Research group Group Gekara

Recent research published in Nucleic Acids Research has uncovered a novel role for small nucleolar RNAs (snoRNAs) in the transcriptional regulation of the anti-viral response. Traditionally, snoRNAs are known for their role in ribosomal biogenesis. Here, the Visa group at the Department of Molecular Biosciences, Wenner-Gren Institute (MBW) at Stockholm University, in collaboration with researchers from various Swedish universities, has demonstrated that snoRNAs also participate in the regulating chromatin accessibility to influence gene transcription profiles. In this study, the fruit fly Drosophila melanogaster was used as a model organism to investigate the regulation of immune responses. When fruit flies are infected with viruses, the host’s cellular machinery is activated, which triggers an effective immune response. U3 small nucleolar RNA (U3 snoRNA) is one of the genes induced during this process. The induced U3 snoRNA helps maintain an open chromatin conformation, thereby facilitating the transcription of various immune pathway genes. U3 snoRNA acts by recruiting the SWI/SNF chromatin remodeler, Brahma, to immune genes. If U3 snoRNA is knocked out, fruit fly larvae fail to efficiently fight viral infections and die during late larval development. Not only does U3 snoRNA facilitate immune gene activation, but it also promotes the chromatin remodelling needed for immune gene expression, establishing it as a key regulator of the antiviral response.

Acetylsalicylic acid (aspirin) is arguably the oldest drug in the history of medicine. In a study published in Cell Research, researchers at Stockholm University and the University Medical Center Freiburg, have identified a new mechanism of aspirin. They show that aspirin promotes genome repair and can protect mice and cells against the toxic effects of irradiation and mutagenic chemicals. This new mechanism may help explain many of the health benefits of aspirin including cancer prevention. Genotoxic injury due to irradiation or chemical mutagens is a major health concern. The search for agents to protect against radiation has been on for almost a century, since the devastation witnessed following the nuclear detonations during the Second World War and has continued through the subsequent radiological accidents around the world. A radioprotector is also required for prophylactic use by staff working at radiation sources, pilots, and astronauts at high risk of space radiation or patients undertaking lengthy radiological procedures. Despite decades of research, a safe, efficient, and cost-effective radioprotector is yet to be unveiled.  Acetylsalicylic acid (aspirin) is probably the oldest drug in the history of medicine and has been used for over 4000 years for the treatment of pain, inflammation, fever, and more recently for cardiovascular prophylaxis and cancer prevention. “Bone marrow failure is the major cause of suffering and death upon exposure to irradiation. Inflammation is a key outcome and driver of irradiation-induced tissue injury. Given the well-established anti-inflammatory effects of aspirin, we inquired if aspirin could protect against irradiation. Indeed, when we administered it into mice, we found that aspirin could protect mice against irradiation-induced bone marrow ablation and extended their survival. We also found that aspirin could protect mice defective in several inflammatory pathways against irradiation-induced bone marrow suppression. This led us to conclude that radioprotection by aspirin was uncoupled from its anti-inflammatory effects” explains Patrycja Swacha, a graduate student at Stockholm University and a co-author of the study. “The discovery that aspirin, a safe, affordable and readily accessible drug is a potent radioprotector is a significant development with the potential to change the quality of life of those at high risk of radiation exposure or patients undergoing prolonged radio/chemotherapy“ Double-stranded DNA breaks are the most deleterious outcomes of irradiation. Upon further investigation, the authors found that following irradiation or exposure to DNA damage inducing anti-cancer chemotherapy drugs, cells treated with aspirin repair DNA breaks faster. How does the aspirin promote the repair of the genome? The estimated length of DNA in a single mammalian cell is about 2 meters. In order to fit inside the nucleus of an average size of 6 µm, DNA does not exist as free linear strands but is wrapped around nucleosomes – complexes of histones. Nucleosomes in turn interact with each other and in a compacted manner to form chromatin. When the genome incurs damage, the chromatin undergoes relaxation to allow the recruitment of DNA repair factors to the damage sites. Histone acetylation - the conjugation of acetyl group onto lysine amino acid residues on histones is a key regulator of chromatin structure and repair. Acetylation of histone H4 at lysine K16 (Ac-H4K16) is vital for decreasing the nucleosome–nucleosome stacking and chromatin folding, to permit the recruitment of repair proteins. The authors showed that by virtue its acetyl-donating potential, aspirin induced H4K16 acetylation thereby causing chromatin relaxation and recruitment of DNA repair proteins to the damaged sites (schematically illustrated in Figure 1 ).