NEAT1 通过 m6A 甲基化依赖性调控 CHD4 促进基因组稳定性。

IF 7.5 1区生物学 Q1 CELL BIOLOGY Genes & development Pub Date : 2024-10-16 DOI:10.1101/gad.351913.124

Victoria Mamontova, Barbara Trifault, Anne-Sophie Gribling-Burrer, Patrick Bohn, Lea Boten, Pit Preckwinkel, Peter Gallant, Daniel Solvie, Carsten P Ade, Dimitrios Papadopoulos, Martin Eilers, Tony Gutschner, Redmond P Smyth, Kaspar Burger

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引用次数: 0

摘要

长非编码（lnc）RNA是基因组稳定性的调节因子。核富集丰富转录本 1（NEAT1）在许多肿瘤中过度表达，并对基因毒性压力有反应。然而，NEAT1与DNA损伤应答（DDR）的关联机制尚不清楚。在这里，我们研究了 NEAT1 在 DNA 双链断裂（DSB）反应中的表达、修饰、定位和结构。DNA损伤增加了NEAT1上的N6-甲基腺苷（m6A）水平和标记，从而促进了NEAT1结构的改变、高甲基化的NEAT1在启动子相关DSB处的积累以及DSB信号转导。NEAT1 的耗竭会损害 DSB 病灶的形成并加剧 DNA 损伤。NEAT1 的基因组保护作用是由 RNA 甲基转移酶 3 (METTL3) 介导的，并涉及从 NEAT1 释放染色质螺旋酶 DNA 结合蛋白 4 (CHD4) 以微调 DSB 处的组蛋白乙酰化。我们的数据表明 NEAT1 在 DDR 中发挥着直接作用。

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NEAT1 promotes genome stability via m⁶A methylation-dependent regulation of CHD4.

Long noncoding (lnc)RNAs emerge as regulators of genome stability. The nuclear-enriched abundant transcript 1 (NEAT1) is overexpressed in many tumors and is responsive to genotoxic stress. However, the mechanism that links NEAT1 to DNA damage response (DDR) is unclear. Here, we investigate the expression, modification, localization, and structure of NEAT1 in response to DNA double-strand breaks (DSBs). DNA damage increases the levels and N6-methyladenosine (m⁶A) marks on NEAT1, which promotes alterations in NEAT1 structure, accumulation of hypermethylated NEAT1 at promoter-associated DSBs, and DSB signaling. The depletion of NEAT1 impairs DSB focus formation and elevates DNA damage. The genome-protective role of NEAT1 is mediated by the RNA methyltransferase 3 (METTL3) and involves the release of the chromodomain helicase DNA binding protein 4 (CHD4) from NEAT1 to fine-tune histone acetylation at DSBs. Our data suggest a direct role for NEAT1 in DDR.

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来源期刊

Genes & development 生物-发育生物学

CiteScore

17.50

自引率

1.90%

发文量

审稿时长

3-6 weeks

期刊介绍： Genes & Development is a research journal published in association with The Genetics Society. It publishes high-quality research papers in the areas of molecular biology, molecular genetics, and related fields. The journal features various research formats including Research papers, short Research Communications, and Resource/Methodology papers. Genes & Development has gained recognition and is considered as one of the Top Five Research Journals in the field of Molecular Biology and Genetics. It has an impressive Impact Factor of 12.89. The journal is ranked #2 among Developmental Biology research journals, #5 in Genetics and Heredity, and is among the Top 20 in Cell Biology (according to ISI Journal Citation Reports®, 2021).