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X. Zhang, N. M. A. Tran, G.-H. Peng, A. K. Hennig, S. Chen; The Xeroderma Pigmentosum Complementation Group D (XPD) Protein in Photoreceptor Gene Transcription, Development and Diseases. Invest. Ophthalmol. Vis. Sci. 2010;51(13):1679. doi: https://doi.org/.
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XPD is a component of the general transcription factor TFIIH complex involved in transcription and nucleotide excision repair. XPD mutations cause the autosomal recessive disorders trichothiodystrophy (TTD), cockayne syndrome (CS), and xeroderma pigmentosum (XP) with skin lesions, neurological defects and developmental delay. The neurological defects appear to be caused by transcriptional defects in nuclear receptor pathways. Using yeast two-hybrid screens, we identified XPD as an interaction partner of the photoreceptor nuclear receptor NR2E3. The goal of this research was to determine the role of TFIIH-XPD in photoreceptor gene transcription and development.
Co-immunoprecipitation, chromatin immunoprecipitation (ChIP) and co-transfection assays investigated XPD interactions with NR2E3 and other photoreceptor transcription factors (PhTFs). Histological and electrophysiological assays revealed retinal phenotypes of XpdTTD mice carrying the R722W mutation linked to TTD.
XPD protein is present in all mouse retina cell types, including photoreceptors and their precursors. Co-immunoprecipitation showed that XPD interacts not only with NR2E3, but also the cone-rod homeobox CRX and bZIP factor NRL. Each PhTF interacts with XPD via its regulatory domain. In transfected NIH3T3 cells, recombinant XPD enhanced the activation of the rhodopsin promoter by PhTFs, while shRNA-mediated XPD knockdown blocked transcriptional activation. ChIP assays on P14 wild-type mouse retinas showed that XPD and other components of TFIIH bind to promoter and coding regions of each opsin gene along with PhTFs. TFIIH target binding is reduced in mutant retinas lacking any PhTF, suggesting that TFIIH is a co-regulator of PhTFs. The importance of XPD-TFIIH was further revealed by photoreceptor defects in XpdTTD mice: Reduced amplitudes of dark and light adapted ERG "a" and "b" waves at P21 and 2 months of age, consistent with decreased transcription levels of PhTF target genes as measured by qRT-PCR.
TFIIH-XPD co-activator complex is essential for PhTF-regulated photoreceptor gene transcription and functional development.
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