Nuclear speckles are detention centers for transcripts containing expanded CAG repeats
PBN-AR
Instytucja
Instytut Chemii Bioorganicznej Polskiej Akademii Nauk
Informacje podstawowe
Główny język publikacji
en
Czasopismo
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
ISSN
0925-4439
EISSN
0006-3002
Wydawca
DOI
Rok publikacji
2016
Numer zeszytu
9
Strony od-do
1513-1520
Numer tomu
1862
Identyfikator DOI
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Autorzy
Pozostali autorzy
+ 2
Słowa kluczowe
en
Polyglutamine diseases
RNA toxicity
CAG foci
CUG foci
Splicing speckles
Streszczenia
Język
en
Treść
The human genetic disorders caused by CAG repeat expansions in the translated sequences of various genes are called polyglutamine (polyQ) diseases because of the cellular "toxicity" of the mutant proteins. The contribution of mutant transcripts to the pathogenesis of these diseases is supported by several observations obtained from cellular models of these disorders. Here, we show that the common feature of cell lines modeling polyQ diseases is the formation of nuclear CAG RNA foci. We performed qualitative and quantitative analyses of these foci in numerous cellular models endogenously and exogenously expressing mutant transcripts by fluorescence in situ hybridization (FISH). We compared the CAG RNA foci of polyQ diseases with the CUG foci of myotonic dystrophy type 1 and found substantial differences in their number and morphology. Smaller differences within the polyQ disease group were also revealed and included a positive correlation between the foci number and the CAG repeat length. We show that expanded CAA repeats, also encoding glutamine, did not trigger RNA foci formation and foci formation is independent of the presence of mutant polyglutamine protein. Using FISH combined with immunofluorescence, we demonstrated partial co-localization of CAG repeat foci with MBNL1 alternative splicing factor, which explains the mild deregulation of MBNL1-dependent genes. We also showed that foci reside within nuclear speckles in diverse cell types: fibroblasts, lymphoblasts, iPS cells and neuronal progenitors and remain dependent on integrity of these nuclear structures.
Inne
System-identifier
PX-5881e1e682ce8c9a4e3d3c9a
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