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

Overview

Journal Mol Cell Biol

Specialty Cell Biology

Date 2005 Jul 1

PMID 15988019

Citations 59

Authors

Emmanuel Compe

Pascal Drane

Camille Laurent

Karin Diderich

Cathy Braun

Jan H J Hoeijmakers

Jean-Marc Egly

Affiliations

Soon will be listed here.

Abstract

Mutations in the XPD subunit of TFIIH give rise to human genetic disorders initially defined as DNA repair syndromes. Nevertheless, xeroderma pigmentosum (XP) group D (XP-D) patients develop clinical features such as hypoplasia of the adipose tissue, implying a putative transcriptional defect. Knowing that peroxisome proliferator-activated receptors (PPARs) are implicated in lipid metabolism, we investigated the expression of PPAR target genes in the adipose tissues and the livers of XPD-deficient mice and found that (i) some genes are abnormally overexpressed in a ligand-independent manner which parallels an increase in the recruitment of RNA polymerase (pol) II but not PPARs on their promoter and (ii) upon treatment with PPAR ligands, other genes are much less induced compared to the wild type, which is due to a lower recruitment of both PPARs and RNA pol II. The defect in transactivation by PPARs is likely attributable to their weaker phosphorylation by the cdk7 kinase of TFIIH. Having identified the phosphorylated residues in PPAR isotypes, we demonstrate how their transactivation defect in XPD-deficient cells can be circumvented by overexpression of either a wild-type XPD or a constitutively phosphorylated PPAR S/E. This work emphasizes that underphosphorylation of PPARs affects their transactivation and consequently the expression of PPAR target genes, thus contributing in part to the XP-D phenotype.

Citing Articles

Emerging roles of cyclin-dependent kinase 7 in health and diseases.

Belew M, Chen J, Cheng Z Trends Mol Med. 2024; 31(2):138-151.

PMID: 39414519 PMC: 11825286. DOI: 10.1016/j.molmed.2024.09.004.

Evaluation of Meibomian gland dysfunction using meibography in patients with xeroderma pigmentosum.

Marcos A, Freitas D, Hazarbassanov R, Fernandes A, Castro L, de Melo D Arq Bras Oftalmol. 2024; 87(2):e20220319.

PMID: 38451683 PMC: 11620332. DOI: 10.5935/0004-2749.2022-0319.

PPARα: An emerging target of metabolic syndrome, neurodegenerative and cardiovascular diseases.

Lin Y, Wang Y, Li P Front Endocrinol (Lausanne). 2023; 13:1074911.

PMID: 36589809 PMC: 9800994. DOI: 10.3389/fendo.2022.1074911.

Nuclear Receptors and Lipid Sensing.

Thorne J, Cioccoloni G Adv Exp Med Biol. 2022; 1390:83-105.

PMID: 36107314 DOI: 10.1007/978-3-031-11836-4_5.

Ercc2/Xpd deficiency results in failure of digestive organ growth in zebrafish with elevated nucleolar stress.

Ma J, Shao X, Geng F, Liang S, Yu C, Zhang R iScience. 2022; 25(9):104957.

PMID: 36065184 PMC: 9440294. DOI: 10.1016/j.isci.2022.104957.

References

Berger J, Moller D . The mechanisms of action of PPARs. Annu Rev Med. 2002; 53:409-35. DOI: 10.1146/annurev.med.53.082901.104018. View

Keriel A, Stary A, Sarasin A, Rochette-Egly C, Egly J . XPD mutations prevent TFIIH-dependent transactivation by nuclear receptors and phosphorylation of RARalpha. Cell. 2002; 109(1):125-35. DOI: 10.1016/s0092-8674(02)00692-x. View

Wang Y, Lee C, Tiep S, Yu R, Ham J, Kang H . Peroxisome-proliferator-activated receptor delta activates fat metabolism to prevent obesity. Cell. 2003; 113(2):159-70. DOI: 10.1016/s0092-8674(03)00269-1. View

Lee C, Olson P, Evans R . Minireview: lipid metabolism, metabolic diseases, and peroxisome proliferator-activated receptors. Endocrinology. 2003; 144(6):2201-7. DOI: 10.1210/en.2003-0288. View

Dubaele S, Proietti De Santis L, Bienstock R, Keriel A, Stefanini M, Van Houten B . Basal transcription defect discriminates between xeroderma pigmentosum and trichothiodystrophy in XPD patients. Mol Cell. 2003; 11(6):1635-46. DOI: 10.1016/s1097-2765(03)00182-5. View

Riedl T, Hanaoka F, Egly J . The comings and goings of nucleotide excision repair factors on damaged DNA. EMBO J. 2003; 22(19):5293-303. PMC: 204472. DOI: 10.1093/emboj/cdg489. View

Zurita M, Merino C . The transcriptional complexity of the TFIIH complex. Trends Genet. 2003; 19(10):578-84. DOI: 10.1016/j.tig.2003.08.005. View

He W, Barak Y, Hevener A, Olson P, Liao D, Le J . Adipose-specific peroxisome proliferator-activated receptor gamma knockout causes insulin resistance in fat and liver but not in muscle. Proc Natl Acad Sci U S A. 2003; 100(26):15712-7. PMC: 307633. DOI: 10.1073/pnas.2536828100. View

Drane P, Compe E, Catez P, Chymkowitch P, Egly J . Selective regulation of vitamin D receptor-responsive genes by TFIIH. Mol Cell. 2004; 16(2):187-97. DOI: 10.1016/j.molcel.2004.10.007. View

10.

Happle R, Traupe H, Grobe H, Bonsmann G . The Tay syndrome (congenital ichthyosis with trichothiodystrophy). Eur J Pediatr. 1984; 141(3):147-52. DOI: 10.1007/BF00443212. View

11.

Johnson R, Squires S, Elliott G, Koch G, Rainbow A . Xeroderma pigmentosum D-HeLa hybrids with low and high ultraviolet sensitivity associated with normal and diminished DNA repair ability, respectively. J Cell Sci. 1985; 76:115-33. DOI: 10.1242/jcs.76.1.115. View

12.

Itin P, Pittelkow M . Trichothiodystrophy: review of sulfur-deficient brittle hair syndromes and association with the ectodermal dysplasias. J Am Acad Dermatol. 1990; 22(5 Pt 1):705-17. DOI: 10.1016/0190-9622(90)70096-z. View

13.

Lu H, Zawel L, Fisher L, Egly J, Reinberg D . Human general transcription factor IIH phosphorylates the C-terminal domain of RNA polymerase II. Nature. 1992; 358(6388):641-5. DOI: 10.1038/358641a0. View

14.

BOOTSMA D, Hoeijmakers J . DNA repair. Engagement with transcription. Nature. 1993; 363(6425):114-5. DOI: 10.1038/363114a0. View

15.

Humbert S, van Vuuren H, Lutz Y, Hoeijmakers J, Egly J, Moncollin V . p44 and p34 subunits of the BTF2/TFIIH transcription factor have homologies with SSL1, a yeast protein involved in DNA repair. EMBO J. 1994; 13(10):2393-8. PMC: 395104. DOI: 10.1002/j.1460-2075.1994.tb06523.x. View

16.

Roy R, Adamczewski J, Seroz T, Vermeulen W, Tassan J, Schaeffer L . The MO15 cell cycle kinase is associated with the TFIIH transcription-DNA repair factor. Cell. 1994; 79(6):1093-101. DOI: 10.1016/0092-8674(94)90039-6. View

17.

Tontonoz P, Hu E, Spiegelman B . Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor. Cell. 1994; 79(7):1147-56. DOI: 10.1016/0092-8674(94)90006-x. View

18.

Lehmann J, Moore L, Wilkison W, Willson T, Kliewer S . An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J Biol Chem. 1995; 270(22):12953-6. DOI: 10.1074/jbc.270.22.12953. View

19.

Grosschedl R . Higher-order nucleoprotein complexes in transcription: analogies with site-specific recombination. Curr Opin Cell Biol. 1995; 7(3):362-70. DOI: 10.1016/0955-0674(95)80091-3. View

20.

Kato S, Endoh H, Masuhiro Y, Kitamoto T, Uchiyama S, Sasaki H . Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase. Science. 1995; 270(5241):1491-4. DOI: 10.1126/science.270.5241.1491. View