TFIIH Kinase Places Bivalent Marks on the Carboxy-Terminal Domain of RNA Polymerase II

Akhtar, Maaz; Heidemann, Martin; Tietjen, Joshua R.; Zhang, David W.; Chapman, Rob D.; Eick, Dirk; Ansari, Aseem Z.

doi:10.1016/j.molcel.2009.04.016

Cited by 254 publications

(271 citation statements)

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“…The conclusion that CDK7 can phosphorylate Ser-7 is entirely consistent with the recent identification of yeast CDK7 (Kin28) as the major Ser-7 kinase (37). Beyond it we characterize the process in which the CTD is modified at residue Ser-7.…”

Section: Discussionsupporting

confidence: 84%

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RNA Polymerase II C-terminal Heptarepeat Domain Ser-7 Phosphorylation Is Established in a Mediator-dependent Fashion

Boeing

Rigault

Heidemann

et al. 2010

Journal of Biological Chemistry

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The largest subunit of RNA polymerase II (RNAPII) C-terminal heptarepeat domain (CTD) is subject to phosphorylation during initiation and elongation of transcription by RNA polymerase II. Here we study the molecular mechanisms leading to phosphorylation of Ser-7 in the human enzyme. Ser-7 becomes phosphorylated before initiation of transcription at promoter regions. We identify cyclin-dependent kinase 7 (CDK7) as one responsible kinase. Phosphorylation of both Ser-5 and Ser-7 is fully dependent on the cofactor complex Mediator. A subform of Mediator associated with an active RNAPII is critical for preinitiation complex formation and CTD phosphorylation. The Mediator-RNAPII complex independently recruits TFIIB and CDK7 to core promoter regions. CDK7 phosphorylates Ser-7 selectively in the context of an intact preinitiation complex. CDK7 is not the only kinase that can modify Ser-7 of the CTD. ChIP experiments with chemical inhibitors provide evidence that other yet to be identified kinases further phosphorylate Ser-7 in coding regions.In mammalian cells the C-terminal domain of the Rpb1 subunit of RNA polymerase II (RNAPII) 2 consists of 52 heptarepeats of the consensus sequence YSPTSPS (for review, see Refs. 1-3). When RNAPII enters the preinitiation complex (PIC) the CTD becomes phosphorylated at least on three serine residues, Ser-2, Ser-5, and Ser-7 (4), at a yet unknown number of repeat elements. In theory, combinations of modifications could generate a complex pattern sometimes referred to as CTD code hypothesis (5), in analogy to the modifications occurring on lysine, arginine, and serine residues within N-terminal tails of histones (6).Several kinases have been identified that modify the CTD. These are CDK1, CDK2, CDK7, CDK8, CDK9, Erk1/2, and DNA-dependent protein kinase. CDK1 and CDK2 phosphorylate preferentially Ser-5 of the CTD (7,8). In the case of CDK1 this has been associated with repression of transcription during mitosis (9). The signaling kinases Erk1/2 phosphorylate the RNAPII CTD in response to oxidative and osmotic stress (10). The promoter-associated kinase DNA-dependent protein kinase phosphorylates the CTD at Ser-7 in vitro, although it remains unclear whether this process is relevant to transcription (11, 12). CDK8 and the paralogue CDC2L6 are associated with the Mediator complex (13, 14). CDK8 has mostly been associated with repression of transcription, yet there are also reports that specific genes are activated by it (15, 16). CDK9 is thought to release RNAPII that is paused by negative inhibitory factors 5,6-dichloro-1-␤-D-ribofuranosylbenzimidazole (DRB) sensitivity-inducing factor and negative elongation factor some 30 -40 base pairs downstream of the transcription start sites. RNAPII then resumes elongation of transcription, during which it becomes further phosphorylated at Ser-2. A marked increase of Ser-2 phosphorylation is often seen near the 3Ј end of genes (4, 17). It is unclear whether this phosphorylation of the CTD near the polyadenylation site is necessary for efficient el...

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Section: Discussionsupporting

confidence: 84%

“…In a recent publication the yeast homologue of CDK7 (termed KIN28) was shown to be responsible for phosphorylation of the CTD at Ser-7 at the 5Ј end of many yeast genes (37). In mammals Ser-7 phosphorylation has been linked to proteincoding and -noncoding small nuclear RNA genes (4,38).…”

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confidence: 99%

RNA Polymerase II C-terminal Heptarepeat Domain Ser-7 Phosphorylation Is Established in a Mediator-dependent Fashion

Boeing

Rigault

Heidemann

et al. 2010

Journal of Biological Chemistry

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“…Once recruited to the DNA damage/ xeroderma pigmentosum group C (XPC)/HR23B complex, CAK dissociates from core-TFIIH and XPD upon the arrival of xeroderma pigmentosum group A (XPA) and other NER factors, thus promoting incision/excision of the damaged oligonucleotide and repair of the DNA (23). The CDK7 subunit of TFIIH phosphorylates residues Ser5 and Ser7 from the C-terminal domain (CTD) of the rpb1 RNA polymerase II (RNA Pol II) subunit and functions in promoter-proximal pausing and termination (24)(25)(26). In addition to its role in basal transcription, CDK7 also participates in the transactivation of several hormone-dependent genes by phosphorylating nuclear receptors (NRs) including retinoic acid receptors (27,28), the estrogen receptor (29), peroxisome proliferator-activated receptor (30), and the androgen receptor (31).…”

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confidence: 99%

ARCH domain of XPD, an anchoring platform for CAK that conditions TFIIH DNA repair and transcription activities

Abdulrahman

Iltis

Radu

et al. 2013

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

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The xeroderma pigmentosum group D (XPD) helicase is a subunit of transcription/DNA repair factor, transcription factor II H (TFIIH) that catalyzes the unwinding of a damaged DNA duplex during nucleotide excision repair. Apart from two canonical helicase domains, XPD is composed of a 4Fe-S cluster domain involved in DNA damage recognition and a module of uncharacterized function termed the "ARCH domain." By investigating the consequences of a mutation found in a patient with trichothiodystrophy, we show that the ARCH domain is critical for the recruitment of the cyclin-dependent kinase (CDK)-activating kinase (CAK) complex. Indeed, this mutation not only affects the interaction with the MAT1 CAK subunit, thereby decreasing the in vitro basal transcription activity of TFIIH itself and impeding the efficient recruitment of the transcription machinery on the promoter of an activated gene, but also impairs the DNA unwinding activity of XPD and the nucleotide excision repair activity of TFIIH. We further demonstrate the role of CAK in downregulating the XPD helicase activity within TFIIH. Taken together, our results identify the ARCH domain of XPD as a platform for the recruitment of CAK and as a potential molecular switch that might control TFIIH composition and play a key role in the conversion of TFIIH from a factor active in transcription to a factor involved in DNA repair.rare disease | regulation of gene expression T he xeroderma pigmentosum group D (XPD) gene encodes a 5′-3′ helicase (XPD) that harbors mutations in patients suffering from three rare autosomal recessive diseases, xeroderma pigmentosum (XP), trichothiodystrophy (TTD), and Cockayne syndrome (CS) (1, 2). XP is characterized by a deficit of the nucleotide excision repair (NER) pathway, leading to sun sensitivity and susceptibility to skin cancer. TTD is characterized by sulfur-deficient brittle hair and a variety of neuroectodermal symptoms (3). XPD is the founding member of a family of DNA helicases conserved in archaea and eukaryotes. All family members share a four-domain organization including a conserved (Fe-S) cluster-binding domain that is essential for the helicase activity and a module of uncharacterized function named the ARCH domain by its arch-shape structure (4-7). Although archeal XPD homologs are monomers and have no known stable interactors, eukaryotic XPD homologs are part of the general transcription/DNA repair factor transcription factor II H (TFIIH), a multisubunit complex made up of 10 subunits (reviewed in ref. 8). Low-resolution models for TFIIH have been obtained for the complex in yeast (9, 10) and for the human complex (11), showing an overall conservation of shape. Human TFIIH can be resolved into two functional and structural entities bridged by XPD: the core-TFIIH consists of XPB, p62, p52, p44, p34, and p8, whereas the cyclin-dependent kinase (CDK)-activating kinase (CAK) subcomplex contains CDK7, cyclin H, and ménage a trois 1 (MAT1). XPD interacts with the p44 core-TFIIH subunit and with MAT1, a subunit of CAK involve...

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“…3 Of the general transcription factors, TFIIH, a 10 subunit complex that contains both kinase and helicase activities, can phosphorylate Ser5 and Ser7 at promoters. 1,[4][5][6][7] The kinase activity is contained within the CAK submodule, which consists of the three subunits Cdk7, cyclin H and Mat1. The helicase subunits, ERCC2 and ERCC3, are thought to be critical for promoter melting, transcriptional initiation and promoter escape.…”

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confidence: 99%

B2 RNA represses TFIIH phosphorylation of RNA polymerase II

2011

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Transcription of mRNA genes by Pol II is a tightly regulated and highly coordinated event that requires numerous factors working in conjunction to control gene-specific transcription with spatial and temporal specificity. Pol II transcription is aided by a set of general factors that function at core promoters, including TFIIA, TFIIB, TFIID, TFIIE, TFIIF, TFIIH and mediator. 1 These factors, along with promoter-specific transcriptional regulator proteins and chromatin-modifying factors, coordinate the assembly of pre-initiation complexes at the promoters of genes. More recently, a model has emerged in which Pol II transcription at many genes is also tightly regulated at steps that occur subsequent to the recruitment of Pol II and general factors to promoters, such as promoter proximal pausing.2 Central to regulating post-initiation events is phosphorylation of Ser2, Ser5 and Ser7 residues in the heptapeptide repeats of the CTD of the largest subunit of Pol II (Rpb1).3 Of the general transcription factors, TFIIH, a 10 subunit complex that contains both kinase and helicase activities, can phosphorylate Ser5 and Ser7 at promoters. 1,[4][5][6][7] The kinase activity is contained within the CAK submodule, which consists of the three subunits Cdk7, cyclin H and Mat1. The helicase subunits, ERCC2 and ERCC3, are thought to be critical for promoter melting, transcriptional initiation and promoter escape. 1Transcription is not only orchestrated by a multitude of protein factors and post-translational modifications, but also by non-coding RNAs (ncRNAs), which are an emerging class of regulators of Pol II transcription. 8 We found that B2 RNA, a ncRNA in mouse cells, functions as a transcriptional regulator Mouse B2 RNA represses RNA polymerase II (Pol II) transcription during the cellular heat shock response. B2 RNA binds Pol II, enters complexes at promoters, and keeps the polymerase from engaging the DNA. Here we show that phosphorylation of Ser5 residues in the Pol II carboxy terminal domain (CTD) decreases after heat shock at the promoter of the repressed actin gene in mouse cells, despite the continued presence of Cdk7 and cyclin H. Biochemical assays revealed that B2 RNA, when present with Pol II in promoter-bound complexes, specifically represses CTD phosphorylation by TFIIH. Transcribed by RNA polymerase III from short interspersed elements (SINEs), B2 RNA is upregulated upon heat shock and other cellular stresses.10 Also upregulated is the other predominant mouse SINE RNA, B1 RNA. B2 RNA binds directly to Pol II and potently represses transcription; by contrast, B1 RNA can bind tightly to Pol II but is not capable of transcriptional repression in vitro. 11,12 We found that in heat-shocked mouse cells, B2 RNA mediates the transcriptional repression of genes such as actin.9 Biochemical experiments to investigate the mechanism of repression showed that B2 RNA, via its interaction with Pol II, assembles into complexes at the promoters of genes and renders the complexes transcriptionally inactive.11 Within these inhibi...

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TFIIH Kinase Places Bivalent Marks on the Carboxy-Terminal Domain of RNA Polymerase II

Cited by 254 publications

References 55 publications

RNA Polymerase II C-terminal Heptarepeat Domain Ser-7 Phosphorylation Is Established in a Mediator-dependent Fashion

RNA Polymerase II C-terminal Heptarepeat Domain Ser-7 Phosphorylation Is Established in a Mediator-dependent Fashion

ARCH domain of XPD, an anchoring platform for CAK that conditions TFIIH DNA repair and transcription activities

B2 RNA represses TFIIH phosphorylation of RNA polymerase II

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