SCF-FBXO31 E3 连接酶将 DNA 复制因子 Cdt1 作为靶标进行蛋白水解，以防止细胞周期 G2 期的再复制。
SCF-FBXO31 E3 ligase targets DNA replication factor Cdt1 for proteolysis in the G2 phase of cell cycle to prevent re-replication.
机构信息
From the Sahlgrenska University Hospital, Department of Clinical Chemistry, Bruna Stråket 16, 41345 Gothenburg, Sweden.
Signal Transduction Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia.
出版信息
J Biol Chem. 2014 Jun 27;289(26):18514-25. doi: 10.1074/jbc.M114.559930. Epub 2014 May 14.
FBXO31 was originally identified as a putative tumor suppressor gene in breast, ovarian, hepatocellular, and prostate cancers. By screening a set of cell cycle-regulated proteins as potential FBXO31 interaction partners, we have now identified Cdt1 as a novel substrate. Cdt1 DNA replication licensing factor is part of the pre-replication complex and essential for the maintenance of genomic integrity. We show that FBXO31 specifically interacts with Cdt1 and regulates its abundance by ubiquitylation leading to subsequent degradation. We also show that Cdt1 regulation by FBXO31 is limited to the G2 phase of the cell cycle and is independent of the pathways previously described for Cdt1 proteolysis in S and G2 phase. FBXO31 targeting of Cdt1 is mediated through the N terminus of Cdt1, a region previously shown to be responsible for its cell cycle regulation. Finally, we show that Cdt1 stabilization due to FBXO31 depletion results in re-replication. Our data present an additional pathway that contributes to the FBXO31 function as a tumor suppressor.
FBXO31 最初被鉴定为乳腺癌、卵巢癌、肝癌和前列腺癌中的一种潜在肿瘤抑制基因。通过筛选一组细胞周期调节蛋白作为潜在的 FBXO31 相互作用伙伴，我们现在已经确定 Cdt1 为一种新的底物。Cdt1 是 DNA 复制起始因子，是复制前复合物的一部分，对维持基因组完整性至关重要。我们表明，FBXO31 特异性地与 Cdt1 相互作用，并通过泛素化调节其丰度，导致随后的降解。我们还表明，FBXO31 对 Cdt1 的调节仅限于细胞周期的 G2 期，并且独立于先前描述的 Cdt1 在 S 和 G2 期的蛋白水解途径。FBXO31 对 Cdt1 的靶向作用是通过 Cdt1 的 N 端介导的，该区域先前被证明负责其细胞周期调节。最后，我们表明，由于 FBXO31 耗竭导致 Cdt1 稳定，从而导致重新复制。我们的数据提出了另一种途径，有助于 FBXO31 作为肿瘤抑制因子的功能。
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