Dataset Information

Control of the function of the transcription and repair factor TFIIH by the action of the cochaperone Ydj1.

ABSTRACT: Yeast rad3-102, a mutant of the TFIIH complex involved in nucleotide excision repair (NER) and transcription, can perform NER initial steps but not late steps of postincision gap filing. Because removal of early-acting NER proteins prevents rad3-102 deleterious action, we used this feature to explore if chaperones act in early NER. We found that the cochaperone Ydj1 is required for NER and that Ydj1 guarantees TFIIH stoichiometry. Importantly, in the absence of Ydj1, the roles of TFIIH in transcription and transactivation, the ability to activate transcription by nuclear receptors in response to hormones, are strongly impaired. We propose that TFIIH constitutes a multitarget complex for Ydj1, as six of the seven TFIIH core components contain biologically relevant Ydj1- binding motives. Our results provide evidence for a role of chaperones in NER and transcription, with implications in cancer and TFIIH-associated syndromes.

SUBMITTER: Moriel-Carretero M

PROVIDER: S-EPMC3174667 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Control of the function of the transcription and repair factor TFIIH by the action of the cochaperone Ydj1.

Moriel-Carretero María M Tous Cristina C Aguilera Andrés A

Proceedings of the National Academy of Sciences of the United States of America 20110829 37

Yeast rad3-102, a mutant of the TFIIH complex involved in nucleotide excision repair (NER) and transcription, can perform NER initial steps but not late steps of postincision gap filing. Because removal of early-acting NER proteins prevents rad3-102 deleterious action, we used this feature to explore if chaperones act in early NER. We found that the cochaperone Ydj1 is required for NER and that Ydj1 guarantees TFIIH stoichiometry. Importantly, in the absence of Ydj1, the roles of TFIIH in transc ...[more]

PMID: 21876155

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Project description:Preeclampsia is a significant cause of maternal and fetal mortality and morbidity worldwide. We previously reported associations between trichothiodystrophy (TTD) nucleotide excision repair (NER) and transcription gene mutations in the fetus and the risk of gestational complications including preeclampsia. TTD NER/transcription genes, XPD, XPB and TTD-A, code for subunits of Transcription Factor (TF)IIH. Interpreting XPD mutations in the context of available biochemical data led us to propose adverse effects on CDK-activating kinase (CAK) subunit of TFIIH and TFIIH-mediated functions as a relevant mechanism in preeclampsia. In order to gain deeper insight into the underlying biologic mechanisms involving TFIIH-mediated functions in placenta, we analyzed NER/transcription and global gene expression profiles of normal and preeclamptic placentas and studied gene regulatory networks.We found high expression of TTD NER/transcription genes in normal human placenta, above the mean of their expression in all organs. XPD and XPB were consistently expressed from 14 to 40 weeks gestation while expression of TTD-A was strongly negatively correlated (r=-0.7, P<0.0001) with gestational age. Analysis of gene expression patterns of placentas from a case-control study of preeclampsia using Algorithm for Reconstruction of Accurate Cellular Networks (ARACNE) revealed GTF2E1, a component of TFIIE which modulates TFIIH, among major regulators of differentially-expressed genes in preeclampsia. The basal transcription pathway was among the largest dysregulated protein-protein interaction networks in this preeclampsia dataset. Within the basal transcription pathway, significantly down-regulated genes besides GTF2E1 included those coding for the CAK complex of TFIIH, namely CDK7, CCNH, and MNAT1. Analysis of other relevant gene expression and gene regulatory network data also underscored the involvement of transcription pathways and identified JUNB and JUND (components of transcription factor AP-1) as transcription regulators of the network involving the TTD genes, GTF2E1, and selected gene regulators implicated in preeclampsia.Our results indicate that TTD NER/transcription genes are expressed in placenta during gestational periods critical to preeclampsia development. Our overall findings suggest that impairment of TFIIH-mediated function in transcription in placenta is a likely mechanism leading to preeclampsia and provide etiologic clues which may be translated into therapeutic and preventive measures.

Dataset Information

Control of the function of the transcription and repair factor TFIIH by the action of the cochaperone Ydj1.

Publications

Control of the function of the transcription and repair factor TFIIH by the action of the cochaperone Ydj1.

Similar Datasets

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