p53 inhibits mRNA 3′ processing through its interaction with the CstF/BARD1 complex
p53 inhibits mRNA 3′ processing through its interaction with the CstF/BARD1 complex
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DOI：
10.1038/onc.2011.29
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发表时间：
2011-07-01
期刊：
影响因子：
8
通讯作者：
Kleiman, F. E.
中科院分区：
文献类型：
--
作者：
Nazeer, F. I.;Devany, E.;Kleiman, F. E.
DNA损伤后p53依赖的基因表达调控机制尚未完全阐明。在这里，我们表明，p53 C末端与紫外线（UV）诱导的多聚腺苷酸化反应的mRNA 3'切割步骤的抑制所需的因子，如肿瘤抑制因子BARD 1和3'加工因子切割刺激因子1（CstF 1）。我们发现p53可以与CstF和BARD 1在UV处理的细胞提取物中共存，这表明p53在DNA损伤后mRNA 3'切割中的作用。与此一致，我们发现p53在体外抑制3'切割，并且在不同细胞条件下，p53表达水平与mRNA 3'切割水平之间存在反向相关性。支持这些结果的是，p53中的肿瘤相关突变不仅降低了与BARD 1和CstF的相互作用，而且降低了UV诱导的3'加工抑制，所有这些都通过野生型p53表达恢复。我们还发现，p53的表达水平影响管家基因的聚腺苷酸化水平，但不影响参与DNA损伤反应（DDR）的p21和c-fos基因。在这里，我们确定了一个新的3' RNA加工抑制功能的p53，增加了一个新的水平的复杂性DDR连接RNA加工的p53网络。Oncogene（2011）3 '，3' 73 - 3 '83; doi：10.1038/onc.2011.29;在线发表2011年3月7日
The mechanisms involved in the p53-dependent control of gene expression following DNA damage have not been completely elucidated. Here, we show that the p53 C terminus associates with factors that are required for the ultraviolet (UV)-induced inhibition of the mRNA 3' cleavage step of the polyadenylation reaction, such as the tumor suppressor BARD1 and the 3' processing factor cleavage-stimulation factor 1 (CstF1). We found that p53 can coexist in complexes with CstF and BARD1 in extracts of UV-treated cells, suggesting a role for p53 in mRNA 3' cleavage following DNA damage. Consistent with this, we found that p53 inhibits 3' cleavage in vitro and that there is a reverse correlation between the levels of p53 expression and the levels of mRNA 3' cleavage under different cellular conditions. Supporting these results, a tumor-associated mutation in p53 not only decreases the interaction with BARD1 and CstF, but also decreases the UV-induced inhibition of 3' processing, all of which is restored by wild-type-p53 expression. We also found that p53 expression levels affect the polyadenylation levels of housekeeping genes, but not of p21 and c-fos genes, which are involved in the DNA damage response (DDR). Here, we identify a novel 3' RNA processing inhibitory function of p53, adding a new level of complexity to the DDR by linking RNA processing to the p53 network. Oncogene (2011) 3', 3'73-3'83; doi: 10.1038/onc.2011.29; published online 7 March 2011