TY  - JOUR
A1  - Waldholm, Johan
A1  - Wang, Zhi
A1  - Brodin, David
A1  - Tyagi, Anu
A1  - Yu, Simei
A1  - Theopold, Ulrich
A1  - Östlund Farrants, Ann Kristin
A1  - Visa, Neus
T1  - SWI/SNF regulates the alternative processing of a specific subset of pre-mRNAs in \(Drosophila\) \(melanogaster\)
JF  - BMC Molecular Biology
N2  - Background: 

The SWI/SNF chromatin remodeling factors have the ability to remodel nucleosomes and play essential roles in key developmental processes. SWI/SNF complexes contain one subunit with ATPase activity, which in Drosophila melanogaster is called Brahma (Brm). The regulatory activities of SWI/SNF have been attributed to its influence on chromatin structure and transcription regulation, but recent observations have revealed that the levels of Brm affect the relative abundances of transcripts that are formed by alternative splicing and/or polyadenylation of the same pre-mRNA. 

Results: 

We have investigated whether the function of Brm in pre-mRNA processing in Drosophila melanogaster is mediated by Brm alone or by the SWI/SNF complex. We have analyzed the effects of depleting individual SWI/SNF subunits on pre-mRNA processing throughout the genome, and we have identified a subset of transcripts that are affected by depletion of the SWI/SNF core subunits Brm, Snr1 or Mor. The fact that depletion of different subunits targets a subset of common transcripts suggests that the SWI/SNF complex is responsible for the effects observed on pre-mRNA processing when knocking down Brm. We have also depleted Brm in larvae and we have shown that the levels of SWI/SNF affect the pre-mRNA processing outcome in vivo. 

Conclusions: 

We have shown that SWI/SNF can modulate alternative pre-mRNA processing, not only in cultured cells but also in vivo. The effect is restricted to and specific for a subset of transcripts. Our results provide novel insights into the mechanisms by which SWI/SNF regulates transcript diversity and proteomic diversity in higher eukaryotes.
KW  - Chromatin-remodeling complexes
KW  - In-vivo
KW  - Genes
KW  - Distinct
KW  - Brahma
KW  - Transcription
KW  - Trithorax
KW  - Subunit
KW  - Exons
KW  - BRM
Y1  - 2011
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-142613
VL  - 12
IS  - 46
ER  - 
TY  - JOUR
A1  - Weis, Eva
A1  - Schoen, Holger
A1  - Victor, Anja
A1  - Spix, Claudia
A1  - Ludwig, Marco
A1  - Schneider-Raetzke, Brigitte
A1  - Kohlschmidt, Nicolai
A1  - Bartsch, Oliver
A1  - Gerhold-Ay, Aslihan
A1  - Boehm, Nils
A1  - Grus, Franz
A1  - Haaf, Thomas
A1  - Galetzka, Danuta
T1  - Reduced mRNA and Protein Expression of the Genomic Caretaker RAD9A in Primary Fibroblasts of Individuals with Childhood and Independent Second Cancer
JF  - PLoS ONE
N2  - Background: 

The etiology of secondary cancer in childhood cancer survivors is largely unclear. Exposure of normal somatic cells to radiation and/or chemotherapy can damage DNA and if not all DNA lesions are properly fixed, the mis-repair may lead to pathological consequences. It is plausible to assume that genetic differences, i.e. in the pathways responsible for cell cycle control and DNA repair, play a critical role in the development of secondary cancer. 

Methodology/Findings: 

To identify factors that may influence the susceptibility for second cancer formation, we recruited 20 individuals who survived a childhood malignancy and then developed a second cancer as well as 20 carefully matched control individuals with childhood malignancy but without a second cancer. By antibody microarrays, we screened primary fibroblasts of matched patients for differences in the amount of representative DNA repair-associated proteins. We found constitutively decreased levels of RAD9A and several other DNA repair proteins in two-cancer patients, compared to one-cancer patients. The RAD9A protein level increased in response to DNA damage, however to a lesser extent in the two-cancer patients. Quantification of mRNA expression by real-time RT PCR revealed lower RAD9A mRNA levels in both untreated and 1 Gy gamma-irradiated cells of two-cancer patients. 

Conclusions/Significance: 

Collectively, our results support the idea that modulation of RAD9A and other cell cycle arrest and DNA repair proteins contribute to the risk of developing a second malignancy in childhood cancer patients.
KW  - DNA methylation
KW  - Malignant neoplasms
KW  - Genes
KW  - Instability
KW  - Stability
KW  - Susceptibility
KW  - Checkpoints
KW  - Repair
KW  - Damage
Y1  - 2011
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-141838
VL  - 6
IS  - 10
ER  -