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 - Radiation Biology Center
Late Effects Studies (Laboratory of DNA Damage Signaling)
Human genome is under constant threat of DNA damage inflicted by exogenous (i.e. ionizing irradiation) or endogenous (i.e. oxygen radical) agents. All cells are equipped with DNA damage signaling network to cope with this. We are studying molecular mechanisms in the hereditary disorders, such as Fanconi anemia or familial breast cancer, which have defects in the network.

  Minoru Takata, M.D., Ph.D.
Research and Education
Genome stability is crucial for maintaining integrity of the organism, and therefore all cells have elaborate systems to prevent, repair, or tolerate endogenous or exogenous DNA damage. In higher organisms, loss of the DNA damage signaling network often leads to cancer predisposition as well as impaired stem cell proliferation. A rare hereditary disorder Fanconi anemia (FA) is a prototype of such conditions. 13 genes have been implicated in FA, while mutation carriers of three FA genes develop familial breast cancer.
 We are trying to elucidate regulatory mechanisms and effecter function of genes involved in FA and familial breast cancer. In response to DNA damage, the key factors FancD2 and FancI are monoubiquitinated by a multi-subunit ubiquitin E3 ligase, consisting of at least ten proteins known as the FA core complex. In turn, FancD2 and FancI are both targeted to chromatin and form colocalizing foci, and function in DNA repair together with downstream molecule FancJ helicase. We have recently found that phosphoryation of FancI serves as a molecular switch to trigger monoubiquitinaion of FancD2. Now we are focusing on (1) how FancI is phosphorylated, (2) chromatin targeting mechanisms of FancD2, (3) the effecter function mediated by FancD2 and FancJ, (4) a role of FancJ in chromosome translocation.

Late Effects Studies
Radiation Biology Center
Professor Minoru Takata, M.D., Ph.D.

Masamichi Ishiai, Ph.D.
TEL +81-75-753-7563
FAX +81-75-753-7564
Co-localization of the core complex component FANCC and FANCD2.
The phospho-mimic mutant of FANCI (Dx6) induced focus formation in a DNA damage-independent manner.
Member of the laboratory.
Recent Publications
1. Sato K, Toda K, Ishiai M, Takata M, Kurumizaka H. DNA robustly stimulates FANCD2 monoubiquitylation in the complex with FANCI. Nucleic Acids Res. 2012 May 1;40(10):4553-61. Epub 2012 Jan 28.
2. Shigechi T, Tomida J, Sato K, Kobayashi M, Eykelenboom JK, Pessina F, Zhang Y, Uchida E, Ishiai M, Lowndes NF, Yamamoto K, Kurumizaka H, Maehara Y, Takata M. ATR-ATRIP kinase complex triggers activation of the Fanconi anemia DNA repair pathway. Cancer Res. 2012 Mar 1;72(5):1149-1156.
3. Kitao H, Nanda I, Sugino RP, Kinomura A, Yamazoe M, Arakawa H, Schmid M, Innan H, Hiom K, Takata M. FancJ/Brip1 helicase protects against genomic losses and gains in vertebrate cells. Genes to Cells 2011 Jun;16(6):714-27.
4. Takata M, Ishiai M, Kitao H. The Fanconi anemia pathway: Insights from somatic cell genetics using DT40 cell line. Invited review. Mutat Res. 2009 Jul 31;668(1-2):92-102.
5. Ishiai M, Kitao H, Smogorzewska A, Tomida J, Kinomura A, Uchida E, Saberi A, Kinoshita E, Kinoshita-Kikuta E, Koike T, Tashiro S, Elledge SJ, & Takata M. FANCI phosphorylation functions as a molecular switch to turn on the Fanconi anemia pathway. Nat Struct Mol Biol. 2008 Nov;15(11):1138-46.
6. Kitao H, Yamamoto K, Matsushita N, Ohzeki M, Ishiai M, Takata M. Functional interplay between BRCA2/FANCD1 and FANCC in DNA repair. J Biol Chem. 2006 Jul 28;281(30):21312-20.
7. 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. A FancD2-Monoubiquitin Fusion Reveals Hidden Functions of Fanconi Anemia Core Complex in DNA Repair. Mol Cell. 2005 Sep 16;19(6):841-7.
8. Hirano S, Yamamoto K, Ishiai M, Yamazoe M, Seki M, Matsushita N, Ohzeki M, Yamashita YM, Arakawa H, Buerstedde JM, Enomoto T, Takeda S,Thompson LH, Takata M. Functional relationships of FANCC to homologous recombination, translesion synthesis, and BLM. EMBO J. 2005 Jan 26;24(2):418-27.