RNA Polymerase II CTD Modifications: How Many Tales From a Single Tail
TL;DR: Results from the most recent CTD‐related literature are examined and an overview of the general function of Rpb1‐CTD in transcription, transcription‐ related and non transcription‐related processes in which it has been recently shown to be involved in are given.
Abstract: Eukaryote's RNA polymerases II (RNAPII) have the feature to contain, at the carbossi-terminal region of their largest subunit Rpb1, a unique CTD domain. Rpb1-CTD is composed of an increasing number of repetitions of the Y1S2P3T4S5P6S7 heptad that goes in parallel with the developmental level of organisms. Because of its composition, the CTD domain has a huge structural plasticity; virtually all the residues can be subjected to post-translational modifications and the two prolines can either be in cis or trans conformations. In light of these features, it is reasonable to think that different specific nuances of CTD modification and interacting factors take place not only on different gene promoters but also during different stages of the transcription cycle and reasonably might have a role even if the polymerase is on or off the DNA template. Rpb1-CTD domain is involved not only in regulating transcriptional rates, but also in all co-transcriptional processes, such as pre-mRNA processing, splicing, cleavage, and export. Moreover, recent studies highlight a role of CTD in DNA replication and in maintenance of genomic stability and specific CTD-modifications have been related to different CTD functions. In this paper, we examine results from the most recent CTD-related literature and give an overview of the general function of Rpb1-CTD in transcription, transcription-related and non transcription-related processes in which it has been recently shown to be involved in. J. Cell. Physiol. 229: 538–544, 2014. © 2013 Wiley Periodicals, Inc.
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TL;DR: M6A marks in eukaryotic DNA and RNA might be more widespread and diversified than previously believed and members of the TET/JBP family of dioxygenases have been suggested to be m6A demethylases, although this proposal needs more careful evaluation.
Abstract: While N(6) -methyladenosine (m(6) A) is a well-known epigenetic modification in bacterial DNA, it remained largely unstudied in eukaryotes. Recent studies have brought to fore its potential epigenetic role across diverse eukaryotes with biological consequences, which are distinct and possibly even opposite to the well-studied 5-methylcytosine mark. Adenine methyltransferases appear to have been independently acquired by eukaryotes on at least 13 occasions from prokaryotic restriction-modification and counter-restriction systems. On at least four to five instances, these methyltransferases were recruited as RNA methylases. Thus, m(6) A marks in eukaryotic DNA and RNA might be more widespread and diversified than previously believed. Several m(6) A-binding protein domains from prokaryotes were also acquired by eukaryotes, facilitating prediction of potential readers for these marks. Further, multiple lineages of the AlkB family of dioxygenases have been recruited as m(6) A demethylases. Although members of the TET/JBP family of dioxygenases have also been suggested to be m(6) A demethylases, this proposal needs more careful evaluation. Also watch the Video Abstract.
128 citations
Cites background from "RNA Polymerase II CTD Modifications..."
...The strong conservation of this enzyme, which is typical of RNA-modification enzymes, and interaction with the CTD, which plays an important role as a scaffold for RNA-processing [81], raises the possibility that it might methylate mRNA or a CTD-associated ribonucleoprotein....
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TL;DR: In this article, the authors discuss an emerging perspective of gene regulation, which moves away from classic models of stoichiometric interactions towards an understanding of how spatial compartmentalization can lead to non-stoichiometric molecular interactions and non-linear regulatory behaviours.
Abstract: Gene regulation requires the dynamic coordination of hundreds of regulatory factors at precise genomic and RNA targets. Although many regulatory factors have specific affinity for their nucleic acid targets, molecular diffusion and affinity models alone cannot explain many of the quantitative features of gene regulation in the nucleus. One emerging explanation for these quantitative properties is that DNA, RNA and proteins organize within precise, 3D compartments in the nucleus to concentrate groups of functionally related molecules. Recently, nucleic acids and proteins involved in many important nuclear processes have been shown to engage in cooperative interactions, which lead to the formation of condensates that partition the nucleus. In this Review, we discuss an emerging perspective of gene regulation, which moves away from classic models of stoichiometric interactions towards an understanding of how spatial compartmentalization can lead to non-stoichiometric molecular interactions and non-linear regulatory behaviours. We describe key mechanisms of nuclear compartment formation, including emerging roles for non-coding RNAs in facilitating their formation, and discuss the functional role of nuclear compartments in transcription regulation, co-transcriptional and post-transcriptional RNA processing, and higher-order chromatin regulation. More generally, we discuss how compartmentalization may explain important quantitative aspects of gene regulation.
83 citations
TL;DR: Evidence is described that the transcription factor general transcription factor II-I (TFII-I) targets CTCF binding to metabolism-related genes across the genome and regulates the transcription of genes within this network on the level of initiation via RNA polymerase II phosphorylation.
Abstract: CCCTC-binding factor (CTCF) is a key regulator of nuclear chromatin structure and gene regulation. The impact of CTCF on transcriptional output is highly varied, ranging from repression to transcriptional pausing and transactivation. The multifunctional nature of CTCF may be directed solely through remodeling chromatin architecture. However, another hypothesis is that the multifunctional nature of CTCF is mediated, in part, through differential association with protein partners having unique functions. Consistent with this hypothesis, our mass spectrometry analyses of CTCF interacting partners reveal a previously undefined association with the transcription factor general transcription factor II-I (TFII-I). Biochemical fractionation of CTCF indicates that a distinct CTCF complex incorporating TFII-I is assembled on DNA. Unexpectedly, we found that the interaction between CTCF and TFII-I is essential for directing CTCF to the promoter proximal regulatory regions of target genes across the genome, particularly at genes involved in metabolism. At genes coregulated by CTCF and TFII-I, we find knockdown of TFII-I results in diminished CTCF binding, lack of cyclin-dependent kinase 8 (CDK8) recruitment, and an attenuation of RNA polymerase II phosphorylation at serine 5. Phenotypically, knockdown of TFII-I alters the cellular response to metabolic stress. Our data indicate that TFII-I directs CTCF binding to target genes, and in turn the two proteins cooperate to recruit CDK8 and enhance transcription initiation.
65 citations
Cites background from "RNA Polymerase II CTD Modifications..."
...Once this complex has been established, and RNA Pol II is recruited, RNA Pol II is able to clear the proximal promoter and initiate mRNA synthesis after it is phosphorylated at serine 5 residue of the C-terminal domain (CTD) on the largest RNA Pol II subunit (36, 37)....
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TL;DR: The role of CDK/cyclin-dependent phosphorylation in the regulation of transcription and RNA splicing is summarized and recent findings that indicate the involvement ofCDK11/ cyclin L complexes at the cross-roads of cell cycle, transcription andRNA splicing are highlighted.
31 citations
TL;DR: Surprisingly, glycosylation on the periodic CTD follows a distributive mechanism, resulting in highly heterogeneous glycoforms, and the results suggest that O-GlcNAc cycling enzymes can employ a similar mechanism to react with other protein substrates on multiple sites.
Abstract: O-GlcNAcylation is a nutrient-responsive glycosylation that plays a pivotal role in transcriptional regulation. Human RNA polymerase II (Pol II) is extensively modified by O-linked N-acetylglucosamine (O-GlcNAc) on its unique C-terminal domain (CTD), which consists of 52 heptad repeats. One approach to understanding the function of glycosylated Pol II is to determine the mechanism of dynamic O-GlcNAcylation on the CTD. Here, we discovered that the Pol II CTD can be extensively O-GlcNAcylated in vitro and in cells. Efficient glycosylation requires a minimum of 20 heptad repeats of the CTD and more than half of the N-terminal domain of O-GlcNAc transferase (OGT). Under conditions of saturated sugar donor, we monitored the attachment of more than 20 residues of O-GlcNAc to the full-length CTD. Surprisingly, glycosylation on the periodic CTD follows a distributive mechanism, resulting in highly heterogeneous glycoforms. Our data suggest that initial O-GlcNAcylation can take place either on the proximal or on the distal region of the CTD, and subsequent glycosylation occurs similarly over the entire CTD with nonuniform distributions. Moreover, removal of O-GlcNAc from glycosylated CTD is also distributive and is independent of O-GlcNAcylation level. Our results suggest that O-GlcNAc cycling enzymes can employ a similar mechanism to react with other protein substrates on multiple sites. Distributive O-GlcNAcylation on Pol II provides another regulatory mechanism of transcription in response to fluctuating cellular conditions.
23 citations
References
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TL;DR: It is reported that high-grade serous ovarian cancer is characterized by TP53 mutations in almost all tumours (96%); low prevalence but statistically recurrent somatic mutations in nine further genes including NF1, BRCA1,BRCA2, RB1 and CDK12; 113 significant focal DNA copy number aberrations; and promoter methylation events involving 168 genes.
Abstract: A catalogue of molecular aberrations that cause ovarian cancer is critical for developing and deploying therapies that will improve patients' lives. The Cancer Genome Atlas project has analysed messenger RNA expression, microRNA expression, promoter methylation and DNA copy number in 489 high-grade serous ovarian adenocarcinomas and the DNA sequences of exons from coding genes in 316 of these tumours. Here we report that high-grade serous ovarian cancer is characterized by TP53 mutations in almost all tumours (96%); low prevalence but statistically recurrent somatic mutations in nine further genes including NF1, BRCA1, BRCA2, RB1 and CDK12; 113 significant focal DNA copy number aberrations; and promoter methylation events involving 168 genes. Analyses delineated four ovarian cancer transcriptional subtypes, three microRNA subtypes, four promoter methylation subtypes and a transcriptional signature associated with survival duration, and shed new light on the impact that tumours with BRCA1/2 (BRCA1 or BRCA2) and CCNE1 aberrations have on survival. Pathway analyses suggested that homologous recombination is defective in about half of the tumours analysed, and that NOTCH and FOXM1 signalling are involved in serous ovarian cancer pathophysiology.
5,878 citations
01 Jun 2011
TL;DR: The Cancer Genome Atlas project has analyzed messenger RNA expression, microRNA expression, promoter methylation and DNA copy number in 489 high-grade serous ovarian adenocarcinomas and the DNA sequences of exons from coding genes in 316 of these tumours as mentioned in this paper.
Abstract: A catalogue of molecular aberrations that cause ovarian cancer is critical for developing and deploying therapies that will improve patients’ lives. The Cancer Genome Atlas project has analysed messenger RNA expression, microRNA expression, promoter methylation and DNA copy number in 489 high-grade serous ovarian adenocarcinomas and the DNA sequences of exons from coding genes in 316 of these tumours. Here we report that high-grade serous ovarian cancer is characterized by TP53 mutations in almost all tumours (96%); low prevalence but statistically recurrent somatic mutations in nine further genes including NF1, BRCA1, BRCA2, RB1 and CDK12; 113 significant focal DNA copy number aberrations; and promoter methylation events involving 168 genes. Analyses delineated four ovarian cancer transcriptional subtypes, three microRNA subtypes, four promoter methylation subtypes and a transcriptional signature associated with survival duration, and shed new light on the impact that tumours with BRCA1/2 (BRCA1 or BRCA2) and CCNE1 aberrations have on survival. Pathway analyses suggested that homologous recombination is defective in about half of the tumours analysed, and that NOTCH and FOXM1 signalling are involved in serous ovarian cancer pathophysiology.
5,609 citations
TL;DR: It is shown that the carboxy-terminal domain of the pol II large subunit is required for efficient RNA processing, and an association between the CTD and 3′-processing factors suggests that an mRNA 'factory' exists which carries out coupled transcription, splicing and cleavage–polyadenylation of mRNA precursors.
Abstract: Messenger RNA is produced by RNA polymerase II (pol II) transcription, followed by processing of the primary transcript Transcription, splicing and cleavage-polyadenylation can occur independently in vitro, but we demonstrate here that these processes are intimately linked in vivo We show that the carboxy-terminal domain (CTD) of the pol II large subunit is required for efficient RNA processing Splicing, processing of the 3' end and termination of transcription downstream of the poly(A) site, are all inhibited by truncation of the CTD We found that the cleavage-polyadenylation factors CPSF and CstF specifically bound to CTD affinity columns and copurified with pol II in a high-molecular-mass complex Our demonstration of an association between the CTD and 3'-processing factors, considered together with reports of a similar interaction with splicing factors, suggests that an mRNA 'factory' exists which carries out coupled transcription, splicing and cleavage-polyadenylation of mRNA precursors
921 citations
"RNA Polymerase II CTD Modifications..." refers background in this paper
...Besides, the CTD tail is necessary for coupling of transcription with both constitutive and alternative splicing as it has been shown that CTD truncation impairs splicing and correct 30-end cleavage (McCracken et al., 1997; Misteli and Spector, 1999)....
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TL;DR: It is reported that the Paf1 protein complex, which is associated with the elongating RNA polymerase II, is required for methylation of lysines 4 and 79 of histone H3 and for silencing of expression of a telomere-associated gene.
751 citations
TL;DR: Recent papers help to explain how the changes in CTD phosphorylation pattern are linked to the progression from initiation through elongation to termination.
750 citations
"RNA Polymerase II CTD Modifications..." refers background in this paper
...The Rpb1-CTD domain is dispensable for transcription in vitro, but it plays a crucial role in vivo (Buratowski, 2003; Buratowski, 2009; Perales and Bentley, 2009; Svejstrup, 2012)....
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