Genome wide array analysis indicates that an amyotrophic lateral sclerosis mutation of FUS causes an early increase of CAMK2N2 in vitro

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1832

Article

Convertini, Paolo¹  Zhang, Jiayu¹  de la Grange, Pierre²  Hayward, Lawrence J.³  Zhu, Haining¹  Stamm, Stefan¹ 

[1] Univ Kentucky, Coll Med, Dept Mol & Cellular Biochem, Lexington, KY 40536 USA

[2] Hop St Louis, GenoSplice Technol, F-75010 Paris, France

[3] Univ Massachusetts, Sch Med, Dept Neurol, Worcester, MA 01655 USA

关键词: FUS;    Fused in sarcoma;    Amyotrophic lateral sclerosis;    ALS;    Array analysis;   

DOI  :  10.1016/j.bbadis.2013.03.015

来源: Elsevier

【 摘 要 】

Mutations in the RNA binding protein PUS (fused in sarcoma) have been linked to a subset of familial amyotrophic lateral sclerosis (ALS) cases. The mutations are clustered in the C-terminal nuclear localization sequence (NLS). Various PUS mutants accumulate in the cytoplasm whereas wild-type (WT) FUS is mainly nuclear. Here we investigate the effect of one ALS causing mutant (FUS-Delta NLS, also known as R495X) on pre-mRNA splicing and RNA expression using genome wide exon-junction arrays. Using a non-neuronal stable cell line with inducible PUS expression, we detected early changes in RNA composition. In particular, mutant FUS-Delta NLS increased calcium/calmodulin-dependent protein kinase II inhibitor 2 (CAMK2N2) at both mRNA and protein levels, whereas WT-FUS had no effect. Chromatin immunoprecipitation experiments showed that FUS-Delta NLS accumulated at the CAMK2N2 promoter region, whereas promoter occupation by WT-FUS remained constant. Given the loss of FUS-Delta NLS in the nucleus through the mutation-induced translocation, this increase of promoter occupancy is surprising. It indicates that, despite the obvious cytoplasmic accumulation, FUS-Delta NLS can act through a nuclear gain of function mechanism. (C) 2013 Elsevier B.V. All rights reserved.

【 授权许可】

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