A small cut with a big impact
During inflammation, controlled gene expression is necessary in order to allow the organism to mount an effective defense response.
For this process, the protein ARTD1 is removed from the DNA. Veterinary biochemists and molecular biologists from the University of Zurich have now elucidated this previously unclear mechanism: ARTD1 is cut into two pieces by molecular scissors, which enhances gene expression. The results are groundbreaking for our understanding of inflammatory responses and the development of new anti-inflammatory drugs.
Diseases and injuries trigger warning signals in our cells. As a result, genes are expressed and proteins produced, modified or degraded to adapt to the external danger and to protect the organism. In order to be able to produce a particular protein, the corresponding DNA segment, the gene, needs to be expressed and translated. The DNA is localized in the cell nucleus, and exists as a long string that is coiled and bound by proteins. ARTD1 is one such protein, and therefore has the potential to regulate the expression level of genes through its interaction with DNA.
If cells detect warning signals or foreign bodies like bacteria and viruses in their surroundings, the expression profile of genes changes and an inflammatory response is triggered. To induce changes in gene expression, ARTD1 is removed from particular sites of the DNA. The process by which this is brought about has, until now, remained elusive. The team headed by Professor Michael O. Hottiger from the Institute of Veterinary Biochemistry and Molecular Biology at the University of Zurich has now discovered how ARTD1’s DNA recruitment is regulated during inflammation, thereby influencing gene expression and subsequently inflammation.
As the researchers demonstrate in Molecular Cell, ARTD1 is cut into two pieces by molecular scissors, the protein caspase 7. Upon cleavage, these pieces can no longer bind to the DNA, thus allowing for more efficient gene expression.
The cleavage of proteins by caspase 7 was so far mainly associated with cell death. “The cleavage of ARTD1 by caspase 7 during inflammation constitutes a new biological function. It permits a new understanding of inflammatory responses and, in the longer term, may lead to the development of new anti-inflammatory drugs,” explains Professor Hottiger. The results are of considerable importance because inflammation underlies most diseases, including cancer, immune disorders or metabolic syndrome.
Süheda Erener, Virginie Pétrilli, Ingrid Kassner, Roberta Minotti, Rosa Castillo, Raffaella Santoro,
Paul O. Hassa, Jürg Tschopp, and Michael O. Hottiger. Inflammasome-Activated Caspase 7 Cleaves PARP1 to Enhance the Expression of a Subset of NF-kB Target Genes. Molecular Cell. March 29, 2012. doi:10.1016/j.molcel.2012.02.016
Professor Michael O. Hottiger
Institute of Veterinary Biochemistry and Molecular Biology
University of Zurich
Tel.: +41 44 635 54 77
Nathalie Huber | Universität Zürich