Dysregulation of the peroxisome proliferator-activated receptor target genes by XPD mutations
Authors: Cathy Braun
Emmanuel Compe
Jan H J Hoeijmakers
Jean-Marc Egly
Camille Laurent
Pascal Drané
Karin Diderich
Journal: Molecular and Cellular Biology (2005)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: XPD; TFIIH; genetic disorders; DNA repair syndromes; xeroderma pigmentosum
Affiliations: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch Cedex, CU Strasbourg, France., Institut de Génétique et de Biologie Moléculaire et Cellulaire, BP 10142, 67404 Illkirch Cedex, C. U. Strasbourg, France, MGC-Department of Cell Biology and Genetics, Centre for Biomedical Genetics, Erasmus Medical Center, 3000 DR Rotterdam, The Netherlands

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. 

Retracted: No

PubPeer comments:
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 Figure 4E. Much more similar than you would expect. ![file] , 
 Figure 4D. Right set panels. Much more similar than you would expect. https: imgur.com RVeh5cv , 
 Figure 5A. Much more similar than you would expect. https: imgur.com oXG2YuL , 
 We apologize for the mistakes found in this paper. We have full confidence in the findings and conclusions of the paper. However, in the interest of maintaining accuracy in the published scientific literature, we wish to contact the editorial in Molecular and Cellular Biology. #1 Image duplication results from carelessness during the construction of the Figure 4, which contains more than sixty different blots. The Input lane for cyclinH has been inconveniently attributed to MAT1, both having nearly the same molecular weight. While experiments for PPARu03b1 and PPARu03b32 have been done in parallel and loaded with the same input, we might provide a new panel for the interaction between MAT1 and PPARu03b32 (boxed in green). To strengthen our results, we provide a second experiment showing that PPARu03b32 interacts with MAT1 but not with cyclinH (Figure 4B#1, 2nd experiment). ![file] #2 These two bands do not look similar, as observed after magnification (Figure 4D#2). The scan from the right (framed in red) shows marks resulting from the clumsy attempt to reduce traces of fibers coming from the autoradiography cassette used (as can be seen on other gels, such as #3 and #4). Unfortunately, the original staining gel generated more than 15 years ago is no longer available. ![file] #3 Bands after Coomassie Blue staining for A B PPARu03b31 S84A and A B PPARu03b32 S112A (framed in red) were inadvertently used twice. While the gel corresponding on A B PPARu03b32 WT is the original one (Figure 4E#3, green frame), we found the appropriated gels for A B PPARu03b31 S84A and A B PPARu03b32 S112A (framed in blue), which share patterns of migration very similar to A B PPARu03b32 WT. The panel has been redesigned, accordingly. ![file] #4 We provide scans without marks of the images (Figure 4D#4). ![file] #5 After magnification (Figure 5A), these lanes appear different, the upper band (PPARu03b32) being weaker to the lower band (PPARu03b31) in BAT wt when compared to that observed in WAT wt. We provide a 2nd experiment, showing a lower phosphorylation of PPARu03b31 and PPARu03b32 in the WAT and BAT isolated from TTD mice. In addition, we observed that the phosphorylated forms of PPARu03b31 2 were no longer visible after treatment of the extracts with calf-intestinal alkaline phosphatase (CIP). ![file] , 
 #6 Could the author provide an update on the discussion with the journal? ,