The pol II CTD: new twists in the tail

Zaborowska, Justyna; Egloff, Sylvain; Murphy, Shona

doi:10.1038/nsmb.3285

Cited by 190 publications

(227 citation statements)

References 89 publications

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“…Early studies of Cdc73 (parafibromin in humans) showed that it interacts directly and stoichiometrically with purified Pol II [2] and is important for Paf1C recruitment [7]. The dynamically modified C-terminal domain (CTD) of Pol II serves as a hub that recruits an array of accessory factors to chromatin [39], and subsequent work showed that a conserved C-terminal domain within Cdc73 preferentially interacts with phosphorylated Pol II CTD peptides in vitro [40, 41]. A second attachment point between Paf1C and the Pol II elongation machinery is mediated by the elongation factor Spt5 [30, 41, 42], which interacts directly with a central region of the Rtf1 subunit [43, 44].…”

Section: Mechanisms Of Targeting Paf1c To Chromatinmentioning

confidence: 99%

Emerging Insights into the Roles of the Paf1 Complex in Gene Regulation

Oss

Cucinotta

Arndt

2017

Trends in Biochemical Sciences

142

130

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The conserved, multifunctional Paf1 complex (Paf1C) regulates all stages of the RNA polymerase II transcription cycle. In this review, we examine a diverse set of recent studies from various organisms that build on foundational studies in budding yeast. These studies identify new roles for Paf1C in the control of gene expression and the regulation of chromatin structure. In exploring these advances, we find that Paf1C’s various functions, such as the regulation of promoter-proximal pausing and development in higher eukaryotes, are complex and context-dependent. As more becomes known about the role of Paf1C in human disease, interest in the molecular mechanisms underpinning Paf1C function will continue to increase.

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Section: Mechanisms Of Targeting Paf1c To Chromatinmentioning

confidence: 99%

Emerging Insights into the Roles of the Paf1 Complex in Gene Regulation

Oss

Cucinotta

Arndt

2017

Trends in Biochemical Sciences

142

130

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“…This unusual and essential domain of Rpb1, the largest component of the 12-subunit polymerase, consists of repeating Y 1 S 2 P 3 T 4 S 5 P 6 S 7 heptapeptides (26 repeats in budding yeast and 52 in humans) (1). The mechanistic consequences of phosphorylating Ser5 and Ser2 have been well documented (2)(3)(4)(5)(6)(7)(8)(9)(10)(11). However, the role of Thr4 phosphorylation (pThr4), and even the necessity of Thr4 for cellular survival, appears to differ among closely related species and between growth conditions within a given species (12)(13)(14)(15).…”

mentioning

confidence: 99%

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

Nemec

Yang

Gilmore

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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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 Y 1 S 2 P 3 T 4 S 5 P 6 S 7 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 phosphoSer2 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.ach stage of transcription relies on ordered recruitment and exchange of specific protein complexes that act on RNA polymerase II, its nascent transcripts, and the underlying chromatin. This dynamic process is orchestrated via patterned posttranslational modifications of the carboxyl-terminal domain (CTD). This unusual and essential domain of Rpb1, the largest component of the 12-subunit polymerase, consists of repeating Y 1 S 2 P 3 T 4 S 5 P 6 S 7 heptapeptides (26 repeats in budding yeast and 52 in humans) (1). The mechanistic consequences of phosphorylating Ser5 and Ser2 have been well documented (2-11). However, the role of Thr4 phosphorylation (pThr4), and even the necessity of Thr4 for cellular survival, appears to differ among closely related species and between growth conditions within a given species (12-15). Recent mass spectrometric analysis of an extensively engineered CTD revealed a paucity of pThr4, raising questions about the importance of this mark (16). In contrast, similar studies found pThr4 marks at levels comparable to or greater than the ubiquitously placed pSer2 mark in both yeast and human cells (17). Thus, much remains to be understood about the natural abundance and functional role of pThr4 marks on the endogenous, unmodified CTD.Previous studies suggest that pThr4 has roles in transcriptional elongation, 3ʹ-...

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“…Nevertheless, it is possible that additional kinases may also be able to phosphorylate the PCF11 CID in certain circumstances. For example, this has been shown for Pol II CTD residues, which are often phosphorylated by multiple kinases (Zaborowska et al 2016). We also note that it is likely that WNK1 has additional substrates and potentially other roles in the nucleus, which will be interesting to investigate further.…”

Section: Discussionmentioning

confidence: 99%

“…As Pol II transcribes a gene, the C-terminal domain (CTD) of its largest subunit, which comprises the heptadic repeat structure YSPTSPS (repeated 52 times in the mammalian enzyme, 26 times in yeast), is progressively phosphorylated, in particular at S2 positions (for reviews, see Milligan et al 2016;Zaborowska et al 2016). This phosphorylation mark is then recognized by the cleavage and polyadenylation complex (CPAC), subsequently leading to 3 ′ end processing of the pre-mRNA.…”

mentioning

confidence: 99%

WNK1 kinase and the termination factor PCF11 connect nuclear mRNA export with transcription

et al. 2017

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Nuclear gene transcription is coordinated with transcript release from the chromatin template and messenger RNA (mRNA) export to the cytoplasm. Here we describe the role of nuclear-localized kinase WNK1 (with no lysine [K] 1) in the mammalian mRNA export pathway even though it was previously established as a critical regulator of ion homeostasis in the cytoplasm. Our data reveal that WNK1 phosphorylates the termination factor PCF11 on its RNA polymerase II (Pol II) C-terminal domain (CTD)-interacting domain (CID). Furthermore, phosphorylation of the PCF11 CID weakens its interaction with Pol II. We predict that WNK1 and the associated phosphorylation of the PCF11 CID act to promote transcript release from chromatin-associated Pol II. This in turn facilitates mRNA export to the cytoplasm.

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The pol II CTD: new twists in the tail

Cited by 190 publications

References 89 publications

Emerging Insights into the Roles of the Paf1 Complex in Gene Regulation

Emerging Insights into the Roles of the Paf1 Complex in Gene Regulation

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

WNK1 kinase and the termination factor PCF11 connect nuclear mRNA export with transcription

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