MEN1 is a regulator of alternative splicing and prevents R-loop-induced genome instability through suppression of RNA polymerase II elongation.
MEN1 is a regulator of alternative splicing and prevents R-loop-induced genome instability through suppression of RNA polymerase II elongation.
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DOI：
10.1093/nar/gkad548
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发表时间：
2023-08-25
影响因子：
14.9
通讯作者：
Chen, Tengxiang
中科院分区：
文献类型：
--
作者：
Jin, Bangming;Zhu, Jiamei;Pan, Ting;Yang, Yunqiao;Liang, Li;Zhou, Yuxia;Zhang, Tuo;Teng, Yin;Wang, Ziming;Wang, Xuyan;Tian, Qianting;Guo, Bing;Li, Haiyang;Chen, Tengxiang
选择性剪接（AS）模式的保真度对生长发育和细胞命运决定至关重要。然而，调节AS的分子开关的范围在很大程度上仍未被探索。在这里，我们表明，MEN1是一个以前未知的剪接调节因子。MEN1缺失导致小鼠肺组织和人肺癌细胞中AS模式的重编程，表明MEN1在调节替代前体mRNA剪接中具有一般功能。MEN1改变了外显子跳跃和具有次优剪接位点的某些基因的mRNA剪接异构体的丰度。染色质免疫沉淀和染色体步移分析表明，MEN1有利于RNA聚合酶II（Pol II）的编码变异外显子的区域的积累。我们的数据表明，MEN1通过减慢Pol II延伸速率来调节AS，并且这些过程中的缺陷触发R环形成、DNA损伤积累和基因组不稳定性。此外，我们在肺癌细胞中鉴定了28个MEN1调节的外显子跳跃事件，这些事件与肺腺癌患者的生存密切相关，并且MEN1缺乏使肺癌细胞对剪接抑制剂敏感。总的来说，这些发现导致了menin在维持AS稳态中的新生物学作用的鉴定，并将这种作用与癌细胞行为的调节联系起来。
The fidelity of alternative splicing (AS) patterns is essential for growth development and cell fate determination. However, the scope of the molecular switches that regulate AS remains largely unexplored. Here we show that MEN1 is a previously unknown splicing regulatory factor. MEN1 deletion resulted in reprogramming of AS patterns in mouse lung tissue and human lung cancer cells, suggesting that MEN1 has a general function in regulating alternative precursor mRNA splicing. MEN1 altered exon skipping and the abundance of mRNA splicing isoforms of certain genes with suboptimal splice sites. Chromatin immunoprecipitation and chromosome walking assays revealed that MEN1 favored the accumulation of RNA polymerase II (Pol II) in regions encoding variant exons. Our data suggest that MEN1 regulates AS by slowing the Pol II elongation rate and that defects in these processes trigger R-loop formation, DNA damage accumulation and genome instability. Furthermore, we identified 28 MEN1-regulated exon-skipping events in lung cancer cells that were closely correlated with survival in patients with lung adenocarcinoma, and MEN1 deficiency sensitized lung cancer cells to splicing inhibitors. Collectively, these findings led to the identification of a novel biological role for menin in maintaining AS homeostasis and link this role to the regulation of cancer cell behavior.
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影响因子：
3.7
作者：
Francis J;Lin W;Rozenblatt-Rosen O;Meyerson M
通讯作者：
Meyerson M
影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
影响因子：
14.9
作者：
Cartegni, L;Wang, JH;Krainer, AR
通讯作者：
Krainer, AR
影响因子：
56.9
作者：
CACERES, JF;STAMM, S;KRAINER, AR
通讯作者：
KRAINER, AR
影响因子：
16.6
作者：
Bayona-Feliu A;Casas-Lamesa A;Reina O;Bernués J;Azorín F
通讯作者：
Azorín F