SUMOylation at K707 of DGCR8 controls direct function of primary microRNA.
SUMOylation at K707 of DGCR8 controls direct function of primary microRNA.
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DGCR8 K707 处的 SUMO 化控制初级 microRNA 的直接功能
DOI：
10.1093/nar/gkv741
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发表时间：
2015-09-18
影响因子：
14.9
通讯作者：
Yu J
中科院分区：
文献类型：
--
作者：
Zhu C;Chen C;Huang J;Zhang H;Zhao X;Deng R;Dou J;Jin H;Chen R;Xu M;Chen Q;Wang Y;Yu J
DGCR8 （diggeorge综合征关键区基因8）是细胞核初级microRNA （pri-miRNA）加工的关键。它特异性地与核RNase III酶Drosha结合，形成微处理器复合物（MC），将pri-miRNA切割成前体miRNA (pre-miRNA)，由细胞质RNase III酶Dicer进一步加工成成熟的miRNA。越来越多的证据表明pri-/pre-miRNAs在基因表达调控中具有直接功能，但其调控机制尚不清楚。这里我们发现DGCR8在主要位点K707被SUMO1修饰，这可以通过其erk激活的磷酸化来促进。DGCR8的SUMOylation通过防止泛素蛋白酶体途径降解来增强蛋白质的稳定性。更重要的是，DGCR8的sumo化并不改变其与Drosha、MC活性和miRNA生物发生的关联，而是影响其与pri-miRNA的亲和力。DGCR8与pri-miRNAs亲和力的改变似乎控制了pri-miRNAs识别和抑制靶mrna的直接功能，这显然与DGCR8调节肿瘤发生和细胞迁移的功能有关。总之，我们的数据提示了一种新的机制，DGCR8的SUMOylation控制了基因沉默中pri- mirna的直接功能。
DGCR8 (DiGeorge syndrome critical region gene 8) is essential for primary microRNA (pri-miRNA) processing in the cell nucleus. It specifically combines with Drosha, a nuclear RNase III enzyme, to form the Microprocessor complex (MC) that cleaves pri-miRNA to precursor miRNA (pre-miRNA), which is further processed to mature miRNA by Dicer, a cytoplasmic RNase III enzyme. Increasing evidences suggest that pri-/pre-miRNAs have direct functions in regulation of gene expression, however the underlying mechanism how it is fine-tuned remains unclear. Here we find that DGCR8 is modified by SUMO1 at the major site K707, which can be promoted by its ERK-activated phosphorylation. SUMOylation of DGCR8 enhances the protein stability by preventing the degradation via the ubiquitin proteasome pathway. More importantly, SUMOylation of DGCR8 does not alter its association with Drosha, the MC activity and miRNA biogenesis, but rather influences its affinity with pri-miRNAs. This altered affinity of DGCR8 with pri-miRNAs seems to control the direct functions of pri-miRNAs in recognition and repression of the target mRNAs, which is evidently linked to the DGCR8 function in regulation of tumorigenesis and cell migration. Collectively, our data suggest a novel mechanism that SUMOylation of DGCR8 controls direct functions of pri-miRNAs in gene silencing.