BRCA1 regulates microRNA biogenesis via the DROSHA microprocessor complex.
BRCA1 regulates microRNA biogenesis via the DROSHA microprocessor complex.
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DOI：
10.1083/jcb.201110008
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发表时间：
2012-04-16
期刊：
影响因子：
--
通讯作者：
Amano A
中科院分区：
文献类型：
--
作者：
Kawai S;Amano A
BRCA 1肿瘤抑制因子与DROSHA microRNA成熟复合物和初级miRNA转录物结合，并促进转录物加工。microRNA（miRNAs）是一类非编码RNA，在基因表达中起着关键的转录后调节作用。miRNA成熟由DROSHA微处理器复合体控制。然而，miRNA生物合成的详细机制仍不清楚。我们发现，肿瘤抑制乳腺癌1（BRCA 1）加速了miRNA初级转录物的加工。BRCA 1增加let-7a-1、miR-16-1、miR-145和miR-34 a的前体和成熟形式的表达。此外，该肿瘤抑制因子与DROSHA微处理器复合体的DROSHA和DDX 5直接相关，并与Smad 3、p53和DHX 9 RNA解旋酶相互作用。我们还发现BRCA 1识别RNA二级结构，并通过DNA结合结构域直接与miRNA的初级转录本结合。总之，这些结果表明BRCA 1通过DROSHA微处理器复合体和Smad 3/p53/DHX 9调节miRNA生物合成。我们的研究结果还表明BRCA 1在miRNA生物发生中的新功能，这可能与其肿瘤抑制机制和维持基因组稳定性有关。
The BRCA1 tumor suppressor associates with both the DROSHA microRNA maturation complex and primary miRNA transcripts, and promotes transcript processing. MicroRNAs (miRNAs) are noncoding RNAs that function as key posttranscriptional regulators of gene expression. miRNA maturation is controlled by the DROSHA microprocessor complex. However, the detailed mechanism of miRNA biogenesis remains unclear. We show that the tumor suppressor breast cancer 1 (BRCA1) accelerates the processing of miRNA primary transcripts. BRCA1 increased the expressions of both precursor and mature forms of let-7a-1, miR-16-1, miR-145, and miR-34a. In addition, this tumor suppressor was shown to be directly associated with DROSHA and DDX5 of the DROSHA microprocessor complex, and it interacted with Smad3, p53, and DHX9 RNA helicase. We also found that BRCA1 recognizes the RNA secondary structure and directly binds with primary transcripts of miRNAs via a DNA-binding domain. Together, these results suggest that BRCA1 regulates miRNA biogenesis via the DROSHA microprocessor complex and Smad3/p53/DHX9. Our findings also indicate novel functions of BRCA1 in miRNA biogenesis, which may be linked to its tumor suppressor mechanism and maintenance of genomic stability.
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