| Budget Amount *help |
¥4,010,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥510,000)
Fiscal Year 2007: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2006: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Research Abstract |
Fanconi anemia is a rare, inherited disorder associate early-onset bone marrow failure, cancer predisposition, and genetic instability, which is characterized by a hypersensitivity to DNA-damaging agents, chromosome instability and overproduction of the myelosuppressive cytokines like TNF-α. Thirteen FA genes were identified, and eight of them, including FancL which has been ubiqutin ligase activity, form a nuclear complex, whole integrity is required for the monoubiquitination of the FA proteins FANCD2 and FANCI in response to DNA damage. We found that FancL induced monoubiquitination of FancD2 is required in DNA damage response, But the function of mono-ubuquitinated FANCD2 is not still unknown.
To identify its function, we performed yeast two-hybrid (Y2H) screens using ubiquitin fusion N-terminal chicken (ch) FancD2 as a bait. We have identified chTaxl-binding protein 1 (TAX1BP1), the ubiquitin fusion FandD2 binding protein. We also found that ectopically expressed FancD2 interacted with TAX1BP1 through monoubiquitination. TAX1BP1 is a negative regulator of TNF-a-and IL-1B-induced NF-KB activation and that binding to mono- and polyubiquitin by a ubiquitin-binding Zn finger domain in TAX1BP1. Our finding suggests that monoubiquitinated FancD2 binds to TAX1Bp 1, and they play inhibitory role in NF-KB induced overproduction of cytokines
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