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首页> 外文期刊>Molecular biology of the cell >Cell Type–dependent Requirement for PIP Box–regulated Cdt1 Destruction During S Phase
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Cell Type–dependent Requirement for PIP Box–regulated Cdt1 Destruction During S Phase

机译：在S期，PIP盒调节的Cdt1破坏的细胞类型依赖性要求

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DNA synthesis–coupled proteolysis of the prereplicative complex component Cdt1 by the CRL4Cdt2 E3 ubiquitin ligase is thought to help prevent rereplication of the genome during S phase. To directly test whether CRL4Cdt2-triggered destruction of Cdt1 is required for normal cell cycle progression in vivo, we expressed a mutant version of Drosophila Cdt1 (Dup), which lacks the PCNA-binding PIP box (DupΔPIP) and which cannot be regulated by CRL4Cdt2. DupΔPIP is inappropriately stabilized during S phase and causes developmental defects when ectopically expressed. DupΔPIP restores DNA synthesis to dup null mutant embryonic epidermal cells, but S phase is abnormal, and these cells do not progress into mitosis. In contrast, DupΔPIP accumulation during S phase did not adversely affect progression through follicle cell endocycles in the ovary. In this tissue the combination of DupΔPIP expression and a 50% reduction in Geminin gene dose resulted in egg chamber degeneration. We could not detect Dup hyperaccumulation using mutations in the CRL4Cdt2 components Cul4 and Ddb1, likely because these cause pleiotropic effects that block cell proliferation. These data indicate that PIP box–mediated destruction of Dup is necessary for the cell division cycle and suggest that Geminin inhibition can restrain DupΔPIP activity in some endocycling cell types.
机译：通过CRL4 Cdt2 E3泛素连接酶进行的DNA合成偶联的复制前复合物Cdt1的蛋白水解被认为有助于防止基因组在S期复制。为了直接测试是否需要CRL4 Cdt2 触发的Cdt1破坏是体内正常细胞周期进程所必需的，我们表达了果蝇Cdt1（Dup）的突变体，该突变体缺少PCNA结合PIP框（Dup ΔPIP），并且不能由CRL4 Cdt2 进行调节。 Dup ΔPIP在S期不稳定，当异位表达时会引起发育缺陷。 Dup ΔPIP将DNA合成恢复为dup null突变型胚胎表皮细胞，但S期异常，并且这些细胞不会发展为有丝分裂。相比之下，Sup期的Dup ΔPIP积累对卵巢中卵泡细胞内循环的进程没有不利影响。在该组织中，Dup ΔPIP表达与Geminin基因剂量减少50％的结合导致卵腔变性。我们无法使用CRL4 Cdt2 组件Cul4和Ddb1中的突变检测到Dup过度积累，可能是因为它们引起了阻止细胞增殖的多效性作用。这些数据表明，PIP盒介导的Dup破坏是细胞分裂周期所必需的，并表明在某些内吞性细胞类型中，Geminin抑制可以抑制Dup ΔPIP活性。

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