Department of Biology, Developmental Biology Research Initiative, McGill University, Montreal, Quebec H3A 1B1 Canada.
Genetics. 2021 Mar 3;217(1):1-15. doi: 10.1093/genetics/iyaa029.
Polyploidy is an integral part of development and is associated with cellular stress, aging, and pathological conditions. The endocycle, comprised of successive rounds of G and S phases without mitosis, is widely employed to produce polyploid cells in plants and animals. In Drosophila, maintenance of the endocycle is dependent on E2F-governed oscillations of Cyclin E (CycE)-Cdk2 activity, which is known to be largely regulated at the level of transcription. In this study, we report an additional level of E2F-dependent control of CycE-Cdk2 activity during the endocycle. Genetic experiments revealed that an alternative isoform of Drosophila de2f1, dE2F1b, regulates the expression of the p27CIP/KIP-like Cdk inhibitor Dacapo (Dap). We provide evidence showing that dE2F1b-dependent Dap expression in endocycling tissues is necessary for setting proper CycE-Cdk2 activity. Furthermore, we demonstrate that dE2F1b is required for proliferating cell nuclear antigen expression that establishes a negative feedback loop in S phase. Overall, our study reveals previously unappreciated E2F-dependent regulatory networks that are critical for the periodic transition between G and S phases during the endocycle.
多倍体是发育的一个组成部分，与细胞应激、衰老和病理状况有关。内周期由连续的 G1 和 S 期组成，没有有丝分裂，广泛用于在植物和动物中产生多倍体细胞。在果蝇中，内周期的维持依赖于 E2F 调控的细胞周期蛋白 E（CycE）-细胞周期蛋白依赖性激酶 2（Cdk2）活性的波动，这在很大程度上被认为是在转录水平上调节的。在这项研究中，我们报告了内周期中 E2F 依赖性控制 CycE-Cdk2 活性的另一个层次。遗传实验表明，果蝇 de2f1 的另一种异构体 dE2F1b 调节 p27CIP/KIP 样细胞周期蛋白依赖性激酶抑制剂 Dacapo（Dap）的表达。我们提供的证据表明，内周期组织中依赖 dE2F1b 的 Dap 表达对于设定适当的 CycE-Cdk2 活性是必要的。此外，我们证明 dE2F1b 是增殖细胞核抗原表达所必需的，该蛋白在 S 期建立了负反馈回路。总的来说，我们的研究揭示了以前未被认识的 E2F 依赖性调节网络，这些网络对于内周期中 G1 和 S 期之间的周期性转变至关重要。
