Cleavage factor I<sub>m</sub>is a key regulator of 3′ UTR length

Gruber, Andreas; Martín, Georges; Keller, Walter; Zavolan, Mihaela

doi:10.4161/rna.22570

Cited by 129 publications

(138 citation statements)

References 42 publications

(69 reference statements)

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“…The same was observed during differentiation of C2C12 myoblasts into myotubes . Our data strengthen the idea that changes in abundance of a single 39 processing factor can modulate APA, similar to what has been shown for CstF64 (Yao et al 2012), CFI68 (Gruber et al 2012), and CFI25 (Masamha et al 2014).…”

Section: Discussionsupporting

confidence: 76%

“…Most human genes encode transcripts with more than one potential poly(A) site, and APA is a widespread mechanism that generates mRNA isoforms with alternative 39 ends (for review, see Di Giammartino et al 2011;Elkon et al 2013;Tian and Manley 2013). A change in the levels or activity of core polyadenylation factors has been shown to affect APA globally (Gruber et al 2012;Yao et al 2012). Given the above results implicating RBBP6 in 39 processing, we wondered whether lowering RBBP6 levels in cells would affect APA.…”

Section: Rbbp6 Modulates Alternative Polyadenylation (Apa)mentioning

confidence: 99%

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RBBP6 isoforms regulate the human polyadenylation machinery and modulate expression of mRNAs with AU-rich 3′ UTRs

Giammartino

Ogami

et al. 2014

Genes Dev.

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Polyadenylation of mRNA precursors is mediated by a large multisubunit protein complex. Here we show that RBBP6 (retinoblastoma-binding protein 6), identified initially as an Rb-and p53-binding protein, is a component of this complex and functions in 39 processing in vitro and in vivo. RBBP6 associates with other core factors, and this interaction is mediated by an unusual ubiquitin-like domain, DWNN (''domain with no name''), that is required for 39 processing activity. The DWNN is also expressed, via alternative RNA processing, as a small single-domain protein (isoform 3 [iso3]). Importantly, we show that iso3, known to be down-regulated in several cancers, competes with RBBP6 for binding to the core machinery, thereby inhibiting 39 processing. Genome-wide analyses following RBBP6 knockdown revealed decreased transcript levels, especially of mRNAs with AU-rich 39 untranslated regions (UTRs) such as c-Fos and c-Jun, and increased usage of distal poly(A) sites. Our results implicate RBBP6 and iso3 as novel regulators of 39 processing, especially of RNAs with AU-rich 39 UTRs.

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Section: Discussionsupporting

confidence: 76%

Section: Rbbp6 Modulates Alternative Polyadenylation (Apa)mentioning

confidence: 99%

RBBP6 isoforms regulate the human polyadenylation machinery and modulate expression of mRNAs with AU-rich 3′ UTRs

Giammartino

Ogami

et al. 2014

Genes Dev.

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“…In eukaryotes, most mature mRNAs are generated from immature pre-mRNA through endonucleolytic splicing of introns and the addition of a poly(A) tail at the 3= end (Gruber et al 2012). Previously, biochemical studies revealed that at least 6 factors are necessary for this modification to occur efficiently in vitro, including the cleavage and polyadenylation specificity factor (CPSF), the cleavage stimulation factor (CstF), and cleavage factors I m and II m (CFI m and CFII m , respectively).…”

Section: Cleavage and Polyadenylation Specific Factor 6 (Cpsf6)mentioning

confidence: 99%

Cellular and viral determinants of retroviral nuclear entry

2016

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Retroviruses must integrate their cDNA into the host genome to generate proviruses. Viral DNA-protein complexes interact with cellular proteins and produce pre-integration complexes, which carry the viral genome and cross the nuclear pore channel to enter the nucleus and integrate viral DNA into host chromosomal DNA. If the reverse transcripts fail to integrate, linear or circular DNA species such as 1-and 2-long terminal repeats are generated. Such complexes encounter numerous cellular proteins in the cytoplasm, which restrict viral infection and protect the nucleus. To overcome host cell defenses, the pathogens have evolved several evasion strategies. Viral proteins often contain nuclear localization signals, allowing entry into the nucleus. Among more than 1000 proteins identified as required for HIV infection by RNA interference screening, karyopherins, cleavage and polyadenylation specific factor 6, and nucleoporins have been predominantly studied. This review discusses current opinions about the synergistic relationship between the viral and cellular factors involved in nuclear import, with focus on the unveiled mysteries of the host-pathogen interaction, and highlights novel approaches to pinpoint therapeutic targets.

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“…CPSF6 has emerged as a dominant player in directing HIV-1 integration into actively transcribing genes (15), yet it is not completely understood how CPSF6 exerts its effects on HIV infection at a biochemical level. CPSF6 was first identified as a subunit of cleavage factor Im (CFI m ), the key regulator of mRNA 3Ј end processing and polyadenylation site selection (31,32). CFI m is a tetramer composed of two 25-kDa (CPSF5) subunits and two proteins of either 59 or 68 kDa (CPSF7 or CPSF6) (31)(32)(33).…”

mentioning

confidence: 99%

The Cleavage and Polyadenylation Specificity Factor 6 (CPSF6) Subunit of the Capsid-recruited Pre-messenger RNA Cleavage Factor I (CFIm) Complex Mediates HIV-1 Integration into Genes

Rasheedi

Shun

Serrao

et al. 2016

Journal of Biological Chemistry

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HIV-1 favors integration into active genes and gene-enriched regions of host cell chromosomes, thus maximizing the probability of provirus expression immediately after integration. This requires cleavage and polyadenylation specificity factor 6 (CPSF6), a cellular protein involved in pre-mRNA 3 end processing that binds HIV-1 capsid and connects HIV-1 preintegration complexes to intranuclear trafficking pathways that link integration to transcriptionally active chromatin. CPSF6 together with CPSF5 and CPSF7 are known subunits of the cleavage factor I (CFI m ) 3 end processing complex; however, CPSF6 could participate in additional protein complexes. The molecular mechanisms underpinning the role of CPSF6 in HIV-1 infection remain to be defined. Here, we show that a majority of cellular CPSF6 is incorporated into the CFI m complex. HIV-1 capsid recruits CFI m in a CPSF6-dependent manner, which suggests that the CFI m complex mediates the known effects of CPSF6 in HIV-1 infection. To dissect the roles of CPSF6 and other CFI m complex subunits in HIV-1 infection, we analyzed virologic and integration site targeting properties of a CPSF6 variant with mutations that prevent its incorporation into CFI m . We show, somewhat surprisingly, that CPSF6 incorporation into CFI m is not required for its ability to direct preferential HIV-1 integration into genes. The CPSF5 and CPSF7 subunits appear to have only a minor, if any, role in this process even though they appear to facilitate CPSF6 binding to capsid. Thus, CPSF6 alone controls the key molecular interactions that specify HIV-1 preintegration complex trafficking to active chromatin.

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Cleavage factor I_mis a key regulator of 3′ UTR length

Cited by 129 publications

References 42 publications

RBBP6 isoforms regulate the human polyadenylation machinery and modulate expression of mRNAs with AU-rich 3′ UTRs

RBBP6 isoforms regulate the human polyadenylation machinery and modulate expression of mRNAs with AU-rich 3′ UTRs

Cellular and viral determinants of retroviral nuclear entry

The Cleavage and Polyadenylation Specificity Factor 6 (CPSF6) Subunit of the Capsid-recruited Pre-messenger RNA Cleavage Factor I (CFIm) Complex Mediates HIV-1 Integration into Genes

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Cleavage factor Imis a key regulator of 3′ UTR length

Cited by 129 publications

References 42 publications

RBBP6 isoforms regulate the human polyadenylation machinery and modulate expression of mRNAs with AU-rich 3′ UTRs

RBBP6 isoforms regulate the human polyadenylation machinery and modulate expression of mRNAs with AU-rich 3′ UTRs

Cellular and viral determinants of retroviral nuclear entry

The Cleavage and Polyadenylation Specificity Factor 6 (CPSF6) Subunit of the Capsid-recruited Pre-messenger RNA Cleavage Factor I (CFIm) Complex Mediates HIV-1 Integration into Genes

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Cleavage factor I_mis a key regulator of 3′ UTR length