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剪接和转录暂停之间的相互作用对可变多聚腺苷酸化进行全基因组控制。

Interplay between splicing and transcriptional pausing exerts genome-wide control over alternative polyadenylation.

机构信息

Department of Immunology and Oncology Centro Nacional De Biotecnología (CNB)/, CSIC Darwin 3, Campus UAM Cantoblanco, Madrid, Spain.

出版信息

Transcription. 2021 Apr-Jun;12(2-3):55-71. doi: 10.1080/21541264.2021.1959244. Epub 2021 Aug 7.

Abstract

Recent studies have identified multiple polyadenylation sites in nearly all mammalian genes. Although these are interpreted as evidence for alternative polyadenylation, our knowledge of the underlying mechanisms is still limited. Most studies only consider the immediate surroundings of gene ends, even though experiments have uncovered the involvement of external factors such as splicing. Whereas splicing manipulation was impracticable until recently, we now used mutants in the () gene to study their impact on 3' end processing. We observe multiple rounds of readthrough and gene fusions, suggesting that no arbitration between polyadenylation sites occurs. Instead, a window of opportunity seems to control end processing. Through the identification of T-rich sequence motifs, our data indicate that splicing and transcriptional pausing interact to regulate alternative polyadenylation. We propose that 3' splice site activation comprises a variable timer, which determines how long transcription proceeds before polyadenylation signals are recognized. Thus, the role of core polyadenylation signals could be more passive than commonly believed. Our results provide new insights into the mechanisms of alternative polyadenylation and expand the catalog of related aberrations. APA: alternative polyadenylation; bp: basepair; MEF: mouse embryonic fibroblasts; PA: polyadenylation; PAS: polyadenylation site; Pol II: (RNA) polymerase II ; RT-PCR:reverse-transcriptase PCR; SF:splicing factor; SFPQ:splicing factor rich in proline and glutamine; SS:splice site; TRSM:Thymidine rich sequence motif; UTR:untranslated terminal region.

摘要

最近的研究已经在几乎所有哺乳动物基因中鉴定出多个多聚腺苷酸化位点。尽管这些被解释为选择多聚腺苷酸化的证据,但我们对潜在机制的了解仍然有限。大多数研究仅考虑基因末端的直接周围环境,尽管实验已经揭示了外部因素(如剪接)的参与。虽然直到最近剪接操作才不可行,但我们现在使用 () 基因中的突变体来研究它们对 3' 末端加工的影响。我们观察到多次通读和基因融合,表明不存在多聚腺苷酸化位点之间的裁决。相反,似乎有一个机会之窗来控制末端处理。通过鉴定富含胸腺嘧啶的序列基序,我们的数据表明剪接和转录暂停相互作用来调节选择多聚腺苷酸化。我们提出 3' 剪接位点的激活包含一个可变定时器,该定时器确定转录进行多长时间后聚腺苷酸化信号被识别。因此,核心多聚腺苷酸化信号的作用可能比通常认为的更为被动。我们的研究结果为选择多聚腺苷酸化的机制提供了新的见解,并扩展了相关异常的目录。APA:选择多聚腺苷酸化;bp:碱基对;MEF:鼠胚胎成纤维细胞;PA:多聚腺苷酸化;PAS:多聚腺苷酸化位点;Pol II:(RNA)聚合酶 II;RT-PCR:逆转录 PCR;SF:剪接因子;SFPQ:富含脯氨酸和谷氨酰胺的剪接因子;SS:剪接位点;TRSM:富含胸腺嘧啶的序列基序;UTR:非翻译末端区域。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0669/8555548/a429d451c3f0/KTRN_A_1959244_F0001_OC.jpg

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