Recent molecular insights into canonical pre-mRNA 3’-end processing

Sun, Yadong; Hamilton, Keith; Tong, Liang

doi:10.1080/21541264.2020.1777047

Cited by 58 publications

(55 citation statements)

References 105 publications

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“…The 3 0 -UTR-APA is the most common type of APA and originates mRNA isoforms that share the same coding region but have different 3 0 -UTRs. The UTRs are depicted in gray; the coding region is represented by colored boxes and the polyadenylation signals (PAS) by black arrows domain 33 (WDR33; Sun et al, 2020;Takagaki et al, 1989). The WDR33 and CPSF-30 subunits recognize the PAS (Chan et al, 2014;Schonemann et al, 2014;Sun et al, 2018), FIPL1 binds to the USE and to U-rich sequences located between the PAS and the cleavage site (Kaufmann et al, 2004), CPSF-73 is the endonuclease that cleaves the pre-mRNA at the cleavage site (Mandel et al, 2006), and CPSF-160 functions as a scaffold, recruiting both WDR33 and CPSF-30 into the correct configuration for PAS binding (Sun et al, 2018).…”

Section: On the Function Of Core 0 -End Processing Factors In Apamentioning

confidence: 99%

On the function and relevance of alternative 3′‐UTRs in gene expression regulation

Pereira-Castro

Moreira

2021

WIREs RNA

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Messanger RNA (mRNA) isoforms with alternative 3 0 -untranslated regions (3 0 -UTRs) are produced by alternative polyadenylation (APA), which occurs during transcription in most eukaryotic genes. APA fine-tunes gene expression in a cell-type-and cellular state-dependent manner. Selection of an APA site entails the binding of core cleavage and polyadenylation factors to a particular polyadenylation site localized in the pre-mRNA and is controlled by multiple regulatory determinants, including transcription, pre-mRNA cis-regulatory sequences, and protein factors. Alternative 3 0 -UTRs serve as platforms for specific RNA binding proteins and microRNAs, which regulate gene expression in a coordinated manner by controlling mRNA fate and function in the cell.Genome-wide studies illustrated the full extent of APA prevalence and revealed that specific 3 0 -UTR profiles are associated with particular cellular states and diseases. Generally, short 3 0 -UTRs are associated with proliferative and cancer cells, and long 3 0 -UTRs are mostly found in polarized and differentiated cells. Fundamental new insights on the physiological consequences of this widespread event and the molecular mechanisms involved have been revealed through single-cell studies. Publicly available comprehensive databases that cover all APA mRNA isoforms identified in many cellular states and diseases reveal specific APA signatures. Therapies tackling APA mRNA isoforms or APA regulators may be regarded as innovative and attractive tools for diagnostics or treatment of several pathologies. We highlight the function of APA and alternative 3 0 -UTRs in gene expression regulation, the control of these mechanisms, their physiological consequences, and their potential use as new biomarkers and therapeutic tools.

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Section: On the Function Of Core 0 -End Processing Factors In Apamentioning

confidence: 99%

On the function and relevance of alternative 3′‐UTRs in gene expression regulation

Pereira-Castro

Moreira

2021

WIREs RNA

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“…In eukaryotes, most mRNA precursors (pre-mRNAs) are cleaved and polyadenylated at their 3 ′ end prior to their export from the nucleus (Zhao et al 1999;Shi and Manley 2015;Sun et al 2020a). This sequence of events is carefully orchestrated, with multiple protein complexes binding to different cis elements in the pre-mRNA, providing both a tight regulation of cleavage/polyadenylation and the opportunity to select from multiple cleavage sites with various affinities (alternative polyadenylation [APA]) (Tian and Manley 2017;Gruber and Zavolan 2019).…”

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confidence: 99%

Molecular mechanism for the interaction between human CPSF30 and hFip1

Hamilton

Tong

2020

Genes Dev.

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Most eukaryotic pre-mRNAs must undergo 3 ′ -end cleavage and polyadenylation prior to their export from the nucleus. A large number of proteins in several complexes participate in this 3 ′ -end processing, including cleavage and polyadenylation specificity factor (CPSF) in mammals. The CPSF30 subunit contains five CCCH zinc fingers (ZFs), with ZF2-ZF3 being required for the recognition of the AAUAAA poly(A) signal. ZF4-ZF5 recruits the hFip1 subunit of CPSF, although the details of this interaction have not been characterized. Here we report the crystal structure of human CPSF30 ZF4-ZF5 in complex with residues 161-200 of hFip1 at 1.9 Å resolution, illuminating the molecular basis for their interaction. Unexpectedly, the structure reveals one hFip1 molecule binding to each ZF4 and ZF5, with a conserved mode of interaction. Our mutagenesis studies confirm that the CPSF30-hFip1 complex has 1:2 stoichiometry in vitro. Mutation of each binding site in CPSF30 still allows one copy of hFip1 to bind, while mutation of both sites abrogates binding. Our fluorescence polarization binding assays show that ZF4 has higher affinity for hFip1, with a K d of 1.8 nM. We also demonstrate that two copies of the catalytic module of poly(A) polymerase (PAP) are recruited by the CPSF30-hFip1 complex in vitro, and both hFip1 binding sites in CPSF30 can support polyadenylation.

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“…Among them, the cleavage and polyadenylation specificity factor proteins exist widely in many organisms ( Shi and Manley, 2015 ). Most mRNA precursors (pre-mRNAs) are cleaved and polyadenylated at the 3’ end prior to their export from the nucleus ( Sun et al., 2020 ). This sequence of events is carefully orchestrated, providing both a tight regulation of cleavage/polyadenylation and the opportunity to select from multiple cleavage sites with various affinities ( Gruber and Zavolan, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Identification of Myoferlin, a Potential Serodiagnostic Antigen of Clonorchiasis, via Immunoproteomic Analysis of Sera From Different Infection Periods and Excretory-Secretory Products of Clonorchis sinensis

Qiu

Chang

et al. 2021

Front. Cell. Infect. Microbiol.

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Clonorchiasis, which is caused by Clonorchis sinensis, is an important foodborne disease worldwide. The excretory-secretory products (ESPs) of C. sinensis play important roles in host-parasite interactions by acting as causative agents. In the present study, the ESPs and sera positive for C. sinensis were collected to identify proteins specific to the sera of C. sinensis (i.e., proteins that do not cross-react with Fasciola hepatica and Schistosoma japonicum) at different infection periods. Briefly, white Japanese rabbits were artificially infected with C. sinensis, and their sera were collected at 7 days post-infection (dpi), 14 dpi, 35 dpi, and 77 dpi. To identify the specific proteins in C. sinensis, a co-immunoprecipitation (Co-IP) assay was conducted using shotgun liquid chromatography tandem-mass spectrometry (LC-MS/MS) to pull down the sera roots of C. sinensis, F. hepatica, and S. japonicum. For the annotated proteins, 32, 18, 39, and 35 proteins specific to C. sinensis were pulled down by the infected sera at 7, 14, 35, and 77 dpi, respectively. Three proteins, Dynein light chain-1, Dynein light chain-2 and Myoferlin were detected in all infection periods. Of these proteins, myoferlin is known to be overexpressed in several human cancers and could be a promising biomarker and therapeutic target for cancer cases. Accordingly, this protein was selected for further studies. To achieve a better expression, myoferlin was truncated into two parts, Myof1 and Myof2 (1,500 bp and 810 bp), based on the antigenic epitopes provided by bioinformatics. The estimated molecular weight of the recombinant proteins was 57.3 ku (Myof1) and 31.3 ku (Myof2). Further, both Myof1 and Myof2 could be probed by the sera from rabbits infected with C. sinensis. No cross-reaction occurred with the positive sera of S. japonica, F. hepatica, and negative controls. Such findings indicate that myoferlin may be an important diagnostic antigen present in the ESPs. Overall, the present study provides new insights into proteomic changes between ESPs and hosts in different infection periods by LC-MS/MS. Moreover, myoferlin, as a biomarker, may be used to develop an objective method for future diagnosis of clonorchiasis.

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Recent molecular insights into canonical pre-mRNA 3’-end processing

Cited by 58 publications

References 105 publications

On the function and relevance of alternative 3′‐UTRs in gene expression regulation

On the function and relevance of alternative 3′‐UTRs in gene expression regulation

Molecular mechanism for the interaction between human CPSF30 and hFip1

Identification of Myoferlin, a Potential Serodiagnostic Antigen of Clonorchiasis, via Immunoproteomic Analysis of Sera From Different Infection Periods and Excretory-Secretory Products of Clonorchis sinensis

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