4roe | pdb_00004roe
Human TFIIB-related factor 2 (Brf2) and TBP bound to RPPH1 promoter
Structural highlights
Disease[TBP_HUMAN] Defects in TBP are the cause of spinocerebellar ataxia type 17 (SCA17) [MIM:607136]. Spinocerebellar ataxia is a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCA17 is an autosomal dominant cerebellar ataxia (ADCA) characterized by widespread cerebral and cerebellar atrophy, dementia and extrapyramidal signs. The molecular defect in SCA17 is the expansion of a CAG repeat in the coding region of TBP. Longer expansions result in earlier onset and more severe clinical manifestations of the disease.[1] [2] [3] Function[BRF2_HUMAN] General activator of RNA polymerase III transcription. Factor exclusively required for RNA polymerase III transcription of genes with promoter elements upstream of the initiation sites.[4] [5] [6] [TBP_HUMAN] General transcription factor that functions at the core of the DNA-binding multiprotein factor TFIID. Binding of TFIID to the TATA box is the initial transcriptional step of the pre-initiation complex (PIC), playing a role in the activation of eukaryotic genes transcribed by RNA polymerase II. Component of the transcription factor SL1/TIF-IB complex, which is involved in the assembly of the PIC (preinitiation complex) during RNA polymerase I-dependent transcription. The rate of PIC formation probably is primarily dependent on the rate of association of SL1 with the rDNA promoter. SL1 is involved in stabilization of nucleolar transcription factor 1/UBTF on rDNA.[7] Publication Abstract from PubMedTFIIB-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. We have solved crystal structures of a human Brf2-TBP complex bound to natural promoters, obtaining a detailed view of the molecular interactions occurring at Brf2-dependent Pol III promoters and highlighting the general structural and functional conservation of human Pol II and Pol III pre-initiation complexes. Surprisingly, our structural and functional studies unravel a Brf2 redox-sensing module capable of specifically regulating Pol III transcriptional output in living cells. Furthermore, we establish 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. Redox Signaling by the RNA Polymerase III TFIIB-Related Factor Brf2.,Gouge J, Satia K, Guthertz N, Widya M, Thompson AJ, Cousin P, Dergai O, Hernandez N, Vannini A Cell. 2015 Dec 3;163(6):1375-87. doi: 10.1016/j.cell.2015.11.005. PMID:26638071[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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