Polyglutamine Disease, the Emerging Role of Transcription Interference

2011 ◽  
Keyword(s):  
Polyglutamine Disease ◽  
Transcription Interference

scholarly journals Generation of inducible SMARCAL1 knock-down iPSC to model severe Schimke immune-osseous dysplasia reveals a link between replication stress and altered expression of master differentiation genes

2019 ◽  
Author(s):  
Giusj Monia Pugliese ◽  
Federico Salaris ◽  
Valentina Palermo ◽  
Veronica Marabitti ◽  
Nicolò Morina ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Severe Form ◽  
Model Systems ◽  
Altered Expression ◽  
Osseous Dysplasia ◽  
Human Ipscs ◽  
Damage Response ◽  
Transcription Interference

ABSTRACTThe Schimke immuno-osseous dysplasia is an autosomal recessive genetic osteochondrodysplasia characterized by dysmorphism, spondyloepiphyseal dysplasia, nephrotic syndrome and frequently T cell immunodeficiency. Several hypotheses have been proposed to explain pathophysiology of the disease, however, the mechanism by which SMARCAL1 mutations cause the syndrome is elusive. Indeed, animal models of the disease are absent or useless to provide insight into the disease mechanism, since they do not recapitulate the phenotype. We generated a conditional knockdown model of SMARCAL1 in iPSCs to mimic conditions of cells with severe form the disease. Here, we characterize this model for the presence of phenotype linked to the replication caretaker role of SMARCAL1 using multiple cellular endpoints. Our data show that conditional knockdown of SMARCAL1 in human iPSCs induces replication-dependent and chronic accumulation of DNA damage triggering the DNA damage response. Furthermore, they indicate that accumulation of DNA damage and activation of the DNA damage response correlates with increased levels of R-loops and replication-transcription interference. Finally, we provide data showing that, in SMARCAL1-deficient iPSCs, DNA damage response can be maintained active also after differentiation, possibly contributing to the observed altered expression of a subset of germ layer-specific master genes. In conclusion, our conditional SMARCAL1 iPSCs may represent a powerful model where studying pathogenetic mechanisms of severe Schimke immuno-osseous dysplasia, thus overcoming the reported inability of different model systems to recapitulate the disease.

scholarly journals The Role of Protein Composition in Specifying Nuclear Inclusion Formation in Polyglutamine Disease

2001 ◽  
Vol 276 (48) ◽  
pp. 44889-44897 ◽  
Author(s):  
Yaohui Chai ◽  
Lizi Wu ◽  
James D. Griffin ◽  
Henry L. Paulson
Keyword(s):  
Protein Composition ◽  
Polyglutamine Disease ◽  
Nuclear Inclusion ◽  
Inclusion Formation

scholarly journals Defining the Role of Ubiquitin-interacting Motifs in the Polyglutamine Disease Protein, Ataxin-3

2005 ◽  
Vol 280 (36) ◽  
pp. 32026-32034 ◽  
Author(s):  
Sarah J. Shoesmith Berke ◽  
Yaohui Chai ◽  
Ginger L. Marrs ◽  
Hsiang Wen ◽  
Henry L. Paulson
Keyword(s):  
Polyglutamine Disease ◽  
Disease Protein

scholarly journals Analysis of the Role of Heat Shock Protein (Hsp) Molecular Chaperones in Polyglutamine Disease

1999 ◽  
Vol 19 (23) ◽  
pp. 10338-10347 ◽  
Author(s):  
Yaohui Chai ◽  
Stacia L. Koppenhafer ◽  
Nancy M. Bonini ◽  
Henry L. Paulson
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Molecular Chaperones ◽  
Polyglutamine Disease

The role of chaperones in polyglutamine disease

2002 ◽  
Vol 8 (5) ◽  
pp. 232-236 ◽  
Author(s):  
Puneet Opal ◽  
Huda Y Zoghbi
Keyword(s):  
Polyglutamine Disease

Role of dactinomycin in the improved survival of children with Wilms' tumor

JAMA ◽  
1966 ◽  
Vol 195 (12) ◽  
pp. 1005-1009 ◽  
Author(s):  
D. J. Fernbach
Keyword(s):  
Wilms Tumor
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