New tricks for an old dog: Brf2-dependent RNA Polymerase III transcription in oxidative stress and cancer

Abstract

Here, we discuss the role of Brf2, an RNA Polymerase III core transcription factor, as a master switch of the oxidative stress response. We highlight the interplay of Brf2 with the Nrf2/Keap1 pathway, as well as the role of Brf2 in cancer and other possible regulations.

Keywords: Brf2; Nrf2; RNA polymerase III; redox stress; transcription.

Figure 1.

Interplay between Nrf2 and Brf2 pathways. The Nrf2 pathway is activated through the redox stress: under basal conditions, Nrf2 is ubiquitinylated by Keap1 and Cul3 and targeted for proteosomal degradation. Under stress, the structure of Keap1 is altered and the newly synthesized Nrf2 molecules can translocate into the nucleus to form a complex with its binding partner sMAF and transcribe target genes. TFIIIB, composed of TBP, Bdp1 and Brf2, recruits the RNA polymerase III machinery to transcribe a small set of genes, including the SeCys tRNA. Brf2 is redox sensitive and, as a consequence, controls the transcriptional output in function of the redox state of the cell. Efficient translation of the phase II detoxification enzymes containing selenocysteine requires both high levels of their mRNA and high levels of SeCys tRNA. At low levels of stress, the proteins can be synthesized due to availability of both components, ensuring cell survival. At high levels of redox stress, however, the lack of SeCys tRNA results in impaired detoxification enzymes and redox homeostasis regulators, triggering apoptosis to protect the cells from further accumulation of damage.