The MYCN oncoprotein binds active promoters in a heterodimer with its partner protein MAX. MYCN also interacts with the nuclear exosome, a 3′-5′ exoribonuclease complex, suggesting a function in RNA metabolism. Here, we show that MYCN forms stable high-molecular-weight complexes with the exosome and multiple RNA-binding proteins. MYCN binds RNA in vitro and in cells via a conserved sequence termed MYCBoxI. In cells, MYCN associates with thousands of intronic transcripts together with the ZCCHC8 subunit of the nuclear exosome targeting complex and enhances their processing. Perturbing exosome function results in global re-localization of MYCN from promoters to intronic RNAs. On chromatin, MYCN is then replaced by the MNT(MXD6) repressor protein, inhibiting MYCN-dependent transcription. RNA-binding-deficient alleles show that RNA-binding limits MYCN’s ability to activate cell growth-related genes but is required for MYCN’s ability to promote progression through S phase and enhance the stress resilience of neuroblastoma cells.

MYCN 癌蛋白与其伴侣蛋白 MAX 结合异二聚体中的活性启动子。 MYCN 还与核外泌体（一种 3'-5' 外切核糖核酸酶复合物）相互作用，表明其在 RNA 代谢中具有功能。在这里，我们证明 MYCN 与外泌体和多种 RNA 结合蛋白形成稳定的高分子量复合物。 MYCN 通过称为 MYCBoxI 的保守序列在体外和细胞内结合 RNA。在细胞中，MYCN 与数千个内含子转录本以及核外泌体靶向复合物的 ZCCHC8 亚基结合在一起，并增强它们的加工。干扰外泌体功能会导致 MYCN 从启动子到内含子 RNA 的整体重新定位。在染色质上，MYCN 随后被 MNT(MXD6) 阻遏蛋白取代，抑制 MYCN 依赖性转录。 RNA结合缺陷等位基因表明，RNA结合限制了MYCN激活细胞生长相关基因的能力，但它是MYCN促进S期进展和增强神经母细胞瘤细胞应激恢复能力所必需的。