MYCN recruits the nuclear exosome complex to RNA polymerase II to prevent transcription replication conflicts

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（核癌蛋白）驱动多种神经内分泌和儿科肿瘤的发展。本研究揭示MYCN与核RNA外切酶复合体——一种3'-5'外切核糖核酸酶复合体——相互作用，并募集外切酶至其靶基因。在没有外切酶的情况下，MYCN通过RNA聚合酶II（RNAPII）指导的延长在大量细胞周期调控基因上缓慢且无成效。在MYCN驱动肿瘤细胞的S期，外切酶对于防止停滞的复制叉和接近转录起始位点的双链断裂的积累至关重要。外切酶耗竭后，ATM的激活导致BRCA1的募集，BRCA1稳定了核mRNA去帽复合体，进而引起MYCN依赖性的转录终止。mRNA去帽的破坏反过来激活ATR，表明转录-复制冲突。我们提出，MYCN通过募集外切酶，在S期维持生产性的转录延长，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。