TFIIB-related factor 1

TFIIB-related factor 2 (Brf2)

TFIIB-related factor 2 (Brf2)

BRF2 (TFIIB-related factor 2) is a component of TFIIIB.

TFIIB-related factor 2 (Brf2) is a member of the family of TFIIB-like core transcription factors. Brf2 recruits RNA polymerase (Pol) III to type III gene-external promoters, including the U6 spliceosomal RNA and selenocysteine tRNA genes. Found only in vertebrates, Brf2 has been linked to tumorigenesis but the underlying mechanisms remain elusive. Brf2-dependent Pol III promoters and highlighting the general structural and functional conservation of human Pol II and Pol III pre-initiation complexes. Brf2 as a central redox-sensing transcription factor involved in the oxidative stress pathway and provide a mechanistic model for Brf2 genetic activation in lung and breast cancer. Brf2 recruits RNA polymerase (Pol) III to type III gene-external promoters, including the U6 spliceosomal RNA and selenocysteine tRNA genes. Found only in vertebrates, Brf2 has been linked to tumorigenesis but the underlying mechanisms remain elusive [Redox Signaling by the RNA Polymerase III TFIIB-Related Factor Brf2.]

Recently, Brf2 was found to be specifically amplified in the squamous

cell carcinoma subtype of non-small cell lung cancer.

Additionally, Brf2 overexpression is observed in several forms of cancers and correlates with poor patient survival rates, implicating Brf2 as a general oncogene, a prognosis marker, and a target for new anticancer therapies.

Brf2 contacts extensively the phosphate backbone of the DNA and establishes sequence-specific contacts with both the upstream and downstream TATA flanking regions.[Redox Signaling by the RNA Polymerase III TFIIBRelated Factor Brf2]

TFIIIB is a complex composed of the TFIIB-related factor 1 (Brf1)

In the eukaryotic nucleus, RNA polymerase (Pol) III transcribes genes encoding essential RNAs, including tRNAs and the 5S rRNA. The accurate recruitment of Pol III to its target genes and the formation of a transcriptionally active pre-initiation complex (PIC) occur through the association of Pol III with several specific transcription factors but TFIIIB is the key factor required for this process.

TFIIIB is a complex composed of the TFIIB-related factor 1 (Brf1), the TATA binding protein (TBP), and Bdp1, a SANT domain-containing protein. Vertebrates contain an alternative TFIIIB complex in which Brf1 is replaced by the TFIIB-related factor 2 (Brf2).

The Brf2-containing TFIIIB complex recruits Pol III to type III promoters, characterized by a TATA box located 20–25 base pairs (bp) upstream of the transcriptional start site and a proximal sequence element (PSE) located further upstream.

The TATA box is recognized by the Brf2-TBP complex, which binds synergistically with SNAPc, a complex binding to the PSE.

U6 snRNA is a core component of the spliceosome.

U6 snRNA is a core component of the spliceosome. The spliceosome is composed of small nuclear ribonucleoprotein particles (snRNPs) and a protein-only complex called the NTC, which are represented as colored circles. Additional transiently bound proteins (not shown) are also necessary for progression through the splicing cycle. The U1, U2, U4, U5, and U6 snRNPs consist of the small nuclear RNA (snRNA) for which they are named and associated proteins. The snRNPs and NTC undergo ordered assembly on the pre-mRNA and experience both conformational and compositional changes throughout the cycle. After splicing is complete, the snRNPs and NTC are released and reused (dotted lines).[The life of U6 small nuclear RNA, from cradle to grave]

U2 and U6 snRNA are extensively base-paired in the catalytically active spliceosome. The proposed base-pairing interactions between the central domains of human U2 (turquoise) and U6 (yellow) snRNAs are shown, along with the pre-mRNA (blue). The interactions between the 5 0 splice site and U6 snRNA and the interaction between the branch site and U2 snRNA are depicted with the bulged adenosine branchpoint indicated in red. The base-paired helices I, II, and III and the intramolecular stem-loop of U6 are shown.[Splicing of mRNA precursors: The role of RNAs and proteins in catalysis]

U6 snRNA gene promoter structure is divergent in eukaryotes. (A) U6 gene promoter structure in S. cerevisiae. The U6 gene is under the control of a Pol III Type II promoter, with an upstream TATA box, an internal A block, and downstream B block. The TFIIIC complex recognizes the A and B blocks and directs binding of the TFIIIB complex to the TATA box. Nhp6 also promotes transcription, but its binding site is uncertain. A possible nucleosome is indicated by a gray oval. (B) U6 promoter structure in humans. U6 synthesis is under the control of a Pol III Type III promoter, where promoter elements (in black) are exclusively upstream of the transcription start site. The TATA box is recognized by the TFIIIB2 complex, while the PSE is recognized by the SNAPc complex. Factors including OCT1, STAF, and CDH2 interact with the DSE. p38 inhibits Oct-1 binding to the DSE. A nucleosome between the DSE and PSE enhances Oct-1 and SNAPc binding. [The life of U6 small nuclear RNA, from cradle to grave]