Rapid degradation of Cdt1 upon UV-induced DNA damage is mediated by SCFSkp2 complex
Rapid degradation of Cdt1 upon UV-induced DNA damage is mediated by SCFSkp2 complex
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DOI：
10.1074/jbc.m314023200
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发表时间：
2004-06-25
影响因子：
4.8
通讯作者：
Asaka, M
中科院分区：
文献类型：
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作者：
Kondo, T;Kobayashi, M;Asaka, M
CDT1是DNA复制的许可因子，其功能受到严格控制，以维持基因组的完整性。以往的研究表明，CDT1的细胞周期依赖性降解是在S期触发的，以防止再次复制。在这项研究中，我们发现CDT1在紫外线或伽马射线(IR)诱导的DNA损伤后被降解。虽然红外引发的CDT1的降解是咖啡因不敏感的，但紫外线引发的CDT1的降解是咖啡因敏感的。这表明紫外线处理的细胞利用了不同于IR触发的检查点途径。最近的一项研究表明，在正常的细胞周期中，CDT1在G(1)/S交界处被磷酸化、泛素化和降解。蛋白酶体抑制剂MG132处理后抑制了CDT1的降解，并导致UV处理后CDT1的磷酸化形式的积累。在紫外线处理的情况下，CDT1的磷酸化诱导CDT1重新聚集到SCFSkp2复合体中。此外，紫外线处理后异位过表达的CDT1干扰了DNA合成的抑制。这些结果表明，在紫外线诱导的DNA损伤中，CDT1是细胞周期检查点的靶分子。
Cdt1 is a licensing factor for DNA replication, the function of which is tightly controlled to maintain genome integrity. Previous studies have indicated that the cell cycle-dependent degradation of Cdt1 is triggered at S phase to prevent re-replication. In this study, we found that Cdt1 is degraded upon DNA damage induced by either UV treatment or gamma-irradiation (IR). Although the IR-triggered degradation of Cdt1 was caffeine-insensitive, the UV-triggered degradation of Cdt1 was caffeine-sensitive. This indicates that the cells treated with UV utilize the checkpoint pathway, which differs from that triggered by IR. A recent study has suggested that Cdt1 is phosphorylated, ubiquitylated, and degraded at the G(1)/S boundary in the normal cell cycle. Treatment with MG132, a proteasome inhibitor, inhibited the degradation of Cdt1 and resulted in the accumulation of the phosphorylated form of Cdt1 after UV treatment. In the case of UV treatment, phosphorylation of Cdt1 induced the recruitment of Cdt1 to a SCFSkp2 complex. Moreover, ectopic overexpression of Cdt1 after UV treatment interfered the inhibition of DNA synthesis. These results indicate that Cdt1 is a target molecule of the cell cycle checkpoint in UV-induced DNA damage.