair and centrosome regulation. Defects in the regulatory mechanisms of centrosome and DNA repair result in defective mitoses, chromosome segregation errors, and the accumulation of DNA damage. These are significant sources of genome instability, a hallmark of cancer.
Although the functions of BRCA1 in DNA repair pathway have been extensively studied, the mechanism of centrosome/mitotic regulation by BRCA1 is largely unknown. Recently, we identified a novel BRCA1-related protein, Obg–like ATPase 1 (OLA1), which functions in centrosome regulation together with BRCA1. The breast cancer-derived OLA1 mutation does not bind to BRCA1 and fails to rescue the OLA1 knockdown-induced centrosome amplification. The familial breast cancer-derived BRCA1 mutation I42V abrogates the binding of BRCA1 to OLA1.
To analyze the further functions of BRCA1 and its related proteins, we perform cytological analyses, analyses using genetically modified mice, and analyses of clinical specimen. These researches will contribute to the further understanding the carcinogenesis and developing the novel cancer therapy.
- Matsuzawa A, Kanno S, Nakayama M, Mochiduki H, Wei L, Shimaoka T, Furukawa Y, Kato K, Shibata S, Yasui A, Ishioka C, and Chiba N. The BRCA1/BARD1-interacting protein OLA1 functions in centrosome regulation. Molecular Cell, 53,101-104, 2014
- Towler W I, Zhang J, Ransburgh D, Toland A, Ishioka C, Chiba N, and Parvin J D. Analysis of BRCA1 variants in double strand break repair by homologous recombination and single strand annealing. Human Mutation, 34(3): 439-445, 2013
- Kais Z, Chiba N, Ishioka C, Parvin J D. Functional differences among BRCA1 missense mutations in the control of centrosome duplication. Oncogene, 31(6): 799-804 2012
- Wei L, Lan L, Yasui A, Tanaka K, Saijo M, Matsuzawa A, Kashiwagi R, Maseki E, Hu Y, Parvin J D, Ishioka C and Chiba N. BRCA1 contributes to transcription-coupled repair of DNA damage through polyubiquitination and degradation of Cockayne syndrome B protein. Cancer Science, 102(10): 1840-1847, 2011
- Parvin J D, Chiba N, and Ransburgh D. Identifying the effect of BRCA1 mutations on homologous recombination using cells that express endogenous wild-type BRCA1. J. Vis. Exp., 48: pii: 2468, 2011
- Ransburgh D*, Chiba N*, Ishioka C, Toland A, and Parvin J D. (*co-first author) Identification of breast tumor mutations in BRCA1 that abolish its function in homologous DNA recombination. Cancer Res., 70(3): 988-995, 2010
- Wei L, Lan L, Hong Z, Yasui A, Ishioka C, and Chiba N. Rapid recruitment of BRCA1 to DNA double-strand breaks is dependent on its association with Ku80. Mol. Cell. Biol. 28(24);7380-93, 2008
- Starita L M, Howitz A A, Keogh M-C, Ishioka C, Parvin J D, and Chiba N. BRCA1/BARD1 ubiquitinate phosphorylated RNA polymerase II. J Biol Chem. 280(26):24498-505, 2005
- You F, Chiba N, Ishioka, C, and Parvin, J D. Expresssion of an amino-terminal BRCA1 deletion mutant causes a dominant growth inhibition in MCF10A cells. Oncogene. 23(34):5792-8, 2004
- Chiba N, and Parvin J D. The BRCA1 and BARD1 association with the RNA polymerase II holoenzyme. Cancer Res. 62:4222-28, 2002.
- Chiba N, and Parvin J D. Redistribution of BRCA1 among four different protein complexes following replication blockage. J Biol Chem. 276(42):38549-54, 2001