A team of researchers from Penn State have shed light on the function of an enzyme, sirtuin that helps in the regulation of aging and other metabolic processes. Both DNA and histone proteins are accessed by sirtuin enzyme, allowing it to modify gene expression within the cell. The study was published in the journal Science Advances on April 14th.
Sirtuins are a type of enzyme found in organisms ranging from bacteria to humans. These enzymes play essential roles in aging, DNA damage detection, and cancer suppression. Pharmaceutical companies are looking for potential biomedical applications of sirtuins. The ability of some sirtuins to reduce gene expression by getting rid of a chemical flag from histone proteins makes them a popular choice.
Professor Song Tan, Verne M. Willaman Professor of Molecular Biology at Penn State, and Jean-Paul Armache, assistant professor of biochemistry and molecular biology at Penn State were the authors of the paper. According to Tan, the nucleosome is a hundred times larger than the typical histone peptides used in previous studies that were focused on the interaction between sirtuins and histone peptides.
The researchers used cryo-electron microscopy–pictured a sirtuin enzyme, SIRT6, on the nucleosome. They saw SIRT6 navigate the nucleosome complex to access both DNA and histone proteins to enable it to remove acetyl groups from the K9 position on the histone H3. Biochemical experiments done by the lab of Craig Peterson at the University of Massachusetts Chan Medical School helped affirm the results.
The researchers have concluded that SIRT6 binds to the nucleosome using an ‘arginine anchor’. This type of connection is used commonly by different proteins to direct towards an acidic patch on the nucleosome’s surface. Structural features of SIRT6 called an extended loop are like a pipe sitting in a ditch as they nestle into a divot in the acidic patch. Mutating SIRT6’s arginine anchor impacted its activity at the K9 and K56 positions. This could mean SIRT6 binds the nucleosome to gain access to both K9 and K56 positions instead of using two different methods to access them.
Penn State is a public, land-grant university located in the State College and University Park metropolitan region of Pennsylvania. It has 24 campuses and more than 100,000 students enrolled. Established in 1855 as the Farmers’ High School of Pennsylvania, it is the State’s only designated land-grant university.
Song Tan, Verne M. Willaman Professor of Molecular Biology at Penn State, has extensive research experience in the gene-regulatory elements that allow cells to read the right genes at the right place at the right time. His research is geared towards finding the physical mechanisms that determine how proteins bind to the nucleus, enabling them to modulate gene expression.
Jean-Paul Armache is an assistant professor of biochemistry and molecular biology at Penn State. He is trained in structural and chemical biology and has expertise in protein-nucleic acid recognition as well as in DNA organization and structure, protein engineering, single molecule force spectroscopy, and electron microscopy. He is also an expert in analyzing protein DNA interactions mechanistically.
Craig Peterson, from the University of Massachusetts Chan Medical School, is a professor at the Departments of Biochemistry and Molecular Biology, and a principal investigator of the Peterson lab that works on gene regulation and epigenetic silencing, chromosomal organization, genomics and bioinformatics, focusing on gene regulation and chromatin structure and organization.
The findings from this research could give insight into how drugs and other therapies could target gene regulation. These methods to access genetic material and modify gene expression could be essential to understand and treat diseases related to ageing.
