| Budget Amount *help |
¥4,050,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥450,000)
Fiscal Year 2007: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2006: ¥2,100,000 (Direct Cost: ¥2,100,000)
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| Research Abstract |
Genome DNA suffers DNA damage by several stresses such as ionizing radiation and DV. Once DNA damage is generated into genome DNA, their cells detects this damage and induce growth arrest by cell cycle checkpoint system to repair damaged DNA, As the remain of DNA damage in genome DNA might lead to gene instability, tumorigenesis or apoptosis, it is much important to clarify the mechanism of DNA damage response. Recently, BRCT (BRCA1 C-Terminal) domain has been noticed in DNA damage response, bemuse some DNA damare response factors function by protein-protein interaction through their BRCT domain. However, the role of most BRCT domain proteins in DNA damage response is unknown Therefore, we identified interaction proteins with BRCT domain by proteomics analysis and investigated their the role of proteins in DNA damage response.
NBS1, the responsible gene product for Nijmegen syndrome, interact with gamma-H2AX through FHA/BRCT domain, and this interaction is indispensable for focus format
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ion of NBS1/MRE11/RAD50 complex at DSB (DNA double-strand break) sites. Moreover, FHA/BRCT domain is also important for Homologous Recombination (HR) activity for DNA repair. TopBP1, which possesses BRCT domains, interacts with NBS1 dependently on the generation of DSB, and this interaction is essential to the DSB-dependent focus formation of TopBP1. Further, knockdown of TopBP1 reduced HR activity and sister chromatid exchange by HR, which suggests that TopBP1 function for HR. Furthermore, we identified nucleolin as a protein interacting with H2AX, which interact with BRCT domain of NBS1. Nucleolin interact with gamma-H2AX following generation of DNA damage. And, knockdown of nucleolin by siRNA increased gamma-H2AX and phosphorylation of ATM substrates and sensitivity to campthotecin (DNA damaging agent). Moreover, nucleolin knockdown cells showed decreases in HR activity. Thus, nuceloin might also be an important factor for HR. Therefore, the protein-protein interaction through BRCT domain could be much important for DNA damage response, particularly HR repair. As the mechanism of DNA damage response is suggested to be indispensable for barrier to tumorigenesis, we have to investigate more detailed role of BRCT domain in DNA damage response. Less
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