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Tissue‐specific mechanisms of alternative polyadenylation: Testis, brain, and beyond (2018 update)

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Alternative polyadenylation (APA) is how genes choose different sites for 3′ end formation for mRNAs during transcription. APA often occurs in a tissue‐ or developmental stage‐specific manner that can significantly affect gene activity by changing the protein product generated, the stability of the transcript, its localization within the cell, or its translatability. Despite the important regulatory effects that APA has on tissue‐specific gene expression, only a few examples have been characterized mechanistically. In this 2018 update to our 2010 review, we examine mechanisms for the control of APA and update our understanding of the older mechanisms since 2010. We once postulated the existence of tissue‐specific factors in APA. However, while a few tissue‐specific polyadenylation factors are known, the emerging conclusion is that the majority of APA is accomplished by altering levels of core polyadenylation proteins. Examples of those core proteins include CSTF2, CPSF1, and subunits of mammalian cleavage factor I. But despite support for these mechanisms, no one has yet documented any of these proteins changing in either a tissue‐specific or developmental manner. Given the profound effect that APA can have on gene expression and human health, improved understanding of tissue‐specific APA could lead to numerous advances in gene activity control. This article is categorized under: RNA Processing > 3′ End Processing RNA in Disease and Development > RNA in Development
Core and auxiliary proteins involved in tissue‐specific alternative polyadenylation. The pre‐mRNA (black line) consists of upstream sequence elements (UGUA), the polyadenylation signal (AAUAAA), a cleavage site (arrow), the downstream sequence element (GU/UUU), and the downstream G‐rich element (GGGGG). The core polyadenylation proteins consist of the CPSF proteins, the CstF proteins, and CFIm (see the text for details), and the template‐independent poly(A) polymerase is indicated. Auxiliary (U2AF, hnRNP F, hnRNP H, hnRNP I) and tissue‐specific (Nova‐1, βCstF‐64, τCstF‐64, ELL2, MBNL1/2, HuR/Elavl1, sex‐lethal, FPA, FY, and FCA) proteins are indicated. It is not entirely clear whether symplekin is a core or an auxiliary polyadenylation protein, but it interacts directly with CstF‐64
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Proteins involved in testis and brain alternative polyadenylation. (a) Three forms of CstF‐64 are involved in polyadenylation. βCstF‐64 (middle) is an alternatively spliced variant of CstF‐64 (top) that is expressed in vertebrate neurons. τCstF‐64 (bottom) is an autosomal paralog of CstF‐64 that is expressed in male germ cells and other tissues in mammals. The RNA‐binding domain (RBD), CstF‐77 interaction domain (Hinge), proline‐ and glycine‐rich domain (Pro/Gly), MEARA repeats, and C‐terminal domain (CTD) are indicated. (b) Expression patterns of alternative polyadenylation proteins during spermatogenesis. Top figure shows a timeline of spermatogenesis in mice (~34 days). Cells that undergo mitotic division (spermatogonia), meiosis (spermatocytes), and postmeiotic development (round or elongating spermatids, spermatozoa) are indicated. Expression periods for CstF‐64, τCstF‐64, CPSF‐160, CFIm25, CFIm68, and Wdr33/WDR33 are shown in the bottom figure. XY inactivation indicates the period of male sex chromosome inactivation
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RNA in Disease and Development > RNA in Development
RNA Processing > 3′ End Processing

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