| Budget Amount *help |
¥4,110,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥510,000)
Fiscal Year 2007: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2006: ¥1,900,000 (Direct Cost: ¥1,900,000)
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| Research Abstract |
Cdt1, an essential factor for DNA replication licensing, is degraded soon after entry into S-phase. We discovered that two ubiquitin ligases, Skp2-Cul1 and DDB1-Cul4, independently recognize the N-terminus of Cdt1 for ubiquitination. The first 10 amino acid region of Cdt1 contains a conserved sequence, PCNA interacting motif (PIP-box). During S-phase, PCNA and DDB1-Cul4 co-operate to ubiquitinate Cdt1. This system also operates after DNA damage, such as UV irradiation. When PIP-box was mutated, Cdt1 became stable after UV irradiation, and during S-phase combined with silencing of Skp2. Many PCNA interacting proteins were isolated. Among them, we found that CDK inhibitor p21 is also degraded through PCNA and DDB1-Cul4 system. Though both Cdt1 and p21 play key roles during G1-phase, their presence after initiation of S-phase is not suitable for proper cell cycle progression., and thus should be degraded upon entry into S-phase. We propose that PCNA dependent DDB1-Cul4 ubiquitin system provides a feedback system that helps the coordination between end of G1-phase and initiation of S-phase.
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