Dysregulation of the Peroxisome Proliferator-Activated Receptor Target Genes by XPD Mutations

Compe, Emmanuel; Drané, Pascal; Laurent, Césari; Diderich, Karin E. M.; Braun, Cathy; Hoeijmakers, Jan H.J.; Egly, Jean‐Marc

doi:10.1128/mcb.25.14.6065-6076.2005

Cited by 122 publications

(106 citation statements)

References 51 publications

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“…[13][14][15] We note that a number of other defects in CS and/or TTD cells and mice have been reported, namely defective transcriptional activation of nuclear hormone receptors (including regulators of fat metabolism) by the TFIIH complex. 16 However, the presence of these defects in different complementation groups of the same disease, or in both CS as well as TTD, and thus their ability to explain common disease symptoms, remains to be determined.…”

Section: Introductionmentioning

confidence: 99%

Nucleotide Excision Repair Disorders and the Balance Between Cancer and Aging

Andressoo¹,

Hoeijmakers²,

Mitchell³

2006

Cell Cycle

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Section: Introductionmentioning

confidence: 99%

Nucleotide Excision Repair Disorders and the Balance Between Cancer and Aging

Andressoo¹,

Hoeijmakers²,

Mitchell³

2006

Cell Cycle

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“…Furthermore, XPG was recently identified as a protein required for maintaining the integrity of the TFIIH complex, and therefore also engaged in the transcription process (20). Even though the contribution of the DNA repair deficiency to the clinical features of patients with XP, CS, or XP/ CS is irrefutable, studies have shown a clear dysregulation of a variety of transcriptional pathways, which may also contribute to the clinical phenotype of these patients (21)(22)(23)(24)(25)(26)(27). Interestingly, at the cellular level, XP/CS cells share with CS cells a sustained global transcriptional arrest after UV irradiation, which has been always explained by the inability of these cells to perform TCR (17,28).…”

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confidence: 99%

Sirt1 suppresses RNA synthesis after UV irradiation in combined xeroderma pigmentosum group D/Cockayne syndrome (XP-D/CS) cells

Vélez-Cruz

Zadorin

Coin

et al. 2012

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

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Specific mutations in the XPD subunit of transcription factor IIH result in combined xeroderma pigmentosum (XP)/Cockayne syndrome (CS), a severe DNA repair disorder characterized at the cellular level by a transcriptional arrest following UV irradiation. This transcriptional arrest has always been thought to be the result of faulty transcription-coupled repair. In the present study, we showed that, following UV irradiation, XP-D/CS cells displayed a gross transcriptional dysregulation compared with "pure" XP-D cells or WT cells. Furthermore, global RNA-sequencing analysis showed that XP-D/CS cells repressed the majority of genes after UV, whereas pure XP-D cells did not. By using housekeeping genes as a model, we demonstrated that XP-D/CS cells were unable to reassemble these gene promoters and thus to restart transcription after UV irradiation. Furthermore, we found that the repression of these promoters in XP-D/CS cells was not a simple consequence of deficient repair but rather an active heterochromatinization process mediated by the histone deacetylase Sirt1. Indeed, RNA-sequencing analysis showed that inhibition of and/or silencing of Sirt1 changed the chromatin environment at these promoters and restored the transcription of a large portion of the repressed genes in XP-D/CS cells after UV irradiation. Our work demonstrates that a significant part of the transcriptional arrest displayed by XP-D/CS cells arises as a result of an active repression process and not simply as a result of a DNA repair deficiency. This dysregulation of Sirt1 function that results in transcriptional repression may be the cause of various severe clinical features in patients with XP-D/ CS that cannot be explained by a DNA repair defect.nucleotide excision repair | sirtuins | aging | progeria

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“…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). The importance of NR phosphorylation by TFIIH in transcription has been highlighted in studies using cells from patients bearing mutations in the XPD subunit of TFIIH or in the xeroderma pigmentosum group G (XPG) endonuclease that established the consequence of hormonal/transcriptional dysfunctions in XP-CS/ TTD phenotypes.…”

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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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Dysregulation of the Peroxisome Proliferator-Activated Receptor Target Genes by XPD Mutations

Cited by 122 publications

References 51 publications

Nucleotide Excision Repair Disorders and the Balance Between Cancer and Aging

Nucleotide Excision Repair Disorders and the Balance Between Cancer and Aging

Sirt1 suppresses RNA synthesis after UV irradiation in combined xeroderma pigmentosum group D/Cockayne syndrome (XP-D/CS) cells

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

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