Researchers from the Institute of Microbial Technology, Chandigarh, discovered a new prion called [SNG2] in fission yeast. This is the first known instance of a prion affecting gene silencing. This discovery highlights the unexpected roles of prions in inheritance and cellular behaviour.

A string of amino acids fold into specific three-dimensional structures to form proteins. The shape of the protein is essential for its various functions, such as catalysis, signalling, or structural support. However, there are some proteins called prions, that misfold and force similar proteins to change their shape. In mammals, prions cause diseases like mad cow, Creutzfeldt-Jakob, and Kuru. In yeast, however, prions are valuable and help them adapt to stress, such as acidic environment or antifungal drugs.

Some areas of DNA are packed tightly into structures called heterochromatin. This packing prevents genes in those areas from being activated or in other words, keep the genes ​“off”, so it doesn’t produce its usual effect. In yeast (Schizosaccharomyces pombe), Cut4 is an important protein involved in cell cycle regulation that also keeps the heterochromatin regions transcriptionally silent. Interestingly, it was originally identified as tumour suppressor gene tsg24 in mouse, suggesting a possible role in cancer.

However, in a recent study done on the cut4 gene and its mutation sng2‑1, it has revealed prion-like behaviour, [SNG2]. The prion disrupts gene silencing in specific parts of the yeast’s DNA, such as the regions involved in mating and chromosome organisation. In addition, this mutation also confers tolerance to stress conditions, like high temperatures, ethanol, etc.

When researchers mixed or crossed yeast having the sng2‑1 mutant with a wild type strain (normal strain), ​“we saw something unexpected. Some offspring were no longer temperature-sensitive but still retained the silencing defects even when the mutation was removed,” remarks Jagmohan Singh, currently working as Emeritus Professor at Amity University Punjab, Mohali. The silencing defects caused by the [SNG2] prion didn’t follow the usual DNA-based inheritance rules. Normally, such defects are linked to mutations in silencing proteins and passed down from parents to offspring through DNA, following Mendel’s laws. But with [SNG2], the defect was passed through the cytoplasm, through changes in protein structure, in a prion-like way. Singh said,

This unconventional way of passing information across generations was unexpected because it showed that prions could influence chromatin states, a process usually thought to depend on DNA.

Additionally, these silencing defects displayed dominance over the wild-type when both were present together. These two features — non-Mendelian inheritance and dominance are classic prion trait.

Researchers further employed protein manipulation strategies to better understand prion behaviour. Firstly, they tagged Cut4 with fluorescent markers to visualise prion aggregates or clumps formed within yeast cells using a microscope. Over-expressing Cut4 protein increased the formation of these aggregates, which is a hallmark of prion activity. But these effects of the prion could also be reversed by treating with chemical agents, specifically guanidine hydrochloride, which disrupts protein propagation. Lastly, the propagation and curing of the prion were found to depend on heat shock proteins like Hsp104.

Some prions help cells survive stress. To confirm this idea, researchers exposed the cells to various stress conditions like ethanol, heat, and oxidative stress and found that [SNG2] prions enhanced survival and growth under these conditions.

There’s a twist: through crossbreeding experiments and reporter assays, researchers saw that the [SNG2] prion can cause defects in silencing at important DNA regions, likely through its overexpression. Additionally, [SNG2] cells show defects in the cell cycle and increased chromosome loss — traits linked to diseases like cancer. It’s possible that these defects contribute to stress tolerance, similar to how cancer cells often resist stress. This highlights prions as epigenetic regulators, mechanisms that influence how genes work without altering DNA, enabling cells to quickly adapt to environmental challenges.

“This is the first study showing a prion’s role in heterochromatin and stress survival in eukaryotes. Future studies will aim to delineate the formation and maintenance of newfound beneficial prions and their roles in fundamental biological processes,” remarks Samrat Mukhopadhyay, Professor, IISER Mohali, who was not involved in the study.