Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.
The problem: As we age, our DNA accumulates more and more damage. This is known as genomic instability, and is considered to be a primary driver of ageing and of cancer. Strategies to delay ageing include enhancing our cells’ inherent ability to repair their DNA, which also declines with age. The more we know about how DNA repair is controlled, the easier it will be to tackle this facet of the ageing process.
The discovery: Researchers at the University of Michigan uncovered a new mechanism through which the repair of DNA is controlled. The mechanism revolves around guanosine triphosphate (GTP), a molecule similar in structure to ATP. If the word ‘guanosine’ sounds familiar, that’s because guanosine is made of a sugar and guanine, the component of DNA represented by G in the genetic code.
Higher levels of GTP within a cell are associated with more rapid DNA repair, and this was previously thought to be because GTP was supplying building blocks for DNA. However, researchers discovered that GTP also activates a previously unknown cellular signal that enhances the repair of damaged DNA. They found that in both human cancer patients and in mouse models of cancer, this signalling pathway enhanced DNA repair, thereby making cancer cells more resistant to chemotherapy and radiation. Importantly from the perspective of ageing, they also found that this signalling pathway works in healthy, non-cancer cells.
We learned that if you increase a cell’s GTP levels, it makes it really resistant to radiation or chemotherapy. Lowering GTP levels, the cell becomes much more sensitive.Daniel Wahl, M.D., Ph.D.
The implications: The aim of chemotherapy and radiotherapy is to inflict enough damage on cancer cells to kill them, so enhanced DNA repair in these cells is undesirable. Depleting GTP is therefore a potential strategy for improving cancer treatments, and one that was already being explored in clinical trials. Now that we know more about how GTP influences DNA repair, we may be able to target this system more effectively. When it comes to delaying the ageing process and preventing cancer, however, we generally want to enhance DNA repair, and this research shows us another potential avenue by which we could achieve that.
Title image by Sangharsh Lohakare, Upslash
Metabolite tells cells whether to repair DNA https://www.michiganmedicine.org/health-lab/metabolite-tells-cells-whether-repair-dna
GTP signaling links metabolism, DNA repair, and responses to genotoxic stress https://doi.org/10.1158/2159-8290.CD-23-0437