Show simple item record

dc.contributor.authorBosshard, Matthias
dc.contributor.authorAprigliano, Rossana
dc.contributor.authorGattiker, Cristina
dc.contributor.authorPalibrk, Vuk
dc.contributor.authorMarkkanen, Enni
dc.contributor.authorBacke, Paul Hoff
dc.contributor.authorPellegrino, Stefania
dc.contributor.authorRaymond, F. Lucy
dc.contributor.authorFroyen, Guy
dc.contributor.authorAltmeyer, Matthias
dc.contributor.authorBjørås, Magnar
dc.contributor.authorDianov, Grigory L.
dc.contributor.authorvan Loon, Barbara
dc.identifier.citationScientific Reports. 2017, 7, 15050.nb_NO
dc.description.abstractMutations in the HECT, UBA and WWE domain-containing 1 (HUWE1) E3 ubiquitin ligase cause neurodevelopmental disorder X-linked intellectual disability (XLID). HUWE1 regulates essential processes such as genome integrity maintenance. Alterations in the genome integrity and accumulation of mutations have been tightly associated with the onset of neurodevelopmental disorders. Though HUWE1 mutations are clearly implicated in XLID and HUWE1 regulatory functions well explored, currently much is unknown about the molecular basis of HUWE1-promoted XLID. Here we showed that the HUWE1 expression is altered and mutation frequency increased in three different XLID individual (HUWE1 p.R2981H, p.R4187C and HUWE1 duplication) cell lines. The effect was most prominent in HUWE1 p.R4187C XLID cells and was accompanied with decreased DNA repair capacity and hypersensitivity to oxidative stress. Analysis of HUWE1 substrates revealed XLID-specific down-regulation of oxidative stress response DNA polymerase (Pol) λ caused by hyperactive HUWE1 p.R4187C. The subsequent restoration of Polλ levels counteracted the oxidative hypersensitivity. The observed alterations in the genome integrity maintenance may be particularly relevant in the cortical progenitor zones of human brain, as suggested by HUWE1 immunofluorescence analysis of cerebral organoids. These results provide evidence that impairments of the fundamental cellular processes, like genome integrity maintenance, characterize HUWE1-promoted XLID.nb_NO
dc.publisherNature Publishing Groupnb_NO
dc.rightsNavngivelse 4.0 Internasjonal*
dc.titleImpaired oxidative stress response characterizes HUWE1-promoted X-linked intellectual disabilitynb_NO
dc.typeJournal articlenb_NO
dc.typePeer reviewednb_NO
dc.source.journalScientific Reportsnb_NO
dc.description.localcode© The Author(s) 2017. Open Access. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.nb_NO
cristin.unitnameInstitutt for klinisk og molekylær medisin

Files in this item


This item appears in the following Collection(s)

Show simple item record

Navngivelse 4.0 Internasjonal
Except where otherwise noted, this item's license is described as Navngivelse 4.0 Internasjonal