The DNA-bound BRF2–TBP complex crystal structure reveals a redox-sensing function of BRF2.

  • Major finding: The DNA-bound BRF2–TBP complex crystal structure reveals a redox-sensing function of BRF2.

  • Mechanism: BRF2 oxidation at C361 impairs formation of the BRF2–TBP–DNA complex and reduces SeCys tRNA expression.

  • Impact: BRF2 upregulation in cancer cells promotes acquired resistance to oxidative stress.

Transcription factor IIB–related factor 2 (BRF2) is a core transcription factor that, in complex with TATA binding protein (TBP), recruits RNA polymerase III (Pol III) to essential gene promoters, including those encoding select tRNAs and the U6 small nuclear RNA (snRNA). BRF2 has recently been described as an oncogene, but its structure and molecular mechanism are poorly understood. Gouge, Satia, and colleagues obtained the X-ray crystallographic structure of the BRF2–TBP complex bound to DNA, including the U6 snRNA promoter (BRF2-TBP/DNA). The BRF2-TBP/DNA complex was similar to the TFIIB-TBP/DNA complex in the manner of TBP binding to TATA boxes. Three conserved C-terminal domain elements were identified: the arch, a semicircular α helix required for binding to the snRNA-activating complex; the anchor domain, which binds to TBP; and the molecular pin, a helical element that holds the BRF2-TBP/DNA complex together. The DNA-binding C361 residue of BRF2 was identified as the only reactive cysteine residue, and BRF2 oxidation at C361 inhibited the formation of the BRF2-TBP/DNA complex, suggesting a redox-sensing function of this residue. In normal lung fibroblast cells, induction of oxidative stress reduced the expression of BRF2-dependent genes, including the selenocysteine (SeCys) tRNA gene, which is essential for the synthesis of selenoproteins involved in reactive oxygen species detoxification. This reduced expression could be reversed by BRF2 overexpression, but not by a BRF2 C361D oxidized mimic mutant. Consistent with this finding, in normal fibroblast cells, oxidative stress reduced the levels of intracellular selenoproteins and promoted apoptosis, whereas BRF2 overexpression conferred resistance to oxidative stress. Furthermore, in lung adenocarcinoma cells with high BRF2 levels, oxidative stress upregulated selenoproteins and protected against apoptosis. Together, these findings reveal a role for BRF2 as a redox-sensing transcription factor involved in transcriptional regulation in response to oxidative stress, and suggest that BRF2 amplification may promote cancer cell survival under oxidative stress.

Gouge J, Satia K, Guthertz N, Widya M, Thompson AJ, Cousin P, et al. Redox signaling by the RNA polymerase III TFIIB-related factor Brf2. Cell 2015;163:1375–87.