Exploring the role of DYRK1A in RNA polymerase III transcription : DYRK1A as a potential regulator of TFIIIC

Cort, Rianne Angelica

Exploring the role of DYRK1A in RNA polymerase III transcription : DYRK1A as a potential regulator of TFIIIC

Document Type

Doctoral thesis
Published Version

Author

Cort, Rianne Angelica

Director

La Luna, Susana de
Di Vona, Chiara

Publication Date

2019-12-13

Pages

140 p.

License

Citation

Cort, R. Exploring the role of DYRK1A in RNA polymerase III transcription : DYRK1A as a potential regulator of TFIIIC. Universitat Pompeu Fabra; 2019. handle: http://hdl.handle.net/10803/668274

This citation was generated automatically.

Doctoral program

Programa de doctorat en Biomedicina

Abstract

The kinase DYRK1A (dual-specificity tyrosine-regulated kinase 1A) is a dosage-sensitive gene, since both haploinsufficiency and overexpression when in trisomy lead to pathological phenotypes in humans. In this Thesis, the possible role of DYRK1A in regulating RNA polymerase III transcription has been explored. The results show that DYRK1A is recruited to RNA polymerase III-bound tRNA genes (tDNAs) in multiple human cell lines. In addition, the tDNAs are occupied by the RNA polymerase III basal transcription factor TFIIIC. DYRK1A is shown to not only interact with TFIIIC but to phosphorylate several subunits of the TFIIIC complex in vitro. Indeed, inhibition of the DYRK1A catalytic activity results in reduction of the recruitment of TFIIIC to tDNAs. These results point to DYRK1A as a novel kinase of the TFIIIC complex, the first described in mammals, and allows to propose DYRK1A as a potential novel regulator of RNA polymerase III transcription by acting on TFIIIC.
La proteína quinasa DYRK1A (dual-specificity tyrosine-regulated kinase 1A) es un gen sensible a dosis, ya que tanto la haploinsuficiencia como la sobreexpresion en el síndrome de Down resultan en fenotipos patológicos en humanos. En esta Tesis se ha explorado el posible papel de DYRK1A como regulador de la transcripción dependiente de la RNA polimerasa III (RNAPIII). DYRK1A se recluta a genes codificantes para tRNAs (tDNAs) que son positivos para RNAPIII y el factor de transcripción basal TFIIIC, en diversas líneas celulares humanas. DYRK1A interacciona con TFIIIC in vivo y fosforila varias de sus subunidades in vitro. De hecho, la inhibición de la actividad catalítica de DYRK1A induce una reducción del reclutamiento de TFIIIC a los tDNAs. Estos resultados sugieren que DYRK1A es un quinasa de TFIIIC, la primera descrita en mamíferos, y permiten proponer que DYRK1A es, potencialmente, un nuevo regulador de la transcripción dependiente de RNAPIII actuando sobre TFIIIC.