SUMOylation of YTHDF2 promotes mRNA degradation and cancer progression by increasing its binding affinity with m6A-modified mRNAs.
SUMOylation of YTHDF2 promotes mRNA degradation and cancer progression by increasing its binding affinity with m6A-modified mRNAs.
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YTHDF2 的 SUMO 化通过增加其与 m6A 修饰的 mRNA 的结合亲和力来促进 mRNA 降解和癌症进展。
DOI：
10.1093/nar/gkab065
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发表时间：
2021-03-18
影响因子：
14.9
通讯作者：
Yu J
中科院分区：
文献类型：
--
作者：
Hou G;Zhao X;Li L;Yang Q;Liu X;Huang C;Lu R;Chen R;Wang Y;Jiang B;Yu J
N-6-甲基腺苷（N6-Methyladenosine，m6 A）是多种RNA（包括mRNA和lncRNA）中最丰富的修饰，受可逆过程调控，具有重要的生物学功能。人YTH结构域家族2（YTHDF 2）选择性识别m6 A-RNA以调节降解。然而，YTHDF 2的蛋白质翻译后修饰的可能调控仍然未知。在这里，我们表明，YTHDF 2是SUMO化在体内和体外的主要网站的K571，这可以诱导缺氧，而减少氧化应激和SUMO化抑制剂。YTHDF 2的SUMO化对其泛素化和定位几乎没有影响，但显著增加了其与m6 A修饰的mRNA的结合亲和力，随后导致基因表达失调，这是癌症进展的原因。此外，来自TCGA数据集的肺腺癌患者的无病生存分析揭示，YTHDF 2的高表达与SUMO 1的高表达一起预测不良预后。我们的工作揭示了YTHDF 2识别m6 A-RNA的新调控机制，并强调了YTHDF 2 SUMO化在转录后基因表达调控和癌症进展中的重要性。
N 6-Methyladenosine (m6A) is the most abundant modification within diverse RNAs including mRNAs and lncRNAs and is regulated by a reversible process with important biological functions. Human YTH domain family 2 (YTHDF2) selectively recognized m6A-RNAs to regulate degradation. However, the possible regulation of YTHDF2 by protein post-translational modification remains unknown. Here, we show that YTHDF2 is SUMOylated in vivo and in vitro at the major site of K571, which can be induced by hypoxia while reduced by oxidative stress and SUMOylation inhibitors. SUMOylation of YTHDF2 has little impact on its ubiquitination and localization, but significantly increases its binding affinity of m6A-modified mRNAs and subsequently results in deregulated gene expressions which accounts for cancer progression. Moreover, Disease-free survival analysis of patients with lung adenocarcinoma derived from TCGA dataset reveals that higher expression of YTHDF2 together with higher expression of SUMO1 predicts poor prognosis. Our works uncover a new regulatory mechanism for YTHDF2 recognition of m6A-RNAs and highlight the importance of YTHDF2 SUMOylation in post-transcriptional gene expression regulation and cancer progression.
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