生物
RNA聚合酶Ⅱ
细胞生物学
外体
抄写(语言学)
外小体复合体
信使核糖核酸
核糖核酸
分子生物学
基因
基因表达
遗传学
非编码RNA
发起人
小RNA
微泡
哲学
语言学
作者
Dimitrios Papadopoulos,Daniel Solvie,Apoorva Baluapuri,Theresa Endres,Stefanie Anh Ha,Steffi Herold,Jacqueline Kalb,Celeste Giansanti,Christina Schülein-Völk,Carsten P. Ade,C. Schneider,Abdallah Gaballa,Seychelle M. Vos,Utz Fischer,Matthias Dobbelstein,Elmar Wolf,Martin Eilers
出处
期刊:Molecular Cell
[Elsevier]
日期:2021-11-18
卷期号:82 (1): 159-176.e12
被引量:6
标识
DOI:10.1016/j.molcel.2021.11.002
摘要
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.
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