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Removing quote marks from the RNA polymerase II ctd 'code'

BIOSYSTEMS 2021年 207卷 104468-104468页

作者： Dieci, Giorgio Univ Parma Dept Chem Life Sci & Environm Sustainabil Parco Area Sci 23-A I-43124 Parma Italy

In eukaryotes, RNA polymerase II (Pol II) is responsible for the synthesis of all mRNAs and myriads of short and long untranslated RNAs, whose fabrication involves close spatiotemporal coordination between transcription, RNA processing and chromatin modification. Crucial for such a coordination is an unusual C-terminal domain (ctd) of the Pol II largest subunit, made of tandem repetitions (26 in yeast, 52 in chordates) of the heptapeptide with the consensus sequence YSPTSPS. Although largely unstructured and with poor sequence content, the Pol II ctd derives its extraordinary functional versatility from the fact that each amino acid in the heptapeptide can be posttranslationally modified, and that different combinations of ctd covalent marks are specifically recognized by different protein binding partners. These features have led to propose the existence of a Pol II ctd code, but this expression is generally used by authors with some caution, revealed by the frequent use of quote marks for the word 'code'. Based on the theoretical framework of code biology, it is argued here that the Pol II ctd modification system meets the requirements of a true organic code, where different ctd modification states represent organic signs whose organic meanings are biological reactions contributing to the many facets of RNA biogenesis in coordination with RNA synthesis by Pol II. Importantly, the Pol II ctd code is instantiated by adaptor proteins possessing at least two distinct domains, one of which devoted to specific recognition of ctd modification profiles. Furthermore, code rules can be altered by experimental interchange of ctd recognition domains of different adaptor proteins, a fact arguing in favor of the arbitrariness, and thus bona fide character, of the Pol II ctd code. Since the growing family of ctd adaptors includes RNA binding proteins and histone modification complexes, the Pol II ctd code is by its nature integrated with other organic codes, in particular the sp

关键词： RNA polymerase II Transcription Chromatin ctd code Histone code Splicing code Liquid-liquid phase separation Intrinsically disordered regions Protein tandem repeats

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Co-transcriptional splicing and the ctd code

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CRITICAL REVIEWS IN BIOCHEMISTRY AND MOLECULAR BIOLOGY 2016年第5期51卷 395-411页

作者： Custodio, Noelia Carmo-Fonseca, Maria Univ Lisbon Fac Med Inst Med Mol Lisbon Portugal

Transcription and splicing are fundamental steps in gene expression. These processes have been studied intensively over the past four decades, and very recent findings are challenging some of the formerly established ideas. In particular, splicing was shown to occur much faster than previously thought, with the first spliced products observed as soon as splice junctions emerge from RNA polymerase II (Pol II). Splicing was also found coupled to a specific phosphorylation pattern of Pol II carboxyl-terminal domain (ctd), suggesting a new layer of complexity in the ctd code. Moreover, phosphorylation of the ctd may be scarcer than expected, and other post-translational modifications of the ctd are emerging with unanticipated roles in gene expression regulation.

关键词： RNA Polymerase II transcription splicing spliceosome ctd code

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A critical role for Pol II ctd phosphorylation in heterochromatic gene activation

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GENE 2024年 918卷 148473页

作者： Kainth, Amoldeep S. Zhang, Hesheng Gross, David S. Louisiana State Univ Hlth Sci Ctr Dept Biochem & Mol Biol Shreveport LA 71130 USA Univ Chicago Dept Mol Genet & Cell Biol Chicago IL 60637 USA

How gene activation works in heterochromatin, and how the mechanism might differ from the one used in euchromatin, has been largely unexplored. Previous work has shown that in SIR -regulated heterochromatin of Saccharomyces cerevisiae , gene activation occurs in the absence of covalent histone modifications and other alterations of chromatin commonly associated with transcription. Here we demonstrate that such activation occurs in a substantial fraction of cells, consistent with frequent transcriptional bursting, and this raises the possibility that an alternative activation pathway might be used. We address one such possibility, Pol II ctd phosphorylation, and explore this idea using a natural telomere-linked gene, YFR057w , as a model. Unlike covalent histone modifications, we find that Ser2, Ser5 and Ser7 ctd phosphorylated Pol II is prevalent at the drug -induced heterochromatic gene. Particularly enriched relative to the euchromatic state is Ser2 phosphorylation. Consistent with a functional role for Ser2P, YFR057w is negligibly activated in cells deficient in the Ser2 ctd kinases Ctk1 and Bur1 even though the gene is strongly stimulated when it is placed in a euchromatic context. Collectively, our results are consistent with a critical role for Ser2 ctd phosphorylation in driving Pol II recruitment and transcription of a natural heterochromatic gene - an activity that may supplant the need for histone epigenetic modifications.

关键词： Bur1 Ctk1 ctd code ChIP Euchromatin Gene Activation Heat Shock Heterochromatin Histone code Fluorescence Microscopy Nucleosomes RNA Polymerase II Sir2/3/4-mediated Silent Chromatin Transcription Yeast

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Genetic screen for suppression of transcriptional interference identifies a gain-of-function mutation in Pol2 termination factor Seb1

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2021年第33期118卷 1页

作者： Schwer, Beate Garg, Angad Jacewicz, Agata Shuman, Stewart Weill Cornell Med Coll Dept Microbiol & Immunol New York NY 10065 USA Sloan Kettering Inst Mol Biol Program New York NY 10065 USA

The system of long noncoding RNA (lncRNA)-mediated transcriptional interference that represses fission yeast phosphate homoeostasis gene phol provides a sensitive readout of genetic influences on cotranscriptional 3'-processing and termination and a tool for discovery of regulators of this phase of the Pol2 transcription cycle. Here, we conducted a genetic screen for relief of transcriptional interference that unveiled a mechanism by which Pol2 termination is enhanced via a gain-of-function mutation, G476S, in the RNA-binding domain of an essential termination factor, Seb1. The genetic and physical evidence for gain-of-function is compelling: 1) seb1-G476S de-represses pho1 and tgp1, both of which are subject to lncRNA-mediated transcriptional interference;2) seb1-G476S elicits precocious lncRNA transcription termination in response to lncRNA 5'-proximal poly(A) signals;3) seb1-G476S derepression of pho1 is effaced by loss-of-function mutations in cleavage and polyadenylation factor (CPF) subunits and termination factor Rhn1;4) synthetic lethality of seb1-G476S with pho1 derepressive mutants rpb1-ctd-S7A and aps1 Delta is rescued by CPF/Rhn1 loss-of-function alleles;and 5) seb1-G476S elicits an upstream shift in poly(A) site preference in several messenger RNA genes. A crystal structure of the Seb1-G4765 RNA-binding domain indicates potential for gain of contacts from Ser476 to RNA nucleobases. To our knowledge, this is a unique instance of a gain-of-function phenotype in a eukaryal transcription termination protein.

关键词： transcription termination RNA 3 '-processing phosphate homeostasis ctd code inositol pyrophosphates

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The Phantom Mark: Enigmatic roles of phospho-Threonine 4 modification of the C-terminal domain of RNA polymerase II

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WILEY INTERDISCIPLINARY REVIEWS-RNA 2023年第4期14卷 e1771-e1771页

作者： Kempen, Ryan P. Dabas, Preeti Ansari, Aseem Z. St Jude Childrens Res Hosp Dept Chem Biol & Therapeut Memphis TN 38105 USA

The largest subunit of RNA polymerase II (Pol II) has an unusual carboxyl-terminal domain (ctd). This domain is composed of a tandemly repeating heptapeptide, Y1S2P3T4S5P6S7, that has multiple roles in regulating Pol II function and processing newly synthesized RNA. Transient phosphorylation of Ser2 and Ser5 of the YS2PTS5PS repeat have well-defined roles in recruiting different protein complexes and coordinating sequential steps in gene transcription. As such, these phospho-marks encipher a molecular recognition code, colloquially termed the ctd code. In contrast, the contribution of phospho-Threonine 4 (pThr4/pT4) to the ctd code remains opaque and contentious. Fuelling the debate on the relevance of this mark to gene expression are the findings that replacing Thr4 with a valine or alanine has varied impact on cellular function in different species and independent proteomic analyses disagree on the relative abundance of pThr4 marks. Yet, substitution with negatively charged residues is lethal and even benign mutations selectively disrupt synthesis and 3 ' processing of distinct sets of coding and non-coding transcripts. Suggestive of non-canonical roles, pThr4 marked Pol II regulates distinct gene classes in a species- and signal-responsive manner. Hinting at undiscovered roles of this elusive mark, multiple signal-responsive kinases phosphorylate Thr4 at target genes. Here, we focus on this under-explored residue and postulate that the pThr4 mark is superimposed on the canonical ctd code to selectively regulate expression of targeted genes without perturbing genome-wide transcriptional *** article is categorized under:RNA Processing > 3 ' End ProcessingRNA Processing > Processing of Small RNAsRNA Processing > Splicing Regulation/Alternative Splicing

关键词： ctd code RNA polymerase Threonine 4 signal-responsive kinase

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Structural determinants for accurate dephosphorylation of RNA polymerase II by its cognate C-terminal domain (ctd) phosphatase during eukaryotic transcription

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JOURNAL OF BIOLOGICAL CHEMISTRY 2019年第21期294卷 8592-8605页

作者： Irani, Seema Sipe, Sarah N. Yang, Wanjie Burkholder, Nathaniel T. Lin, Brian Sim, Kelly Matthews, Wendy L. Brodbelt, Jennifer S. Zhang, Yan Univ Texas Austin Dept Chem Engn Austin TX 78712 USA Univ Texas Austin Dept Mol Biosci Austin TX 78712 USA Univ Texas Austin Dept Chem Austin TX 78712 USA Univ Texas Austin Inst Cellular & Mol Biol Austin TX 78712 USA

The C-terminal domain (ctd) of RNA polymerase II contains a repetitive heptad sequence (YSPTSPS) whose phosphorylation states coordinate eukaryotic transcription by recruiting protein regulators. The precise placement and removal of phosphate groups on specific residues of the ctd are critical for the fidelity and effectiveness of RNA polymerase II-mediated transcription. During transcriptional elongation, phosphoryl-Ser(5) (pSer(5)) is gradually dephosphorylated by ctd phosphatases, whereas Ser(2) phosphorylation accumulates. Using MS, X-ray crystallography, protein engineering, and immunoblotting analyses, here we investigated the structure and function of SSU72 homolog, RNA polymerase II ctd phosphatase (Ssu72, from Drosophila melanogaster), an essential ctd phosphatase that dephosphorylates pSer(5) at the transition from elongation to termination, to determine the mechanism by which Ssu72 distinguishes the highly similar pSer(2) and pSer(5) ctds. We found that Ssu72 dephosphorylates pSer(5) effectively but only has low activities toward pSer(7) and pSer(2). The structural analysis revealed that Ssu72 requires that the proline residue in the substrate's SP motif is in the cis configuration, forming a tight -turn for recognition by Ssu72. We also noted that residues flanking the SP motif, such as the bulky Tyr(1) next to Ser(2), prevent the formation of such configuration and enable Ssu72 to distinguish among the different SP motifs. The phosphorylation of Tyr(1) further prohibited Ssu72 binding to pSer(2) and thereby prevented untimely Ser(2) dephosphorylation. Our results reveal critical roles for Tyr(1) in differentiating the phosphorylation states of Ser(2)/Ser(5) of ctd in RNA polymerase II that occur at different stages of transcription.

关键词： RNA polymerase II phosphatase mass spectrometry (MS) X-ray crystallography DNA transcription intrinsically disordered protein ctd code phosphoryl motif proline isomerization tyrosine phosphorylation

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RNA polymerase II ctd interactome with 3′ processing and termination factors in fission yeast and its impact on phosphate homeostasis

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2018年第45期115卷 E10652-E10661页

作者： Sanchez, Ana M. Shuman, Stewart Schwer, Beate Weill Cornell Med Coll Dept Microbiol & Immunol New York NY 10065 USA Sloan Kettering Inst Mol Biol Program New York NY 10065 USA

The carboxy-terminal domain (ctd) code encrypted within the (YSPTSPS7)-S-1-P-2-T-3-S-4-P-5-S-6 heptad repeats of RNA polymerase II (Pol2) is deeply rooted in eukaryal biology. Key steps to deciphering the code are identifying the events in gene expression that are governed by individual "letters" and then defining a vocabulary of multiletter "words" and their meaning. Thr4 and Ser7 exert opposite effects on the fission yeast pho1 gene, expression of which is repressed under phosphate-replete conditions by transcription of an upstream flanking long noncoding RNA (lncRNA). Here we attribute the derepression of pho1 by a ctd-S7A mutation to precocious termination of lncRNA synthesis, an effect that is erased by mutations of cleavage-polyadenylation factor (CPF) subunits Ctf1, Ssu72, Ppn1, Swd22, and Dis2 and termination factor Rhn1. By contrast, a ctd-T4A mutation hyperrepresses pho1, as do CPF subunit and Rhn1 mutations, implying that T4A reduces lncRNA termination. Moreover, ctd-T4A is synthetically lethal with ppn1 Delta and swd22 Delta, signifying that Thr4 and the Ppn1 center dot Swd22 module play important, functionally redundant roles in promoting Pol2 termination. We find that Ppn1 and Swd22 become essential for viability when the ctd array is curtailed and that S7A overcomes the need for Ppn1 center dot Swd22 in the short ctd context. Mutational synergies highlight redundant essential functions of (i) Ppn1 center dot Swd22 and Rhn1, (ii) Ppn1 center dot Swd22 Delta and Ctf1, and (iii) Ssu72 and Dis2 phosphatases. ctd alleles Y1F, S2A, and T4A have overlapping synthetic lethalities with ppn1 Delta and swd22., suggesting that Tyr1-Ser2-Thr4 form a threeletter ctd word that abets termination, with Rhn1 being a likely "reader" of this word.

关键词： Pol2 ctd code transcription termination synthetic lethality

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Different phosphoisoforms of RNA polymerase II engage the Rtt103 termination factor in a structurally analogous manner

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2017年第20期114卷 E3944-E3953页

作者： Nemec, Corey M. Yang, Fan Gilmore, Joshua M. Hintermair, Corinna Ho, Yi-Hsuan Tseng, Sandra C. Heidemann, Martin Zhang, Ying Florens, Laurence Gasch, Audrey P. Eick, Dirk Washburn, Michael P. Varani, Gabriele Ansari, Aseem Z. Univ Wisconsin Madison Dept Biochem Madison WI 53706 USA Univ Washington Dept Chem Seattle WA 98195 USA Stowers Inst Med Res Kansas City MO 64110 USA Helmholtz Ctr Munich Ctr Integrated Prot Sci Dept Mol Epigenet D-81377 Munich Germany Univ Wisconsin Madison Lab Genet Madison WI 53706 USA Univ Wisconsin Madison Genome Ctr Wisconsin Madison WI 53706 USA Univ Kansas Med Ctr Dept Pathol & Lab Med Kansas City KS 66150 USA Univ Calif San Diego Cell & Dev Biol La Jolla CA 92093 USA

The carboxyl-terminal domain (ctd) of the largest subunit of RNA polymerase II (Pol II) orchestrates dynamic recruitment of specific cellular machines during different stages of transcription. Signature phosphorylation patterns of Y1S2P3T4S5P6S7 heptapeptide repeats of the ctd engage specific "readers." Whereas phospho-Ser5 and phospho-Ser2 marks are ubiquitous, phospho-Thr4 is reported to only impact specific genes. Here, we identify a role for phospho-Thr4 in transcription termination at noncoding small nucleolar RNA (snoRNA) genes. Quantitative proteomics reveals an interactome of known readers as well as protein complexes that were not known to rely on Thr4 for association with Pol II. The data indicate a key role for Thr4 in engaging the machinery used for transcription elongation and termination. We focus on Rtt103, a protein that binds phospho-Ser2 and phospho-Thr4 marks and facilitates transcription termination at protein-coding genes. To elucidate how Rtt103 engages two distinct ctd modifications that are differentially enriched at noncoding genes, we relied on NMR analysis of Rtt103 in complex with phospho-Thr4- or phospho-Ser2-bearing ctd peptides. The structural data reveal that Rtt103 interacts with phospho-Thr4 in a manner analogous to its interaction with phospho-Ser2-modified ctd. The same set of hydrogen bonds involving either the oxygen on phospho-Thr4 and the hydroxyl on Ser2, or the phosphate on Ser2 and the Thr4 hydroxyl, can be formed by rotation of an arginine side chain, leaving the intermolecular interface otherwise unperturbed. This economy of design enables Rtt103 to engage Pol II at distinct sets of genes with differentially enriched ctd marks.

关键词： ctd code ctd interactome noncoding RNA NMR phosphothreonine

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Ras and Rho GTPase regulation of Pol II transcription: A shortcut model revisited

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TRANSCRIPTION-AUSTIN 2017年第4期8卷 268-274页

作者： Zheng, Zhi-Liang CUNY Lehman Coll Dept Biol Sci Bronx NY USA Southwest Univ Citrus Res Inst Plant Nutrient Signaling & Fruit Qual Improvement Chongqing Peoples R China

Transcriptional control is critical in relaying signals mediated by Ras and Rho family small GTPases to effect gene expression. In the classical model, signaling components such as MAP kinase target sequence-specific transcription factors, which in turn recruit RNA polymerase (Pol) II holoenzyme to the promoter and activate transcription. Findings in recent years have led to the proposal of a shortcut model in which the Mediator components of the Pol II holoenzyme are regulated by signaling pathways. A very recent finding shows that an evolutionarily conserved Rho GTPase signaling pathway can directly modulate the Pol II C-terminal domain (ctd) phosphorylation by inhibiting the ctd phosphatase in yeast and Arabidopsis. This shortcut model allows direct targeting of the Pol II ctd code and thus has an advantage over the classical model in bringing about rapid, large-scale changes in gene expression.

关键词： ctd code ctd phosphatase Ras GTPase Rho GTPase Pol II shortcut model transcription

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C-terminal domain (ctd) phosphatase links Rho GTPase signaling to Pol II ctd phosphorylation in Arabidopsis and yeast

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2016年第50期113卷 E8197-E8206页

作者： Zhang, Bo Yang, Guohua Chen, Yu Zhao, Yihong Gao, Peng Liu, Bo Wang, Haiyang Zheng, Zhi-Liang Southwest Univ Citrus Res Inst Plant Nutrient Signaling & Fruit Qual Improvement Chongqing 400712 Peoples R China CUNY Lehman Coll Dept Biol Sci Bronx NY 10468 USA NYU Dept Child & Adolescent Psychiat Langone Med Ctr Div Biostat 550 1St Ave New York NY 10016 USA Univ Calif Davis Dept Plant Biol Davis CA 95616 USA Chinese Acad Agr Sci Biotechnol Res Inst Beijing 100081 Peoples R China Southwest Univ Natl Citrus Engn Res Ctr Citrus Res Inst Chongqing 400712 Peoples R China CUNY Grad Sch & Univ Ctr Biol PhD Program Bronx NY 10016 USA St Jude Childrens Res Hosp Dept Infect Dis Memphis TN 38105 USA Genewiz NGS Dept Suzhou 215123 Jiangsu Peoples R China Natl Res Council Canada Saskatoon SK S7N 0W9 Canada

Rho GTPases, including the Rho, Cdc42, Rac, and ROP subfamilies, act as pivotal signaling switches in various growth and developmental processes. Compared with the well-defined role of cytoskeletal organization in Rho signaling, much less is known regarding transcriptional regulation. In a mutant screen for phenotypic enhancers of transgenic Arabidopsis plants expressing a constitutively active form of ROP2 (designated CA1-1), we identified RNA polymerase II (Pol II) C-terminal domain (ctd) phosphatase-like 1 (CPL1) as a transcriptional regulator of ROP2 signaling. We show that ROP2 activation inhibits CPL1 activity by promoting its degradation, leading to an increase in ctd Ser5 and Ser2 phosphorylation. We also observed similar modulation of ctd phosphorylation by yeast Cdc42 GTPase and enhanced degradation of the yeast ctd phosphatase Fcp1 by activated ROP2 signaling. Taken together, our results suggest that modulation of the Pol II ctd code by Rho GTPase signaling represents an evolutionarily conserved mechanism in both unicellular and multicellular eukaryotes.

关键词： Rho GTPase ROP GTPase Pol II ctd code CPL1

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