Systems modelling of NHEJ reveals the importance of redox regulation of Ku70/80 in the dynamics of dna damage foci.

The presence of DNA double-stranded breaks in a mammalian cell typically activates the Non-Homologous End Joining (NHEJ) pathway to repair the damage and signal to downstream systems that govern cellular decisions such as apoptosis or senescence. The signalling system also stimulates effects such as...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	David Dolan, Glyn Nelson, Anze Zupanic, Graham Smith, Daryl Shanley
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/d5b4ba74bf394007a98fe443a502d4d6
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:d5b4ba74bf394007a98fe443a502d4d6
record_format	dspace
spelling	oai:doaj.org-article:d5b4ba74bf394007a98fe443a502d4d62021-11-18T07:58:25ZSystems modelling of NHEJ reveals the importance of redox regulation of Ku70/80 in the dynamics of dna damage foci.1932-620310.1371/journal.pone.0055190https://doaj.org/article/d5b4ba74bf394007a98fe443a502d4d62013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23457464/?tool=EBIhttps://doaj.org/toc/1932-6203The presence of DNA double-stranded breaks in a mammalian cell typically activates the Non-Homologous End Joining (NHEJ) pathway to repair the damage and signal to downstream systems that govern cellular decisions such as apoptosis or senescence. The signalling system also stimulates effects such as the generation of reactive oxygen species (ROS) which in turn feed back into the damage response. Although the overall process of NHEJ is well documented, we know little of the dynamics and how the system operates as a whole. We have developed a computational model which includes DNA Protein Kinase (DNA-PK) dependent NHEJ (D-NHEJ) and back-up NHEJ mechanisms (B-NHEJ) and use it to explain the dynamic response to damage induced by different levels of gamma irradiation in human fibroblasts. Our work suggests that the observed shift from fast to slow repair of DNA damage foci at higher levels of damage cannot be explained solely by inherent stochasticity in the NHEJ system. Instead, our model highlights the importance of Ku oxidation which leads to increased Ku dissociation rates from DNA damage foci and shifts repair in favour of the less efficient B-NHEJ system.David DolanGlyn NelsonAnze ZupanicGraham SmithDaryl ShanleyPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 2, p e55190 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q David Dolan Glyn Nelson Anze Zupanic Graham Smith Daryl Shanley Systems modelling of NHEJ reveals the importance of redox regulation of Ku70/80 in the dynamics of dna damage foci.
description	The presence of DNA double-stranded breaks in a mammalian cell typically activates the Non-Homologous End Joining (NHEJ) pathway to repair the damage and signal to downstream systems that govern cellular decisions such as apoptosis or senescence. The signalling system also stimulates effects such as the generation of reactive oxygen species (ROS) which in turn feed back into the damage response. Although the overall process of NHEJ is well documented, we know little of the dynamics and how the system operates as a whole. We have developed a computational model which includes DNA Protein Kinase (DNA-PK) dependent NHEJ (D-NHEJ) and back-up NHEJ mechanisms (B-NHEJ) and use it to explain the dynamic response to damage induced by different levels of gamma irradiation in human fibroblasts. Our work suggests that the observed shift from fast to slow repair of DNA damage foci at higher levels of damage cannot be explained solely by inherent stochasticity in the NHEJ system. Instead, our model highlights the importance of Ku oxidation which leads to increased Ku dissociation rates from DNA damage foci and shifts repair in favour of the less efficient B-NHEJ system.
format	article
author	David Dolan Glyn Nelson Anze Zupanic Graham Smith Daryl Shanley
author_facet	David Dolan Glyn Nelson Anze Zupanic Graham Smith Daryl Shanley
author_sort	David Dolan
title	Systems modelling of NHEJ reveals the importance of redox regulation of Ku70/80 in the dynamics of dna damage foci.
title_short	Systems modelling of NHEJ reveals the importance of redox regulation of Ku70/80 in the dynamics of dna damage foci.
title_full	Systems modelling of NHEJ reveals the importance of redox regulation of Ku70/80 in the dynamics of dna damage foci.
title_fullStr	Systems modelling of NHEJ reveals the importance of redox regulation of Ku70/80 in the dynamics of dna damage foci.
title_full_unstemmed	Systems modelling of NHEJ reveals the importance of redox regulation of Ku70/80 in the dynamics of dna damage foci.
title_sort	systems modelling of nhej reveals the importance of redox regulation of ku70/80 in the dynamics of dna damage foci.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/d5b4ba74bf394007a98fe443a502d4d6
work_keys_str_mv	AT daviddolan systemsmodellingofnhejrevealstheimportanceofredoxregulationofku7080inthedynamicsofdnadamagefoci AT glynnelson systemsmodellingofnhejrevealstheimportanceofredoxregulationofku7080inthedynamicsofdnadamagefoci AT anzezupanic systemsmodellingofnhejrevealstheimportanceofredoxregulationofku7080inthedynamicsofdnadamagefoci AT grahamsmith systemsmodellingofnhejrevealstheimportanceofredoxregulationofku7080inthedynamicsofdnadamagefoci AT darylshanley systemsmodellingofnhejrevealstheimportanceofredoxregulationofku7080inthedynamicsofdnadamagefoci
_version_	1718422698098425856

Systems modelling of NHEJ reveals the importance of redox regulation of Ku70/80 in the dynamics of dna damage foci.

Ejemplares similares