Phosphorylated RNA polymerase II stimulates pre-mRNA splicing

Hirose, Yutaka; Tacke, Roland; Manley, James L.

doi:10.1101/gad.13.10.1234

Cited by 248 publications

(253 citation statements)

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“…Proteins that interact with active telomerase (brown) may regulate its recruitment to telomeres by interacting with telomeric chromatin directly or by a ecting telomerase subnuclear localization including capping, editing, splicing and cleavage, by factors associated with the transcribing polymerase itself (reviewed by Hirose and Manley, 2000).…”

Section: Rna Accumulationmentioning

confidence: 99%

Telomerase in the human organism

2002

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The intent of this review is to describe what is known and unknown about telomerase in somatic cells of the human organism. First, we consider the telomerase enzyme. Human telomerase ribonucleoproteins undergo at least three stages of cellular biogenesis: accumulation, catalytic activation and recruitment to the telomere. Next, we describe the patterns of telomerase regulation in the human soma. Telomerase activation in some cell types appears to o set proliferation-dependent telomere shortening, delaying but not defeating the inherent mitotic clock. Finally, we elaborate the connection between telomerase misregulation and human disease, in the contexts of inappropriate telomerase activation and telomerase de®ciency. We discuss how our current perspectives on telomerase function could be applied to improving human health.

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Section: Rna Accumulationmentioning

confidence: 99%

Telomerase in the human organism

2002

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“…Our data together with the data accumulated on SR proteins, point to the involvement of several different kinases and phosphatases in the phosphorylation status of nuclear factors. Regulation by phosphorylation is also an end to modulate the activity of the components of the transcription and polyadenylation complexes (Hunter and Karin, 1992;Colgan et al, 1996) and provides a linkage between processes of transcription and splicing (Hirose et al, 1999). …”

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confidence: 99%

Nuclear Relocalization of the Pre-mRNA Splicing Factor PSF during Apoptosis Involves Hyperphosphorylation, Masking of Antigenic Epitopes, and Changes in Protein Interactions

Shav‐Tal

Cohen

Lapter

et al. 2001

MBoC

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The spatial nuclear organization of regulatory proteins often reflects their functional state. PSF, a factor essential for pre-mRNA splicing, is visualized by the B92 mAb as discrete nuclear foci, which disappeared during apoptosis. Because this mode of cell death entails protein degradation, it was considered that PSF, which like other splicing factors is sensitive to proteolysis, might be degraded. Nonetheless, during the apoptotic process, PSF remained intact and was N-terminally hyperphosphorylated on serine and threonine residues. Retarded gel migration profiles suggested differential phosphorylation of the molecule in mitosis vs. apoptosis and under-phosphorylation during blockage of cells at G1/S. Experiments with the use of recombinant GFP-tagged PSF provided evidence that in the course of apoptosis the antigenic epitopes of PSF are masked and that PSF reorganizes into globular nuclear structures. In apoptotic cells, PSF dissociated from PTB and bound new partners, including the U1-70K and SR proteins and therefore may acquire new functions. INTRODUCTIONSplicing factors are found within the nucleus both in a diffuse form and in distinct domains termed interchromatin granules (IG) or "speckles" (Spector, 1993). These functional compartments are spatially dynamic with regard to movement and composition (Eils et al., 2000). Splicing factors within IGs are highly mobile and are constantly associating and dissociating from their compartments (Phair and Misteli, 2000). The mAb, B92, which recognizes the polypyrimidine tract binding protein (PTB)-associated splicing factor (PSF), produces typical specked nuclear pattern in immunostaining. These PSF speckles disappear during granulocytic differentiation (Lee et al., 1996;Shav-Tal et al., 2000). We recently showed that this disappearance is associated with partial degradation (Shav-Tal et al., 2000) and by the formation of alternative nuclear structures (Shav-Tal et al., 2001). The present study indicates that PSF speckles disappear also through a different mechanism, involving conformational changes that cause breakdown of PSF speckles and relocalization of the molecule in the nucleus. The functional nature of speckles is a matter of some controversy (for review, see Park and De Boni, 1999). These structures have been suggested to play a role in storage and recycling of splicing factors (Jimenez-Garcia and Spector, 1993), whereas a portion may act as reservoirs for the recruitment to active sites of transcription (Huang and Spector, 1996;Zeng et al., 1997). This view does not predict a direct involvement of speckles in pre-mRNA splicing. On the other hand, it has been shown that nascent mRNA transcripts and transcription sites are closely associated with speckles, that transcription occurs at the surface of speckles (Clemson and Lawrence, 1996), and that microinjected pre-mRNAs have high affinity to speckles (Wang et al., 1991). It has thus been proposed that speckles can act coordinately in transcription and splicing and that pre-mRNA splicing can take place bo...

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“…Indeed, a phosphorylated CTD is required for the efficient splicing reaction (Bird et al, 2004;Millhouse and Manley, 2005). RNA pol IIo stimulates the in vitro reconstituted splicing reaction of pre-mRNAs, while the addition of the phosphorylated CTD peptides inhibits this reaction (Du and Warren, 1997;Hirose et al, 1999). This indicates that an elongating pol II with phosphorylated CTD is an active component of the splicing reaction.…”

Section: Deciphering the Ctd Codementioning

confidence: 99%

RNA polymerase II carboxy-terminal domain with multiple connections

Cho¹

2007

Exp Mol Med

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The largest subunit of eukaryotic RNA polymerase II contains a unique domain at its carboxy-terminus, which is referred to as the carboxy-terminal domain (CTD). The CTD is made up of an evolutionarily conserved heptapeptide repeat (YSPTSPS). Over the past decade, there has been increasing attention on the role of the CTD in transcription regulation in the view of mRNA processing and chromatin remodeling. This paper provides a brief overview of the recent progress in the dynamic changes in CTD phosphorylation and its role in integrating multiple nuclear events.Keywords: carboxy-terminal domain kinase; chromatin; phosphorylation; histones; RNA polymerase II; RNA processing, post-transcriptional IntroductionThe largest subunit of eukaryotic RNA polymerase II (pol II) carboxy-terminal domain (CTD) consists of conserved heptapeptide repeats (Y 1 S 2 P 3 T 4 S 5 P 6 S 7 ) (Dahmus, 1996). Mammalian pol II CTD contains 52 repeats, whereas the yeast Saccharomyces cerevisiae CTD has 26-27. A deletion of the mouse, Drosophila, or yeast CTD is lethal. Therefore, the CTD is essential for the viability of an organism, even though the number of repeats can be reduced.Partial deletions of the CTD result in reduced transcription in vivo, and defective responses to various activators. The CTD acts as a platform to couple the mRNA metabolism and chromatin function to the transcription as it recruits various RNA processing/export and histone modifying factors to the transcription complex (Bentley, 2005;Buratowski, 2005;Phatnani and Greenleaf, 2006). This means that the CTD is very important for organizing various nuclear functions to acquire the proper regulation of gene expression. Those functions often depend on the CTD modification such as phosphorylation. Indeed, the CTD is rich in phosphoacceptor amino acid residues and undergoes reversible phosphorylation during the transcription cycle. Two forms of RNA pol II, which differ in the level of phosphorylation of the CTD, can be distinguished and are believed to have distinct functions in the transcription cycle; RNA pol IIa, with a hypophosphorylated CTD, is the form that assembles into the transcription initiation complexes, whereas pol IIo, with a hyperphosphorylated CTD is associated with the transcription elongation complexes. Phosphorylation occurs mainly at discrete serines (S) within the CTD repeats (S2, S5), which is then recognized by different proteins that interconnect the transcription to various nuclear metabolisms. Accordingly, serine phosphorylation is known as the 'CTD code', in a similar way that the 'histone code' refers to the histone modification (Buratowski, 2003). CTD with the phosphorylation codeEarlier models based on a two-step transcription cycle, in which pol IIa was assembled at the promoter and pol IIo carried out transcription elongation, have evolved to one with a more complex CTD phosphorylation cycle. Different modified forms of pol II dominate different stages of transcription (Komarnisky et al., 2000). Pol II assembled at the promoter is...

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Phosphorylated RNA polymerase II stimulates pre-mRNA splicing

Cited by 248 publications

References 35 publications

Telomerase in the human organism

Telomerase in the human organism

Nuclear Relocalization of the Pre-mRNA Splicing Factor PSF during Apoptosis Involves Hyperphosphorylation, Masking of Antigenic Epitopes, and Changes in Protein Interactions

RNA polymerase II carboxy-terminal domain with multiple connections

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