Stockholm university

Aspirin protects against genotoxicity by promoting genome repair

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).

Figure 1. Aspirin protects against genotoxicity by promoting genome repair. A schematic depiction of how by acetylating histones, aspirin promotes chromatin relaxation essential for recruitment of DNA repair proteins to DNA break sites. Schematic prepared by Nelson Gekara.

“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“ notes Prof. Nelson Gekara the senior investigator of the study. 

“Until now, the effects of aspirin have largely been assumed to be linked to its ability to suppress inflammation and pain by targeting prostaglandin-endoperoxide synthases (COX1 and COX2). This widely accepted mechanism was awarded the Nobel Prize for Medicine and Physiology (1982). Thus, the demonstration that aspirin is a modulator of chromatin structure and an accelerator of genome repair represents a significant advance in our understanding of the mechanisms of aspirin. This new mechanism may help to explain many of aspirin’s acclaimed health benefits including cancer prevention” concludes Prof. Gekara.

The results are published in the scientific journal Cell Research, March 2023.

For more information, please contact

Nelson Gekara 
Department of Molecular Biosciences, The Wenner-Gren Institute
Stockholm University
Email: nelson.gekara@su.se
Tel. +46 8-16 41 89

Institute of Medical Microbiology and Hygiene, Medical Center - University of Freiburg, Faculty of Medicine, Freiburg, Germany. 
Email: nelson.ongondo.gekara@uniklinik-freiburg.de

About the publication

Aspirin protects against genotoxicity by promoting genome repair
Hui Jiang, Patrycja Swacha, Kyaw Min Aung and Nelson O Gekara
Cell Research, DOI: 10.1038/s41422-023-00783-6.