New study finds novel protein linked to water bears’ extreme radiation resistance with applications to cancer treatment.
Water bears, or tardigrades, are microscopic creatures with eight legs. They are so hardy, Stan Lee may very well have drawn inspiration from them while writing X-men. What they lack in telekinesis, invisibility, and shapeshifting, they make up for in resilience to extreme temperatures, high pressures, vacuum environments, dehydration, starvation, and DNA-damaging ionizing radiation (IR). To put things into perspective: Humans can tolerate at most 5 grays (unit of radiation), while tardigrades can survive upwards of 4,000 grays. The exact mechanisms behind their IR resistance remain unclear, prompting researchers to investigate their genetic code in hopes of uncovering insights that could benefit human health.
When IR comes in contact with DNA, it can cut through one or both strands of the DNA double helix structure, leaving behind single or double-stranded breaks. To prevent genomic instability and cell death, some genes encode proteins that form mini shields against IR, while others encode corrective proteins involved in repair mechanisms after IR damage. A team of researchers at Paris-Saclay university in Orsay, France found that human and tardigrade cells sustain similar damage after IR exposure, but that human cells died, whereas tardigrade cells did not. This suggests humans and tardigrades have similar preventative strategies, but only tardigrades are equipped with the repair mechanisms needed to recover.
To explore the possible genes involved in these repair mechanisms, the researchers used a technique called transcriptomics on three species of tardigrades. With this technique, they sequenced RNA from cells of the three species after IR exposure. The sequences told the researchers which genes were turned on in response to IR, and how those differed among the three species. They found upregulated expression of numerous previously described DNA repair genes across all three species. However, one gene – also shared across the three species – stood out in particular. When examining its RNA sequence, the researchers realized they had encountered the code to a novel protein. They called it TDR1, or Tardigrade Damage Response 1.
The exact role TDR1 plays in DNA repair is unclear. Nevertheless, observations of TDR1 aggregates in tardigrade cells suggest TDR1 might be involved in a DNA condensation mechanism. In other words, when DNA experiences breakage from IR, TDR1 proteins mobilize to change the DNA’s three-dimensional structure into a densely packed cellular space around the breakage. This structural change introduces DNA pockets where crucial repair enzymes are more likely to come in contact with broken DNA segments. This way, TDR1 helps restore the DNA’s structural integrity.
Besides merely describing TDR1, the researchers also sought to understand whether TDR1 protein could be applied to human cells. They found that, when expressed in human cells, the TDR1 gene also helped our cells recover from IR damage. This advance in understanding IR resistance could have immediate applications to cancer treatment because today’s methods still often rely on heavy doses of ionizing radiation. IR does not only cut through the cancer cells’ DNA, it cuts through all the healthy cells caught in its crosshairs as well. Therefore, with the development of new IR resistance tools, we may be able to reduce the side effects resulting from healthy cell damage after radiation therapy.
Sources:
Dall’Agnese, G., Dall’Agnese, A., Banani, S. F., Codrich, M., Matilde Clarissa Malfatti, Giulia Antoniali, & Tell, G. (2023). Role of condensates in modulating DNA repair pathways and its implication for chemoresistance. Journal of Biological Chemistry, 299(6), 104800–104800. https://doi.org/10.1016/j.jbc.2023.104800
M. Anoud, E. Delagoutte, Q. Helleu, Brion, A., E. Duvernois-Berthet, M. As, Marques, X., K. Lamribet, C. Senamaud, L. Jourdren, A. Adrait, Heinrich, S., G. Toutirais, S. Hamlaoui, G. Gropplero, Giovannini, I., L. Ponger, M. Gèze, C. Blugeon, & Coute, Y. (2024). Comparative transcriptomics reveal a novel tardigrade specific DNA binding protein induced in response to ionizing radiation. PubMed Central, 13:RP92621. https://doi.org/10.7554/elife.92621
Cover image credit: “Mikrofoto.de-Baertierchen3” by Frank Fox at http://www.mikro-foto.de/ is licensed under CC BY-SA 3.0 Germany.