RBBP6 isoforms regulate the human polyadenylation machinery and modulate expression of mRNAs with AU-rich 3' UTRs.
RBBP6 isoforms regulate the human polyadenylation machinery and modulate expression of mRNAs with AU-rich 3' UTRs.
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DOI：
10.1101/gad.245787.114
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发表时间：
2014-10-15
影响因子：
10.5
通讯作者：
Manley JL
中科院分区：
文献类型：
--
作者：
Di Giammartino DC;Li W;Ogami K;Yashinskie JJ;Hoque M;Tian B;Manley JL
Campigli Di Giammartino等人发现RBBP 6是介导mRNA前体多腺苷酸化的大型多亚基蛋白复合物的组分。RBBP 6敲除后的全基因组分析显示转录水平下降，特别是具有富含AU的3 'UTR（例如c-Fos和c-Jun）的mRNA，并且远端poly（A）位点的使用增加。mRNA前体的聚腺苷酸化由一个大的多亚基蛋白复合物介导。在这里，我们表明RBBP 6（视网膜母细胞瘤结合蛋白6），最初被确定为Rb和p53结合蛋白，是这种复合物的一个组成部分，并在体外和体内的3′加工功能。RBBP 6与其他核心因子相关，这种相互作用由一个不寻常的泛素样结构域DWNN（“没有名字的结构域”）介导，该结构域是3′加工活性所必需的。DWNN也通过替代RNA加工表达为小的单结构域蛋白（同种型3 [iso 3]）。重要的是，我们发现，已知在几种癌症中下调的iso 3与RBBP 6竞争结合核心机制，从而抑制3′加工。RBBP 6敲低后的全基因组分析显示转录水平降低，特别是具有AU丰富的3′非翻译区（UTR）（如c-Fos和c-Jun）的mRNA，以及远端poly（A）位点的使用增加。我们的研究结果暗示RBBP 6和iso 3是3′加工的新调节剂，特别是具有富含AU的3′ UTR的RNA。
Campigli Di Giammartino et al. find that RBBP6 is a component of a large multisubunit protein complex that mediates polyadenylation of mRNA precursors. Genome-wide analyses following RBBP6 knockdown revealed decreased transcript levels, especially of mRNAs with AU-rich 3′ UTRs such as c-Fos and c-Jun, and increased usage of distal poly(A) sites. Polyadenylation of mRNA precursors is mediated by a large multisubunit protein complex. Here we show that RBBP6 (retinoblastoma-binding protein 6), identified initially as an Rb- and p53-binding protein, is a component of this complex and functions in 3′ processing in vitro and in vivo. RBBP6 associates with other core factors, and this interaction is mediated by an unusual ubiquitin-like domain, DWNN (“domain with no name”), that is required for 3′ processing activity. The DWNN is also expressed, via alternative RNA processing, as a small single-domain protein (isoform 3 [iso3]). Importantly, we show that iso3, known to be down-regulated in several cancers, competes with RBBP6 for binding to the core machinery, thereby inhibiting 3′ processing. Genome-wide analyses following RBBP6 knockdown revealed decreased transcript levels, especially of mRNAs with AU-rich 3′ untranslated regions (UTRs) such as c-Fos and c-Jun, and increased usage of distal poly(A) sites. Our results implicate RBBP6 and iso3 as novel regulators of 3′ processing, especially of RNAs with AU-rich 3′ UTRs.
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