Screening and analyses of novel BRCA1/2-associated proteins

2010 Fiscal Year Final Research Report

• Project/Area Number: 21790311
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Pathological medical chemistry
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: TAKENAKA Katsuya Tokyo Medical and Dental University, 難治疾患研究所, 助教 (20378706)
• Project Period (FY): 2009 – 2010
• Keywords: 分子腫瘍学

Research Abstract

BRCA2 germline mutations account for the majority of heredity breast and ovarian cancer. Besides its role in DNA damage repair, it was hypothesized that BRCA2 might have a role in centrosomal amplification, since BRCA2 localizes to centrosomes as well as nuclei and the dysfunction of BRCA2 in a centrosome causes abnormalities in cell division. We identified nucleophosmin (NPM) and Rho-associated coiled-coil containing protein kinase 2 (ROCK2) as novel BRCA2-associated proteins by mass spectrometry. Because it is known that ROCK2 binds to NPM at centrosomes, these 3 proteins may form a complex. NPM-binding region in BRCA2 was determined to be within amino acids 639-1,000. Exogenous expression of this BRCA2 region resulted in aberrant centrosome amplification and a high frequency of multinucleated cells. Our results suggested that a complex consisting of BRCA2, NPM, and ROCK2 maintains the numerical integrity of centrosomes and accurate cell division and that dysfunction of this regulation might be involved in the tumorigenesis of breast cancer.

Research Products

• [Journal Article] BRCA2 and nucleophosmin coregulate centrosome amplification and form a complex with ROCK2. (2010)
  • Author(s): Hui-Feng Wang, Katsuya Takenaka, Akira Nakanishi, Yoshio Miki.
  • Journal Title: Cancer Research 71 Pages: 68-77
  • Peer Reviewed
• [Journal Article] Three DNA polymerases, recruited by different mechanisms, carry out NER repair synthesis in human cells. (2010)
  • Author(s): Tomoo Ogi, Siripan Limsirichaikul^+, Ren M.Overmeer^+, Marcel Volker^+, Katsuya Takenaka^+, Ross Cloney^+, Yuka Nakazawa^+, Atsuko Niimi, Yoshio Miki, Nicolaas G.Jaspers, Leon H.F.Mullenders, Shunichi Yamashita, Maria I.Fousteri, Alan R.Lehmann.
  • Journal Title: Molecular Cell 37 Pages: 714-727
  • Peer Reviewed
• [Journal Article] PTIP promotes DNA double-strand break repair through homologous recombination. (2010)
  • Author(s): Xin Wang, Katsuya Takenaka, Shunichi Takeda.
  • Journal Title: Genes to Cells 15 Pages: 243-254
  • Peer Reviewed
• [Journal Article] Introduction and characterization of a polymerase-dead point mutation into the POLK gene in vertebrates. (2009)
  • Author(s): Katsuya, Takenaka, Yoshio Miki.
  • Journal Title: FEBS Letters 583 Pages: 661-664
  • Peer Reviewed
• [Journal Article] Genetic evidence for single-strand lesions initiating Nbs1-dependent homologous recombination in diversification of Ig V in chicken B lymphocytes. (2009)
  • Author(s): Makoto Nakahara, Eiichiro Sonoda, Kuniharu Nojima, Julian E.Sale, Katsuya Takenaka, Koji Kikuchi, Yoshihito Taniguchi, Kyoko Nakamura, Yoshiki Sumitomo, Ronan T.Bree, Noel F.Lowndes, Shunichi Takeda.
  • Journal Title: PLoS Genetics 5 Pages: 1000356
  • Peer Reviewed
• [Presentation] BRCA2 and nucleophosmin coregulate centrosome amplification and form a complex with (2010)
  • Author(s): Katsuya Takenaka, Hui-Feng Wang, Akira Nakanishi, Yoshio Miki.
  • Organizer: ROCK2.BMB2010
  • Place of Presentation: Kobe
  • Year and Date: 20101207-20101210
• [Presentation] BRCA2 and nucleophosmin coregulate centrosome amplification and form a complex with ROCK2. (2010)
  • Author(s): Hui-Feng Wang, Katsuya Takenaka, Akira Nakanishi, Yoshio Miki.
  • Organizer: The Sixth International Symposium on Hormononmonnium on Hormonal Oncogenesis
  • Place of Presentation: Urayasu
  • Year and Date: 20100912-20100916
• [Presentation] Introduction and characterization of a polymerase-dead point mutation into the POLK gene in vertebrates. (2010)
  • Author(s): Katsuya Takenaka, Yoshio Miki.
  • Organizer: International Conference on Radiation and Cancer Biology at Nagasaki 2010
  • Place of Presentation: Nagasaki
  • Year and Date: 20100217-20100220
• [Presentation] Three DNA polymerases, recruited by different mechanisms, carry out NER repair synthesis in human cells. (2010)
  • Author(s): Tomoo Ogi, Siripan Limsirichaikul, Ren M. Overmeer, Marcel Volker, Katsuya Takenaka, Ross Cloney, Yuka Nakazawa, Atsuko Niimi, Yoshio Miki, Nicolaas G., Jaspers, Leon H.F., Mullenders, Shunichi Yamashita, Maria I., Fousteri, Alan R.Lehmann.
  • Organizer: International Conference on Radiation and Cancer Biology at Nagasaki 2010
  • Place of Presentation: Nagasaki
  • Year and Date: 20100217-20100220
• [Presentation] Introduction and characterization of a polymerase-dead point mutation into the POLK gene in vertebrates. (2009)
  • Author(s): Katsuya Takenaka, Yoshio Miki.
  • Organizer: 第32回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 20091209-20091212
• [Presentation] Three DNA polymerases, recruited by different mechanisms, carry out NER repair synthesis in human cells. (2009)
  • Author(s): Tomoo Ogi, Limsirichaikul Siripan, Marcel Volker, Rene Overmeer, Katsuya Takenaka, Ross Cloney, Yuka Nakazawa, Atsuko Niimi, Yoshio Miki, Nicolaas Jaspers, Leon Mullenders, Maria Fousteri, Shunichi Yamashita, Alan Lehmann.
  • Organizer: 第32回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 20091209-20091212
• [Presentation] ゲノム上点変異導入によるPolκ活性中心変異株の作製と解析 (2009)
  • Author(s): 竹中克也, 三木義男
  • Organizer: 第82回日本生化学会大会
  • Place of Presentation: 神戸
  • Year and Date: 20091021-20091024