TFIIH is a 10-subunit complex that regulates RNA polymerase II (pol II) transcription but
also serves other important biological roles. Although much remains unknown about TFIIH function
in eukaryotic Show more
TFIIH is a 10-subunit complex that regulates RNA polymerase II (pol II) transcription but
also serves other important biological roles. Although much remains unknown about TFIIH function
in eukaryotic cells, much progress has been made even in just the past few years, due in part to
technological advances (e.g. cryoEM and single molecule methods) and the development of chemical inhibitors of TFIIH enzymes. This review focuses on the major cellular roles for TFIIH, with an
emphasis on TFIIH function as a regulator of pol II transcription. We describe the structure of TFIIH
and its roles in pol II initiation, promoter-proximal pausing, elongation, and termination. We also
discuss cellular roles for TFIIH beyond transcription (e.g. DNA repair, cell cycle regulation) and
summarize small molecule inhibitors of TFIIH and diseases associated with defects in TFIIH structure and function. Show less
Impaired selective turnover of p62 by autophagy causes severe liver injury accompanied by the formation of p62-positive inclusions and upregulation of detoxifying enzymes. These phenotypes correspond Show more
Impaired selective turnover of p62 by autophagy causes severe liver injury accompanied by the formation of p62-positive inclusions and upregulation of detoxifying enzymes. These phenotypes correspond closely to the pathological conditions seen in human liver diseases, including alcoholic hepatitis and hepatocellular carcinoma. However, the molecular mechanisms and pathophysiological processes in these events are still unknown. Here we report the identification of a novel regulatory mechanism by p62 of the transcription factor Nrf2, whose target genes include antioxidant proteins and detoxification enzymes. p62 interacts with the Nrf2-binding site on Keap1, a component of Cullin-3-type ubiquitin ligase for Nrf2. Thus, an overproduction of p62 or a deficiency in autophagy competes with the interaction between Nrf2 and Keap1, resulting in stabilization of Nrf2 and transcriptional activation of Nrf2 target genes. Our findings indicate that the pathological process associated with p62 accumulation results in hyperactivation of Nrf2 and delineates unexpected roles of selective autophagy in controlling the transcription of cellular defence enzyme genes. Show less