Guarner Ana, Morris Robert, Korenjak Michael, Boukhali Myriam, Zappia Maria Paula, Van Rechem Capucine, Whetstine Johnathan R, Ramaswamy Sridhar, Zou Lee, Frolov Maxim V, Haas Wilhelm, Dyson Nicholas J
Massachusetts General Hospital Cancer Center and Harvard Medical School, Building 149 13(th) Street, Charlestown, MA 02129, USA.
Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, 900 S Ashland Avenue, Chicago, IL 60607, USA.
Dev Cell. 2017 Dec 18;43(6):689-703.e5. doi: 10.1016/j.devcel.2017.11.008. Epub 2017 Dec 7.
To understand the consequences of the complete elimination of E2F regulation, we profiled the proteome of Drosophila dDP mutants that lack functional E2F/DP complexes. The results uncovered changes in the larval fat body, a differentiated tissue that grows via endocycles. We report an unexpected mechanism of E2F/DP action that promotes quiescence in this tissue. In the fat body, dE2F/dDP limits cell-cycle progression by suppressing DNA damage responses. Loss of dDP upregulates dATM, allowing cells to sense and repair DNA damage and increasing replication of loci that are normally under-replicated in wild-type tissues. Genetic experiments show that ectopic dATM is sufficient to promote DNA synthesis in wild-type fat body cells. Strikingly, reducing dATM levels in dDP-deficient fat bodies restores cell-cycle control, improves tissue morphology, and extends animal development. These results show that, in some cellular contexts, dE2F/dDP-dependent suppression of DNA damage signaling is key for cell-cycle control and needed for normal development.
为了解完全消除E2F调控的后果，我们对缺乏功能性E2F/DP复合物的果蝇dDP突变体的蛋白质组进行了分析。结果揭示了幼虫脂肪体中的变化，脂肪体是一种通过核内复制生长的分化组织。我们报告了一种E2F/DP作用的意外机制，该机制促进了该组织中的静止状态。在脂肪体中，dE2F/dDP通过抑制DNA损伤反应来限制细胞周期进程。dDP的缺失上调了dATM，使细胞能够感知和修复DNA损伤，并增加了在野生型组织中通常复制不足的基因座的复制。遗传实验表明，异位表达的dATM足以促进野生型脂肪体细胞中的DNA合成。引人注目的是，降低dDP缺陷型脂肪体中的dATM水平可恢复细胞周期控制，改善组织形态，并延长动物发育时间。这些结果表明，在某些细胞环境中，dE2F/dDP依赖的DNA损伤信号抑制对于细胞周期控制至关重要，并且是正常发育所必需的。
