Inhibition of human dyskerin as a new approach to target ribosome biogenesis.

The product of the DKC1 gene, dyskerin, is required for both ribosome biogenesis and telomerase complex stabilization. Targeting these cellular processes has been explored for the development of drugs to selectively or preferentially kill cancer cells. Presently, intense research is conducted involv...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Laura Rocchi, Arménio J M Barbosa, Carmine Onofrillo, Alberto Del Rio, Lorenzo Montanaro
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/5efc0721b12048fd853604959789ddf1
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:5efc0721b12048fd853604959789ddf1
record_format	dspace
spelling	oai:doaj.org-article:5efc0721b12048fd853604959789ddf12021-11-25T06:08:52ZInhibition of human dyskerin as a new approach to target ribosome biogenesis.1932-620310.1371/journal.pone.0101971https://doaj.org/article/5efc0721b12048fd853604959789ddf12014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/25010840/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203The product of the DKC1 gene, dyskerin, is required for both ribosome biogenesis and telomerase complex stabilization. Targeting these cellular processes has been explored for the development of drugs to selectively or preferentially kill cancer cells. Presently, intense research is conducted involving the identification of new biological targets whose modulation may simultaneously interfere with multiple cellular functions that are known to be hyper-activated by neoplastic transformations. Here, we report, for the first time, the computational identification of small molecules able to inhibit dyskerin catalytic activity. Different in silico techniques were applied to select compounds and analyze the binding modes and the interaction patterns of ligands in the human dyskerin catalytic site. We also describe a newly developed and optimized fast real-time PCR assay that was used to detect dyskerin pseudouridylation activity in vitro. The identification of new dyskerin inhibitors constitutes the first proof of principle that the pseudouridylation activity can be modulated by means of small molecule agents. Therefore, the presented results, obtained through the usage of computational tools and experimental validation, indicate an alternative therapeutic strategy to target ribosome biogenesis pathway.Laura RocchiArménio J M BarbosaCarmine OnofrilloCarmine OnofrilloAlberto Del RioLorenzo MontanaroPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 7, p e101971 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Laura Rocchi Arménio J M Barbosa Carmine Onofrillo Carmine Onofrillo Alberto Del Rio Lorenzo Montanaro Inhibition of human dyskerin as a new approach to target ribosome biogenesis.
description	The product of the DKC1 gene, dyskerin, is required for both ribosome biogenesis and telomerase complex stabilization. Targeting these cellular processes has been explored for the development of drugs to selectively or preferentially kill cancer cells. Presently, intense research is conducted involving the identification of new biological targets whose modulation may simultaneously interfere with multiple cellular functions that are known to be hyper-activated by neoplastic transformations. Here, we report, for the first time, the computational identification of small molecules able to inhibit dyskerin catalytic activity. Different in silico techniques were applied to select compounds and analyze the binding modes and the interaction patterns of ligands in the human dyskerin catalytic site. We also describe a newly developed and optimized fast real-time PCR assay that was used to detect dyskerin pseudouridylation activity in vitro. The identification of new dyskerin inhibitors constitutes the first proof of principle that the pseudouridylation activity can be modulated by means of small molecule agents. Therefore, the presented results, obtained through the usage of computational tools and experimental validation, indicate an alternative therapeutic strategy to target ribosome biogenesis pathway.
format	article
author	Laura Rocchi Arménio J M Barbosa Carmine Onofrillo Carmine Onofrillo Alberto Del Rio Lorenzo Montanaro
author_facet	Laura Rocchi Arménio J M Barbosa Carmine Onofrillo Carmine Onofrillo Alberto Del Rio Lorenzo Montanaro
author_sort	Laura Rocchi
title	Inhibition of human dyskerin as a new approach to target ribosome biogenesis.
title_short	Inhibition of human dyskerin as a new approach to target ribosome biogenesis.
title_full	Inhibition of human dyskerin as a new approach to target ribosome biogenesis.
title_fullStr	Inhibition of human dyskerin as a new approach to target ribosome biogenesis.
title_full_unstemmed	Inhibition of human dyskerin as a new approach to target ribosome biogenesis.
title_sort	inhibition of human dyskerin as a new approach to target ribosome biogenesis.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/5efc0721b12048fd853604959789ddf1
work_keys_str_mv	AT laurarocchi inhibitionofhumandyskerinasanewapproachtotargetribosomebiogenesis AT armeniojmbarbosa inhibitionofhumandyskerinasanewapproachtotargetribosomebiogenesis AT carmineonofrillo inhibitionofhumandyskerinasanewapproachtotargetribosomebiogenesis AT carmineonofrillo inhibitionofhumandyskerinasanewapproachtotargetribosomebiogenesis AT albertodelrio inhibitionofhumandyskerinasanewapproachtotargetribosomebiogenesis AT lorenzomontanaro inhibitionofhumandyskerinasanewapproachtotargetribosomebiogenesis
_version_	1718414103523885056

Inhibition of human dyskerin as a new approach to target ribosome biogenesis.

Ejemplares similares