Auxiliary downstream elements are required for efficient polyadenylation of mammalian pre-mRNAs

Chen, Fan; Wilusz, Jeffrey

doi:10.1093/nar/26.12.2891

Cited by 50 publications

(49 citation statements)

References 44 publications

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“…These findings support a model whereby DNA damage-induced hnRNP H/F expression promotes its association with the p53 G4, resulting in maintained 39-end processing efficiency. This can occur by recruiting factors that are essential for the cleavage and pA reaction; namely, CstF (Bagga et al 1998;Chen and Wilusz 1998) and poly(A) polymerase (PAP) (Millevoi et al 2009). Since DNA damage induces CstF sequestration in complexes with BRCA1/BARD1 Manley 1999, 2001), RNA Pol II (Kleiman et al 2005), and PARN (Cevher et al 2010), which inhibit 39-end processing, the function of hnRNP H/F in DNA-damaged cells could be to prevent CstF from being hijacked in alternative protein complexes.…”

Section: Hnrnp H/f Regulates P53 Expression and Function In Apoptosismentioning

confidence: 99%

Essential role for the interaction between hnRNP H/F and a G quadruplex in maintaining p53 pre-mRNA 3′-end processing and function during DNA damage

Decorsière¹,

Cayrel²,

Vagner³

et al. 2011

Genes Dev.

156

155

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Following DNA damage, mRNA 39-end formation is inhibited, contributing to repression of mRNA synthesis. Here we investigated how DNA-damaged cells accomplish p53 mRNA 39-end formation when normal mechanisms of pre-mRNA 39-end processing regulation are inhibited. The underlying mechanism involves the interaction between a G-quadruplex structure located downstream from the p53 cleavage site and hnRNP H/F. Importantly, this interaction is critical for p53 expression and contributes to p53-mediated apoptosis. Our results uncover the existence of a specific rescue mechanism of 39-end processing regulation allowing stress-induced p53 accumulation and function in apoptosis.

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Section: Hnrnp H/f Regulates P53 Expression and Function In Apoptosismentioning

confidence: 99%

Essential role for the interaction between hnRNP H/F and a G quadruplex in maintaining p53 pre-mRNA 3′-end processing and function during DNA damage

Decorsière¹,

Cayrel²,

Vagner³

et al. 2011

Genes Dev.

156

155

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“…There are numerous examples of poly(A) signals for which the flanking RNA immediately upstream (8,10,26,33,50,53,60) or downstream (5,12,26) of the core poly(A) signal is essential for full activity. In some cases, specific elements in these flanking sequences serve as binding sites for additional trans-acting factors (5,44,50).…”

mentioning

confidence: 99%

“…In some cases, specific elements in these flanking sequences serve as binding sites for additional trans-acting factors (5,44,50). In other cases, the involvement of additional factors is not apparent though the flanking RNA is known to be important (12,25,26,32,33). For several poly(A) sites, direct interactions of the flanking RNA with CPSF and CstF have been demonstrated (25,50) or are likely (26,33).…”

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confidence: 99%

“…Figure 9C, which presents a physical interpretation of the present work, also accommodates our functional understanding of the 3Ј-end processing domain (see the introduction). Thus, RNA sequences immediately flanking the core poly(A) signal are important for function (5,8,10,12,26,33,50,53,60), and in at least one in vitro study, the presence of flanking RNA per se was important, regardless of the sequence (36). Also, all elements in the poly(A) signal domain (upstream flanking, AAUAAA hexamer, cleavage site, U/GU rich, and downstream flanking) occupy narrowly prescribed positions relative to each other (2,5,9,11,24,33,59), suggesting that they, and the factors that bind to them, comprise a single, well-defined structure.…”

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confidence: 99%

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Assembly of the Cleavage and Polyadenylation Apparatus Requires About 10 Seconds In Vivo and Is Faster for Strong than for Weak Poly(A) Sites

Chao

Jamil

Kim

et al. 1999

Molecular and Cellular Biology

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We have devised a cis-antisense rescue assay of cleavage and polyadenylation to determine how long it takes the simian virus 40 (SV40) early poly(A) signal to commit itself to processing in vivo. An inverted copy of the poly(A) signal placed immediately downstream of the authentic one inhibited processing by means of senseantisense duplex formation in the RNA. The antisense inhibition was gradually relieved when the inverted signal was moved increasing distances downstream, presumably because cleavage and polyadenylation occur before the polymerase reaches the antisense sequence. Antisense inhibition was unaffected when the inverted signal was moved upstream. Based on the known rate of transcription, we estimate that the cleavagepolyadenylation process takes between 10 and 20 s for the SV40 early poly(A) site to complete in vivo. Relief from inhibition occurred earlier for shorter antisense sequences than for longer ones. This indicates that a brief period of assembly is sufficient for the poly(A) signal to shield itself from a short (50-to 70-nucleotide) antisense sequence but that more assembly time is required for the signal to become immune to the longer ones (ϳ200 nucleotides). The simplest explanation for this target size effect is that the assembly process progressively sequesters more and more of the RNA surrounding the poly(A) signal up to a maximum of about 200 nucleotides, which we infer to be the domain of the mature apparatus. We compared strong and weak poly(A) sites. The SV40 late poly(A) site, one of the strongest, assembles several times faster than the weaker SV40 early or synthetic poly(A) site.

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“…[20][21][22][23] One mechanism of how the GRS may affect polyadenylation is by stabilizing the CstF subunit binding to the CDE. 24 To date, the cited examples of auxiliary elements do not reveal a single consensus sequence, with the exception of the UGUA Factor (CstF), Cleavage Factors I m and II m (CFI m and CFII m ), and PAP. CPSF and CstF bind to specific sequences on the premRNA (Fig.…”

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confidence: 99%

Novel upstream and downstream sequence elements contribute to polyadenylation efficiency

Darmon

Lutz²

2012

RNA Biology

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Pre-mRNA must be processed to make mature translatable mRNA. The main processes involved in maturation of a mature mRNA are capping, splicing and polyadenylation.1 Capping involves the addition of a 7 methylguanosine ( 7 meG) cap at the 5' end of the mRNA. Splicing includes the removal of introns and the re-ligation of exons. Polyadenylation is a two-step coupled process of 3' end cleavage and subsequent addition of a non-templated poly A tail.Polyadenylation occurs in almost all eukaryotic mRNAs with the exception of histone mRNAs.2,3 Polyadenylation factors, made up of multi-subunit protein complexes, first cleave the 3' end of the mRNA at a specific cleavage site and then employ poly A polymerase (PAP) to add approximately 200 adenosine residues to the cleaved mRNA.2,4 Polyadenylation is essential for gene expression. Polyadenylation increases the stability of the mRNA, aids in the export out of the nucleus to the cytoplasm, and promotes transcription termination (reviewed in ref.3). Without a poly(A) tail, the mRNA is degraded, is inefficiently exported from the nucleus, or is unable to be translated. Therefore, defects polyadenylation is a 3' mRNA processing event that contributes to gene expression by affecting stability, export and translation of mRNA. human polyadenylation signals (pAs) have core and auxiliary elements that bind polyadenylation factors upstream and downstream of the cleavage site. The majority of mRNAs do not have optimal upstream and downstream core elements and therefore auxiliary elements can aid in polyadenylation efficiency.Auxiliary elements have previously been identified and studied in a small number of mRNAs. We previously used a global approach to examine auxiliary elements to identify overrepresented motifs by a bioinformatic survey. This predicted information was used to direct our in vivo validation studies, all of which were accomplished using both a tandem in vivo polyadenylation assay and using reporter protein assays measured as luciferase activity. Novel auxiliary elements were placed in a test polyadenylation signal. An in vivo polyadenylation assay was used to determine the strength of the polyadenylation signal. All but one of the novel auxiliary elements enhanced the test polyadenylation signal. effects of these novel auxiliary elements were also measured by a luciferase assay when placed in the 3' UTR of a firefly luciferase reporter. Two novel downstream auxiliary elements and all of the novel upstream auxiliary elements showed an increase in reporter protein levels.Many well known auxiliary polyadenylation elements have been found to occur in multiple sets. however, in our study, multiple copies of novel auxiliary elements brought reporter protein levels as well as polyadenylation choice back to wild type levels. structural features of these novel auxiliary elements may also affect the role of auxiliary elements. A Ms2 structure placed upstream of the polyadenylation signal can affect polyadenylation in both the positive and negative direction. A large change in ...

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Auxiliary downstream elements are required for efficient polyadenylation of mammalian pre-mRNAs

Cited by 50 publications

References 44 publications

Essential role for the interaction between hnRNP H/F and a G quadruplex in maintaining p53 pre-mRNA 3′-end processing and function during DNA damage

Essential role for the interaction between hnRNP H/F and a G quadruplex in maintaining p53 pre-mRNA 3′-end processing and function during DNA damage

Assembly of the Cleavage and Polyadenylation Apparatus Requires About 10 Seconds In Vivo and Is Faster for Strong than for Weak Poly(A) Sites

Novel upstream and downstream sequence elements contribute to polyadenylation efficiency

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