Nonsense-mediated mRNA decay in human cells: mechanistic insights, functions beyond quality control and the double-life of NMD factors

Nonsense-mediated decay is well known by the lucid definition of being a RNA surveillance mechanism that ensures the speedy degradation of mRNAs containing premature translation termination codons. However, as we review here, NMD is far from being a simple quality control mechanism; it also regulates the stability of many wild-type transcripts. We summarise the abundance of research that has characterised each of the NMD factors and present a unified model for the recognition of NMD substrates. The contentious issue of how and where NMD occurs is also discussed, particularly with regard to P-bodies and SMG6-driven endonucleolytic degradation. In recent years, the discovery of additional functions played by several of the NMD factors has further complicated the picture. Therefore, we also review the reported roles of UPF1, SMG1 and SMG6 in other cellular processe

Posttranscriptional Gene Regulation by Spatial Rearrangement of the 3′ Untranslated Region

Translation termination at premature termination codons (PTCs) triggers degradation of the aberrant mRNA, but the mechanism by which a termination event is defined as premature is still unclear. Here we show that the physical distance between the termination codon and the poly(A)-binding protein PABPC1 is a crucial determinant for PTC recognition in human cells. “Normal” termination codons can trigger nonsense-mediated mRNA decay (NMD) when this distance is extended; and vice versa, NMD can be suppressed by folding the poly(A) tail into proximity of a PTC or by tethering of PABPC1 nearby a PTC, indicating an evolutionarily conserved function of PABPC1 in promoting correct translation termination and antagonizing activation of NMD. Most importantly, our results demonstrate that spatial rearrangements of the 3′ untranslated region can modulate the NMD pathway and thereby provide a novel mechanism for posttranscriptional gene regulation

El fútbol ¿Fuente de una masculinidad tradicional? Programa Diálogos del Pensamiento 129

Para concluir los diálogos futboleros discutimos en esta emisión en torno a la masculinidad hegemónica (es decir una forma ideal, buena, adecuada de ser hombre) emanada de los deportes, particularmente del futbol; a la vez que, en compañía del Antropólogo Rodolfo Aceves se analiza el proceso de naturalización e incorporación de esos postulados a nuestro pensamiento. Las identidades colectivas se conforman de diferentes dimensiones, pero una de ellas, la masculinidad, hace alusión a un tipo específico de ser hombre, lo cual tiene repercusión no sólo en el ámbito individual de los jugadores, sino también en el mediático, e incluso en el ánimo de quienes se sienten representados por alguno de los equipos de fútbol. Más que indagar sobre la vida privada y sexual de los jugadores, el plantear sobre la mesa casos de futbolistas homosexuales tiene la finalidad de debatir qué tipo de repercusiones tendría una decisión personal de una figura pública de un deporte sumamente mediatizado generalmente asociado a la generación de un tipo específico de ser (muy) hombre: entrones, recios, que no se cansan, que no deja de jugar aunque esté lesionado o vaya perdiendo. ¿Qué pasa entonces con este imaginario cuando el jugador es gay o mujer, asociados directamente con otras características? ¿Cómo se construyen las identidades a través del fútbol? ¿Se podría considerar este deporte como un ritual masculino en el que se reafirman las diferencias entre lo homosexual/macho o masculino/femenino? ¿Alrededor de qué elementos emerge esta masculinidad

Cotranscriptional effect of a premature termination codon revealed by live-cell imaging

Aberrant mRNAs with premature translation termination codons (PTCs) are recognized and eliminated by the nonsense-mediated mRNA decay (NMD) pathway in eukaryotes. We employed a novel live-cell imaging approach to investigate the kinetics of mRNA synthesis and release at the transcription site of PTC-containing (PTC+) and PTC-free (PTC−) immunoglobulin-μ reporter genes. Fluorescence recovery after photobleaching (FRAP) and photoconversion analyses revealed that PTC+ transcripts are specifically retained at the transcription site. Remarkably, the retained PTC+ transcripts are mainly unspliced, and this RNA retention is dependent upon two important NMD factors, UPF1 and SMG6, since their depletion led to the release of the PTC+ transcripts. Finally, ChIP analysis showed a physical association of UPF1 and SMG6 with both the PTC+ and the PTC− reporter genes in vivo. Collectively, our data support a mechanism for regulation of PTC+ transcripts at the transcription site