RESUMEN
Spt4/5 in archaea and eukaryote and its bacterial homolog NusG is the only elongation factor conserved in all three domains of life and plays many key roles in cotranscriptional regulation and in recruiting other factors to the elongating RNA polymerase. Here, we present the crystal structure of Spt4/5 as well as the structure of RNA polymerase-Spt4/5 complex using cryoelectron microscopy reconstruction and single particle analysis. The Spt4/5 binds in the middle of RNA polymerase claw and encloses the DNA, reminiscent of the DNA polymerase clamp and ring helicases. The transcription elongation complex model reveals that the Spt4/5 is an upstream DNA holder and contacts the nontemplate DNA in the transcription bubble. These structures reveal that the cellular RNA polymerases also use a strategy of encircling DNA to enhance its processivity as commonly observed for many nucleic acid processing enzymes including DNA polymerases and helicases.
Asunto(s)
Proteínas Cromosómicas no Histona/fisiología , ARN Polimerasas Dirigidas por ADN/metabolismo , ADN/genética , Proteínas Nucleares/fisiología , Pyrococcus furiosus/genética , Proteínas de Saccharomyces cerevisiae/fisiología , Factores de Elongación Transcripcional/fisiología , Secuencia de Aminoácidos , Animales , Microscopía por Crioelectrón/métodos , Cristalografía por Rayos X/métodos , ADN Polimerasa Dirigida por ADN/genética , Humanos , Datos de Secuencia Molecular , Ácidos Nucleicos/química , Homología de Secuencia de Aminoácido , Transcripción GenéticaRESUMEN
The IL-1 family of cytokines currently comprises of seven ligands with pro-inflammatory activity (IL-1α and IL-1ß, IL-18, IL-33, IL-36α, IL-36ß, IL-36γ) as well as two ligands with anti-inflammatory activity (IL-37, IL-38). These cytokines are known to play a key role in modulating both the innate and adaptive immunes response, with dysregulation linked to a variety of autoimmune and inflammatory diseases. Given the increasing appreciation of the link between inflammation and cancer, the role of several members of this family in the pathogenesis of cancer has been extensively investigated. In this review, we highlight both the pro- and anti-tumorigenic effects identified for almost all members of this family, and explore potential underlying mechanisms accounting for these divergent effects. Such dual functions need to be carefully assessed when developing therapeutic intervention strategies targeting these cytokines in cancer.