The Role of Sirtuin Enzymes in Ageing: Unravelling the Mysteries
Pennsylvania , April 24, 2023 : Ageing in humans is the accumulation of changes that occur to a person over time and can include social, psychological, and physical changes. For instance, while memories and general knowledge normally get better with age, reaction time may slow down. This theory could be changed according to recent research by Penn State University on Sirtuin Enzymes with amazing results.
The ability of the SIRT6 sirtuin enzyme, which controls ageing and other metabolic processes, to access genetic material within the cell is now better-understood thanks to new photos of the enzyme. The enzyme is shown in association with the nucleosome, a compact structure made of DNA and the proteins histones, in this cryo-electron microscopy map. Credit: Penn State's Song Tan Lab. Sirtuin enzymes interact with nucleosomes to control ageing and metabolic processes, according to Penn State researchers. Their results using cryo-electron microscopy could help in the development of drugs that target sirtuins for biological uses.
A new study sheds light on the mechanism of an enzyme that controls ageing and other metabolic processes in our genetic material to control how genes are expressed inside cells. Images of a sirtuin enzyme bound to a nucleosome, a tightly packed complex of DNA and proteins known as histones, have been created by a team led by Penn State researchers. These images demonstrate how the enzyme navigates the nucleosome complex to access both DNA and histone proteins and clarify how it functions in humans and other animals. The findings were detailed in a report that appeared in the journal Science Advances on April 14. Sirtuins are a class of enzymes that are present in all living things, including bacteria and humans. They play crucial roles in ageing, detecting DNA damage, and reducing tumour growth in a variety of malignancies. Pharmaceutical companies are investigating their potential for biomedical applications as a result of their diverse roles.
The capacity of some sirtuins to reduce gene expression by removing a chemical flag from histone proteins has received a lot of attention. "In our cells, DNA is not naked like we see it in textbooks; it is spooled around proteins called histones within a large complex called the nucleosome," Song Tan, Verne M. Willaman Professor of Molecular Biology at Penn State and one of the paper's authors, stated. Additionally, this packing can contribute to the signals that turn on or off genes: A gene is activated by adding a "acetyl" chemical flag to the histone packing material, and it is turned off by removing the chemical flag. By removing the acetyl flag from histones packed into nucleosomes, sirtuins can turn off gene activity.
Future efforts to find new drugs might be aided by knowing how sirtuins interact with the nucleosome to remove this marker. Due in part to the fact that histone "tail" peptides are much simpler to work with in the laboratory, earlier research has concentrated on how sirtuins interact with short histone segments in isolation. Tan claims that because the nucleosome is a hundred times bigger than the conventional histone peptides utilised in these experiments, it is considerably harder to work with them. The complete nucleosome is a sirtuin enzyme termed SIRT6's physiologically relevant substrate, according to Jean-Paul Armache, an author of the study and assistant professor of biochemistry and molecular biology at Penn State.
And we discovered that SIRT6 interacts with more than only the histone where the acetyl flag is to be changed in the nucleosome. The scientists discovered how SIRT6 positions itself on the nucleosome in order to remove an acetyl group from the K9 position on the histone known as H3 using equipment at the National Cancer Institute, the Pacific Northwest Cryo-EM Centre, and the Penn State Cryo-Electron Microscopy Facility. Their findings were supported by additional biochemical studies conducted in partnership with Craig Peterson's team at the University of Massachusetts Chan Medical School. According to the study's findings, SIRT6 binds to the nucleosome by a mechanism known as a "arginine anchor."
Many proteins that target a particularly acidic area on the nucleosome's surface use this sort of interaction, which Tan's lab first described in 2014.An extended loop, a structural characteristic of SIRT6, is seen here nestling into an acidic patch's divot like a pipe in a ditch.According to Tan, the arginine anchor is a typical example of how various chromatin proteins interact with the nucleosome.The activity at the K9 site was significantly reduced when we altered the SIRT6 arginine anchor, indicating that the arginine anchor plays a crucial function in SIRT6.Surprisingly, this mutation also affected the enzymatic activity of SIRT6 at a different, much farther-off location, K56.
It's plausible that SIRT6 binds to the nucleosome to access K9 in a way that also might provide access to K56, as opposed to connecting to the nucleosome in two distinct ways to access the two different histone locations.According to Armache, "SIRT6 binds to a partially unwrapped nucleosome, with DNA displaced from the nucleosome end."This makes the K56 position visible, and SIRT6 might be able to practically stoop to get there. In the future, we want to confirm this theory. In order to better understand SIRT6's function in the response to DNA damage, we also intend to investigate how it functions in conjunction with other enzymes.
Reference: "Cryo-EM structure of the human Sirtuin 6-nucleosome complex," Un Seng Chio, Othman Rechiche, Alysia R. Bryll, Jiang Zhu, Erik M. Leith, Jessica L. Feldman, Craig L. Peterson, Song Tan, and Jean-Paul Armache, Science Advances, 14 April 2023. The research team at Penn State also comprises graduate student Erik Leith, postdoctoral scholars Un Seng Chio, Othman Rechiche, and Jiang Zhu in addition to Tan, Armache, and Peterson.Alysia Bryll and Jessica Feldman are additional members of the study team at the UMass Chan Medical School. The Pennsylvania Department of Health and the American National Institutes of Health provided funding for this study under the Tobacco CURE programme.