A novel transcriptional cascade is involved in Fzr-mediated endoreplication
A novel transcriptional cascade is involved in Fzr-mediated endoreplication
复制标题
Fzr介导的内复制涉及一种新的转录级联
DOI：
10.1093/nar/gkaa158
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发表时间：
2020-05-07
影响因子：
14.9
通讯作者：
Cheng, Daojun
中科院分区：
文献类型：
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作者：
Qian, Wenliang;Li, Zheng;Cheng, Daojun
内复制，称为内周期，是细胞周期的一种变体，与有丝分裂不同，发生在不同生物体的特定组织中。内复制细胞通常经历多轮基因组复制而没有染色体分离。先前的研究表明，果蝇泡沫相关蛋白 (Fzr) 及其哺乳动物同源物 Cdh1 通过激活后期促进复合物/环体启动细胞周期因子（如细胞周期蛋白 B (CycB)）的泛素化和随后的降解，作为内复制入口的关键调节因子。然而，Fzr 介导的内复制的分子机制尚不完全清楚。在这项研究中，我们证明转录因子 Myc 在果蝇唾液腺内复制过程中作用于 Fzr 下游。从机制上讲，Fzr 与染色质相关组蛋白 H2B 相互作用，增强 Myc 启动子中的 H2B 泛素化并促进 Myc 转录。除了负向调节 CycB 转录外，Fzr 泛素化 H2B (H2Bub)-Myc 信号级联还通过直接结合启动子内的特定基序，正向调节参与 DNA 复制的 MCM6 基因的转录。我们进一步发现调节内复制进程的 Fzr-H2Bub-Myc 信号级联在昆虫和哺乳动物细胞之间是保守的。总而言之，我们的工作揭示了一种参与 Fzr 介导的内复制的新型转录级联反应。
Endoreplication, known as endocycle, is a variant of the cell cycle that differs from mitosis and occurs in specific tissues of different organisms. Endoreplicating cells generally undergo multiple rounds of genome replication without chromosome segregation. Previous studies demonstrated that Drosophila fizzy-related protein (Fzr) and its mammalian homolog Cdh1 function as key regulators of endoreplication entrance by activating the anaphase-promoting complex/cyclosome to initiate the ubiquitination and subsequent degradation of cell cycle factors such as Cyclin B (CycB). However, the molecular mechanism underlying Fzr-mediated endoreplication is not completely understood. In this study, we demonstrated that the transcription factor Myc acts downstream of Fzr during endoreplication in Drosophila salivary gland. Mechanistically, Fzr interacts with chromatin-associated histone H2B to enhance H2B ubiquitination in the Myc promoter and promotes Myc transcription. In addition to negatively regulating CycB transcription, the Fzr-ubiquitinated H2B (H2Bub)-Myc signaling cascade also positively regulates the transcription of the MCM6 gene that is involved in DNA replication by directly binding to specific motifs within their promoters. We further found that the Fzr-H2Bub-Myc signaling cascade regulating endoreplication progression is conserved between insects and mammalian cells. Altogether, our work uncovers a novel transcriptional cascade that is involved in Fzr-mediated endoreplication.