The research of the group aims at understanding the mechanisms by which RNA and RNA degradation by the exosome contribute to chromatin regulation and genome integrity. The organization of the DNA into chromatin and the maintenance of the integrity of the genome are essential biological processes, and research from many laboratories has provided knowledge about the proteins that are responsible for these processes. In recent years, we have learned that not only proteins but also RNAs play important roles in genome organization, regulation and repair. Indeed, eukaryotic genomes are transcribed to a much larger extent than previously anticipated, and different types of non-coding RNAs (ncRNAs) have been identified in the last decade. Some of these ncRNAs regulate chromatin structure and gene expression, and their biogenesis and turnover depend on the activity of the exosome. The exosome is a multiprotein complex that is responsible for the processing and degradation of many RNAs in eukaryotic cells. As part of our studies on the function of the exosome, we discovered unexpected links between the exosome, chromatin proteins and DNA repair factors, and this discovery prompted us to investigate the roles of the exosome in the maintenance of genome integrity. Our research addresses the following specific questions:
- the roles the exosome in the organization of the chromatin
- the importance of RNA synthesis and degradation at DNA double-strand breaks
In collaboration with the Östlund Farrants Group at MBW, we are also interested in understanding the crosstalk between transcription, chromatin structure and pre-mRNA processing, with focus on the mechanisms by which SWI/SNF regulates pre-mRNA processing.
We use the fruit fly (Drosophila melanogaster) as a model organism to study chromatin-associated ncRNAs and to investigate the regulation of pre-mRNA processing by SWI/SNF. We use mammalian cell systems for studies of DNA repair. We combine biochemistry, molecular biology and advanced cell biology, including high-throughput methods such as RNA-seq and ChIP-seq.
Our research provides knowledge about fundamental genetic processes. Furthermore, our work is interesting from a biomedical perspective. Novel strategies to treat human diseases, including cancer and neurological disorders, target chromatin regulatory pathways and DNA repair factors. The exosome itself has been linked to human diseases and proposed as a possible target for therapeutic intervention. Thus, understanding the mechanisms of chromatin regulation and exosome function is of outmost strategic relevance.
Keywords
Non-coding RNA, exosome, DNA repair, heterochromatin, SWI/SNF, alternative pre-mRNA processing, nuclear actin
Selected publications
Yu S, Jordán-Pla A, Gañez-Zapater A, Jain S, Rolicka A, Östlund Farrants AK, Visa N.
Nucleic Acids Res. 2018 May 31. doi: 10.1093/nar/gky438.
PMID: 29860334
Eberle AB, Jordán-Pla A, Gañez-Zapater A, Hessle V, Silberberg G, von Euler A, Silverstein RA, Visa N.
PLoS Genet. 2015 Sep 21;11(9):e1005523. doi: 10.1371/journal.pgen.1005523.
PMID: 26389589
RRP6/EXOSC10 is required for the repair of DNA double-strand breaks by homologous recombination.
Marin-Vicente C, Domingo-Prim J, Eberle AB, Visa N.
J Cell Sci. 2015 Mar 15;128(6):1097-107. doi: 10.1242/jcs.158733.
PMID: 25632158
Rrp6 is recruited to transcribed genes and accompanies the spliced mRNA to the nuclear pore.
Hessle V, von Euler A, González de Valdivia E, Visa N.
RNA. 2012 Aug;18(8):1466-74.
Hessle V, Björk P, Sokolowski M, González de Valdivia E, Silverstein R, Artemenko K, Tyagi A, Maddalo G, Ilag L, Helbig R, Zubarev RA, Visa N.
Mol Biol Cell. 2009 Aug;20(15):3459-70.
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