Theodor Boveri Institute, Department of Biochemistry and Molecular Biology, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
Cancer Systems Biology Group, Department of Biochemistry and Molecular Biology, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
Mol Cell. 2022 Jan 6;82(1):159-176.e12. doi: 10.1016/j.molcel.2021.11.002. Epub 2021 Nov 29.
The MYCN oncoprotein drives the development of numerous neuroendocrine and pediatric tumors. Here we show that MYCN interacts with the nuclear RNA exosome, a 3'-5' exoribonuclease complex, and recruits the exosome to its target genes. In the absence of the exosome, MYCN-directed elongation by RNA polymerase II (RNAPII) is slow and non-productive on a large group of cell-cycle-regulated genes. During the S phase of MYCN-driven tumor cells, the exosome is required to prevent the accumulation of stalled replication forks and of double-strand breaks close to the transcription start sites. Upon depletion of the exosome, activation of ATM causes recruitment of BRCA1, which stabilizes nuclear mRNA decapping complexes, leading to MYCN-dependent transcription termination. Disruption of mRNA decapping in turn activates ATR, indicating transcription-replication conflicts. We propose that exosome recruitment by MYCN maintains productive transcription elongation during S phase and prevents transcription-replication conflicts to maintain the rapid proliferation of neuroendocrine tumor cells.
MYCN 癌基因驱动着许多神经内分泌和儿科肿瘤的发展。在这里，我们发现 MYCN 与核 RNA 外切酶体相互作用，后者是一种 3'-5'外切核酸酶复合物，并将外切酶体募集到其靶基因上。在没有外切酶体的情况下，RNA 聚合酶 II（RNAPII）在一大组细胞周期调控基因上的 MYCN 指导的延伸是缓慢且非生产性的。在 MYCN 驱动的肿瘤细胞的 S 期，外切酶体需要防止停滞的复制叉和靠近转录起始位点的双链断裂的积累。当外切酶体耗尽时，ATM 的激活导致 BRCA1 的募集，其稳定核 mRNA 去帽复合物，导致 MYCN 依赖性转录终止。mRNA 去帽的破坏转而激活 ATR，表明转录-复制冲突。我们提出，MYCN 募集外切酶体可在 S 期维持有效的转录延伸，并防止转录-复制冲突，以维持神经内分泌肿瘤细胞的快速增殖。
