Bloom syndrome DNA helicase deficiency is associated with oxidative stress and mitochondrial network changes

Abstract Bloom Syndrome (BS; OMIM #210900; ORPHA #125) is a rare genetic disorder that is associated with growth deficits, compromised immune system, insulin resistance, genome instability and extraordinary predisposition to cancer. Most efforts thus far have focused on understanding the role of the...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Veena Subramanian, Brian Rodemoyer, Vivek Shastri, Lene J. Rasmussen, Claus Desler, Kristina H. Schmidt
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/5530adb9437f48af9424959207bebd7f
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:5530adb9437f48af9424959207bebd7f
record_format	dspace
spelling	oai:doaj.org-article:5530adb9437f48af9424959207bebd7f2021-12-02T10:48:13ZBloom syndrome DNA helicase deficiency is associated with oxidative stress and mitochondrial network changes10.1038/s41598-021-81075-02045-2322https://doaj.org/article/5530adb9437f48af9424959207bebd7f2021-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-81075-0https://doaj.org/toc/2045-2322Abstract Bloom Syndrome (BS; OMIM #210900; ORPHA #125) is a rare genetic disorder that is associated with growth deficits, compromised immune system, insulin resistance, genome instability and extraordinary predisposition to cancer. Most efforts thus far have focused on understanding the role of the Bloom syndrome DNA helicase BLM as a recombination factor in maintaining genome stability and suppressing cancer. Here, we observed increased levels of reactive oxygen species (ROS) and DNA base damage in BLM-deficient cells, as well as oxidative-stress-dependent reduction in DNA replication speed. BLM-deficient cells exhibited increased mitochondrial mass, upregulation of mitochondrial transcription factor A (TFAM), higher ATP levels and increased respiratory reserve capacity. Cyclin B1, which acts in complex with cyclin-dependent kinase CDK1 to regulate mitotic entry and associated mitochondrial fission by phosphorylating mitochondrial fission protein Drp1, fails to be fully degraded in BLM-deficient cells and shows unscheduled expression in G1 phase cells. This failure to degrade cyclin B1 is accompanied by increased levels and persistent activation of Drp1 throughout mitosis and into G1 phase as well as mitochondrial fragmentation. This study identifies mitochondria-associated abnormalities in Bloom syndrome patient-derived and BLM-knockout cells and we discuss how these abnormalities may contribute to Bloom syndrome.Veena SubramanianBrian RodemoyerVivek ShastriLene J. RasmussenClaus DeslerKristina H. SchmidtNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-18 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Veena Subramanian Brian Rodemoyer Vivek Shastri Lene J. Rasmussen Claus Desler Kristina H. Schmidt Bloom syndrome DNA helicase deficiency is associated with oxidative stress and mitochondrial network changes
description	Abstract Bloom Syndrome (BS; OMIM #210900; ORPHA #125) is a rare genetic disorder that is associated with growth deficits, compromised immune system, insulin resistance, genome instability and extraordinary predisposition to cancer. Most efforts thus far have focused on understanding the role of the Bloom syndrome DNA helicase BLM as a recombination factor in maintaining genome stability and suppressing cancer. Here, we observed increased levels of reactive oxygen species (ROS) and DNA base damage in BLM-deficient cells, as well as oxidative-stress-dependent reduction in DNA replication speed. BLM-deficient cells exhibited increased mitochondrial mass, upregulation of mitochondrial transcription factor A (TFAM), higher ATP levels and increased respiratory reserve capacity. Cyclin B1, which acts in complex with cyclin-dependent kinase CDK1 to regulate mitotic entry and associated mitochondrial fission by phosphorylating mitochondrial fission protein Drp1, fails to be fully degraded in BLM-deficient cells and shows unscheduled expression in G1 phase cells. This failure to degrade cyclin B1 is accompanied by increased levels and persistent activation of Drp1 throughout mitosis and into G1 phase as well as mitochondrial fragmentation. This study identifies mitochondria-associated abnormalities in Bloom syndrome patient-derived and BLM-knockout cells and we discuss how these abnormalities may contribute to Bloom syndrome.
format	article
author	Veena Subramanian Brian Rodemoyer Vivek Shastri Lene J. Rasmussen Claus Desler Kristina H. Schmidt
author_facet	Veena Subramanian Brian Rodemoyer Vivek Shastri Lene J. Rasmussen Claus Desler Kristina H. Schmidt
author_sort	Veena Subramanian
title	Bloom syndrome DNA helicase deficiency is associated with oxidative stress and mitochondrial network changes
title_short	Bloom syndrome DNA helicase deficiency is associated with oxidative stress and mitochondrial network changes
title_full	Bloom syndrome DNA helicase deficiency is associated with oxidative stress and mitochondrial network changes
title_fullStr	Bloom syndrome DNA helicase deficiency is associated with oxidative stress and mitochondrial network changes
title_full_unstemmed	Bloom syndrome DNA helicase deficiency is associated with oxidative stress and mitochondrial network changes
title_sort	bloom syndrome dna helicase deficiency is associated with oxidative stress and mitochondrial network changes
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/5530adb9437f48af9424959207bebd7f
work_keys_str_mv	AT veenasubramanian bloomsyndromednahelicasedeficiencyisassociatedwithoxidativestressandmitochondrialnetworkchanges AT brianrodemoyer bloomsyndromednahelicasedeficiencyisassociatedwithoxidativestressandmitochondrialnetworkchanges AT vivekshastri bloomsyndromednahelicasedeficiencyisassociatedwithoxidativestressandmitochondrialnetworkchanges AT lenejrasmussen bloomsyndromednahelicasedeficiencyisassociatedwithoxidativestressandmitochondrialnetworkchanges AT clausdesler bloomsyndromednahelicasedeficiencyisassociatedwithoxidativestressandmitochondrialnetworkchanges AT kristinahschmidt bloomsyndromednahelicasedeficiencyisassociatedwithoxidativestressandmitochondrialnetworkchanges
_version_	1718396646293766144

Bloom syndrome DNA helicase deficiency is associated with oxidative stress and mitochondrial network changes

Ejemplares similares