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Sci Rep. 2017 Nov 8;7(1):15050. doi: 10.1038/s41598-017-15380-y.

Impaired oxidative stress response characterizes HUWE1-promoted X-linked intellectual disability.

Author information

1
Department of Molecular Mechanisms of Disease, University of Zurich, Zürich, 8057, Switzerland.
2
Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, 7491, Norway.
3
Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, 0318, Norway.
4
Department of Medical Genetics, Cambridge Institute for Medical Research, Cambridge, CB2 0XY, United Kingdom.
5
Human Genome Laboratory, Department of Human Genetics, Leuven, 3000KU, Belgium.
6
Department of Pathology and Medical Genetics, St. Olavs Hospital, Trondheim University Hospital, Trondheim, 7491, Norway.
7
CRUK/MRC Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, OX3 7DQ, United Kingdom.
8
Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, 630090, Russia.
9
Department of Molecular Mechanisms of Disease, University of Zurich, Zürich, 8057, Switzerland. barbara.v.loon@ntnu.no.
10
Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, 7491, Norway. barbara.v.loon@ntnu.no.
11
Department of Pathology and Medical Genetics, St. Olavs Hospital, Trondheim University Hospital, Trondheim, 7491, Norway. barbara.v.loon@ntnu.no.

Abstract

Mutations 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.

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