PRMT1 mediated methylation of TAF15 is required for its positive gene regulatory function

Jobert, Laure; Argentini, Manuela; Tora, Làszlò

doi:10.1016/j.yexcr.2008.12.008

Cited by 75 publications

(80 citation statements)

References 50 publications

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“…Studies of the yeast SR-like protein Npl3p (52,63); other shuttling RNA-binding proteins in mammals, such as some hnRNPs (24,40,47); and the transcription factors TAF15 and Ewing's sarcoma oncoprotein (EWS) (3,29) have shown that the Arg methylation of RGG motifs is involved in controlling the nucleocytoplasmic distribution of these proteins. However, no obvious defect in the nuclear export or localization of Npl3p was observed upon the replacement of Arg residues in the RGG motifs with Lys (45,61).…”

Section: Discussionmentioning

confidence: 99%

Arginine Methylation Controls the Subcellular Localization and Functions of the Oncoprotein Splicing Factor SF2/ASF

Sinha

Allemand

Zuo

et al. 2010

Molecular and Cellular Biology

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Alternative splicing and posttranslational modifications (PTMs) are major sources of protein diversity in eukaryotic proteomes. The SR protein SF2/ASF is an oncoprotein that functions in pre-mRNA splicing, with additional roles in other posttranscriptional and translational events. Functional studies of SR protein PTMs have focused exclusively on the reversible phosphorylation of Ser residues in the C-terminal RS domain. We confirmed that human SF2/ASF is methylated at residues R93, R97, and R109, which were identified in a global proteomic analysis of Arg methylation, and further investigated whether these methylated residues regulate the properties of SF2/ASF. We show that the three arginines additively control the subcellular localization of SF2/ASF and that both the positive charge and the methylation state are important. Mutations that block methylation and remove the positive charge result in the cytoplasmic accumulation of SF2/ASF. The consequent decrease in nuclear SF2/ASF levels prevents it from modulating the alternative splicing of target genes, results in higher translation stimulation, and abrogates the enhancement of nonsense-mediated mRNA decay. This study addresses the mechanisms by which Arg methylation and the associated positive charge regulate the activities of SF2/ASF and emphasizes the significance of localization control for an oncoprotein with multiple functions in different cellular compartments.Pre-mRNA splicing is a required step for the expression of most human genes. Alternative splicing plays a key role in regulating gene expression and is a major source of protein isoform diversity. SR proteins are a family of closely related and highly expressed eukaryotic RNA-binding proteins that regulate both general and alternative splicing (22) and have additional roles in other aspects of gene expression (41). SF2/ ASF, a prototypical member of the SR protein family, has a modular structure with two RNA recognition motifs (RRMs), which recognize a 7-nucleotide exonic splicing enhancer (ESE) motif on pre-mRNA, and an RS domain with numerous repeats of serine-arginine dipeptides (Fig. 1A). SF2/ASF is required for general splicing, though sometimes interchangeably with other SR proteins (33), and also plays a role in the regulation of alternative splicing in a concentration-dependent manner, in part through the recognition of ESEs (16). In addition to its role as a broad-specificity splicing regulator, SF2/ ASF strongly enhances nonsense-mediated mRNA decay (NMD) upon overexpression (65), stimulates translation both in vivo and in vitro in an enhancer-dependent manner (50), and functions as an adaptor protein for mRNA export (26). Some of these additional functions of SF2/ASF reflect its ability to shuttle between the nucleus and the cytoplasm (13). Reflecting its multifaceted role as a regulator in various cellular processes, SF2/ASF is a potent oncoprotein whose overexpression by as little as 2-fold is sufficient to transform immortal rodent fibroblasts (30). Conversely, the knockdown of SF2/...

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Section: Discussionmentioning

confidence: 99%

Arginine Methylation Controls the Subcellular Localization and Functions of the Oncoprotein Splicing Factor SF2/ASF

Sinha

Allemand

Zuo

et al. 2010

Molecular and Cellular Biology

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“…Another example is TATA-binding protein-associated factor 2N (TAF15) which was identified in 7 tissues with 6 citrullination sites. TAF15, together with RNAPII, is part of the transcription preinitiation complex at distinct promoters (56). It is interesting that all of the identified citrullination sites are located between residues 428-550.…”

Section: The Landscape Of Protein Citrullination Of Human Tissuesmentioning

confidence: 99%

Mining the Human Tissue Proteome for Protein Citrullination

Lee

Wang

Wilhelm

et al. 2018

Molecular & Cellular Proteomics

175

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SummaryCitrullination is a post-translational modification of arginine catalyzed by five peptidylarginine deiminases (PADs) in humans. The loss of a positive charge may cause structural or functional alterations and while the modification has been linked to several diseases including rheumatoid arthritis and cancer, its physiological or pathophysiological roles remain largely unclear. In part this is owing to limitations in available methodology able to robustly enrich, detect and localize the modification. As a result, only few citrullination sites have been identified on human proteins with high confidence. In this study, we mined data from mass spectrometry-based deep proteomic profiling of 30 human tissues to identify citrullination sites on endogenous proteins. Database searching of ~70 million tandem mass spectra yielded ~13,000 candidate spectra which were further triaged by spectrum quality metrics and the detection of the specific neutral loss of isocyanic acid from citrullinated peptides to reduce false positives. Because citrullination is easily confused with deamidation, we synthetized ~2,200 citrullinated and 1,300 deamidated peptides to build a library of reference spectra. This led to the validation of 375 citrullination sites on 209 human proteins. Further analysis showed that >80% of the identified modifications sites were new and for 56% of the proteins, citrullination was detected for the first time. Sequence motif analysis revealed a strong preference for Asp and Gly, residues around the citrullination site. Interestingly, while the modification was detected in 26 human tissues with the highest levels found in brain and lung, citrullination levels did not correlate well with protein expression of the PAD enzymes.Even though the current work represents the largest survey of protein citrullination to date, the modification was mostly detected on high abundant proteins arguing that the development of specific enrichment methods would be required in order to study the full extent of cellular protein citrullination.

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“…6 FET proteins have been involved in both transcriptional and post-transcriptional regulatory processes of gene expression, such as transcription initiation, splicing, DNA repair and RNA maturation. 6,7 However, to date the majority of studies have focused on the functions of FUS and EWS and their aberrant products, but the role of TAF15 in various cellular metabolisms remains unclear. Recently, we showed that a chromatin-associated fraction of TAF15 associates with a human U1 small nuclear RNA.…”

Section: Taf15 (Formerly Tafmentioning

confidence: 99%

TAF15 is important for cellular proliferation and regulates the expression of a subset of cell cycle genes through miRNAs

et al. 2012

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1TAF15 (formerly TAFII68) is a member of the FET (FUS, EWS, TAF15) family of RNA-and DNA-binding proteins whose genes are frequently translocated in sarcomas. By performing global gene expression profiling, we found that TAF15 knockdown affects the expression of a large subset of genes, of which a significant percentage is involved in cell cycle and cell death. In agreement, TAF15 depletion had a growth-inhibitory effect and resulted in increased apoptosis. Among the TAF15-regulated genes, targets of microRNAs (miRNAs) generated from the onco-miR-17 locus were overrepresented, with CDKN1A/p21 being the top miRNAstargeted gene. Interestingly, the levels of onco-miR-17 locus coded miRNAs (miR-17-5p and miR-20a) were decreased upon TAF15 depletion and shown to affect the post-transcriptional regulation of TAF15-dependent genes, such as CDKN1A/p21. Thus, our results demonstrate that TAF15 is required to regulate gene expression of cell cycle regulatory genes post-transcriptionally through a pathway involving miRNAs. The findings that high TAF15 levels are needed for rapid cellular proliferation and that endogenous TAF15 levels decrease during differentiation strongly suggest that TAF15 is a key regulator of maintaining a highly proliferative rate of cellular homeostasis.Oncogene ( Keywords: FUS/EWS/TAF15 (FET) proteins; miRNAs; transcription; proliferation; neuronal differentiation; neuroblastoma INTRODUCTION TAF15 (formerly TAF II 68) is a nuclear protein known to associate with a distinct subpopulation of transcription factor IID (TFIID), a multi-subunit complex that nucleates the pre-initiation complex on the promoters of on protein-coding genes.1,2 As TAF15 was not found to be associated with all human TFIID complexes and has no ortholog in other non-vertebrate species, TAF15 is not considered a canonical TAF.3 TAF15 harbors a transcriptional activation domain, a RNA recognition motif and many Arg-Gly-Gly (RGG) repeats known to participate in RNA binding.1 TAF15 together with the related FUS and EWS constitutes the FET (FUS/EWS/TAF15) protein family whose genes are frequently translocated in sarcomas and rare hematopoietic and epithelial cancers. 4 In each case, the N-terminus of the proteins, containing a potent transcriptional activation domain, 5 is fused to the DNA-binding domain of a transcription factor to form oncogenic chimeras.

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PRMT1 mediated methylation of TAF15 is required for its positive gene regulatory function

Cited by 75 publications

References 50 publications

Arginine Methylation Controls the Subcellular Localization and Functions of the Oncoprotein Splicing Factor SF2/ASF

Arginine Methylation Controls the Subcellular Localization and Functions of the Oncoprotein Splicing Factor SF2/ASF

Mining the Human Tissue Proteome for Protein Citrullination

TAF15 is important for cellular proliferation and regulates the expression of a subset of cell cycle genes through miRNAs

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