RNA has newly identified role: Repairing serious DNA damage to maintain the genome
Your DNA is continually damaged by sources both inside and outside your body. One especially severe form of damage called a double-strand break involves the severing of both strands of the DNA double helix.
Double-strand breaks are among the most difficult forms of DNA damage for cells to repair because they disrupt the continuity of DNA and leave no intact template to base new strands on. If misrepaired, these breaks can lead to other mutations that make the genome unstable and increase the risk of many diseases, including cancer, neurodegeneration and immunodeficiency.
Cells primarily repair double-strand breaks by either rejoining the broken DNA ends or by using another DNA molecule as a template for repair. However, my team and I discovered that RNA, a type of genetic material best known for its role in making proteins, surprisingly plays a key role in facilitating the repair of these harmful breaks.
These insights could not only pave the way for new treatment strategies for genetic disorders, cancer and neurodegenerative diseases, but also enhance gene-editing technologies.
I have spent the past two decades investigating the relationship between RNA and DNA in order to understand how cells maintain genome integrity and how these mechanisms could be harnessed for genetic engineering.
A long-standing question in the field has been whether RNA in cells helps keep the genome stable beyond acting as a copy of DNA in the process of making proteins and a regulator of gene expression. Studying how RNA might do this has been especially difficult due to its similarity to DNA and how fast it degrades. It's also technically challenging to tell whether the RNA is directly working to repair DNA or indirectly regulating the process. Traditional models and tools for studying DNA repair have for the most part focused on proteins and DNA, leaving RNA's potential contributions largely unexplored.
My team and I were curious about whether RNA might actively participate in fixing double-strand breaks as a first line of defense. To explore this, we used the gene-editing tool CRISPR-Cas9 to make breaks at specific spots in the DNA of human and yeast cells. We then analyzed how RNA influences various aspects of the repair process, including efficiency and outcomes.
We found that RNA can actively guide the repair process of double-strand breaks. It does this by binding to broken DNA ends, helping align sequences of DNA on a matching strand that isn't broken. It can also seal gaps or remove mismatched segments, further influencing whether and how the original sequence is restored.
Additionally, we found that RNA aids in double-strand break repair in both yeast and human cells, suggesting that its role in DNA repair is evolutionary conserved across species. Notably, even low levels of RNA were sufficient to influence the efficiency and outcome of repair, pointing to its broad and previously unrecognized function in maintaining genome stability.
By uncovering RNA's previously unknown function to repair DNA damage, our findings show how RNA may directly contribute to the stability and evolution of the genome. It's not merely a passive messenger, but an active participant in genome maintenance.
These insights could help researchers develop new ways to target the genomic instability that underlies many diseases, including cancer and neurodegeneration. Traditionally, treatments and gene-editing tools have focused almost exclusively on DNA or proteins. Our findings suggest that modifying RNA in different ways could also influence how cells respond to DNA damage. For example, researchers could design RNA-based therapies to enhance the repair of harmful breaks that could cause cancer, or selectively disrupt DNA break repair in cancer cells to help kill them.
In addition, these findings could improve the precision of gene-editing technologies like CRISPR by accounting for interactions between RNA and DNA at the site of the cut. This could reduce off-target effects and increase editing precision, ultimately contributing to the development of safer and more effective gene therapies.
There are still many unanswered questions about how RNA interacts with DNA in the repair process. The evolutionary role that RNA plays in maintaining genome stability is also unclear. But one thing is certain: RNA is no longer just a messenger, it is a molecule with a direct hand in DNA repair, rewriting what researchers know about how cells safeguard their genetic code.
This article is republished from The Conversation, a nonprofit, independent news organization bringing you facts and trustworthy analysis to help you make sense of our complex world. It was written by: Francesca Storici, Georgia Institute of Technology
Read more:
How does RNA know where to go in the city of the cell? Using cellular ZIP codes and postal carrier routes
Cells have more mini 'organs' than researchers thought − unbound by membranes, these rogue organelles challenge biology's fundamentals
Drugs of the future will be easier and faster to make, thanks to mRNA – after researchers work out a few remaining kinks
Francesca Storici consults at Tessera Therapeutics. She has received funding from the National Institutes of Health and the National Science Foundation.
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These spiked can also be affected by other factors like stress level, exercise, dehydration and even whether you have a sunburn. Many glucose monitors use a custom range that adapts to your body's baseline and patterns over time. When looking at your graph, it's important to keep in mind that context and trends matter more than one-off spikes. For example, seeing a spike after dessert isn't a sign that something is wrong. It's a sign that your body is doing its job. What matters most is how quickly your glucose returns to baseline and how often your levels stay elevated over time. "I would not see signs for concern for occasional (one to three times per day) moderate spikes (less than 160mg/dL) that resolve within about 30 mins. When reaching more frequent, especially if they are higher spikes (for example, above 180mg/dL), that take a long time to resolve (over 60 minutes), then there may be concerns about metabolic health," Fitton explained. 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Left Image: CGM in the self-injector. Right image: CGM on the back of my right arm. Nasha Addarich Martínez/CNET From the Oura app, I could see how my glucose levels fluctuated throughout the day. You can easily access it at the top of the app, where you also see other data metrics like sleep, heart rate, activity and readiness score (a personalized score, ranging from 0 to 100, that provides a snapshot of how well your body has recovered from the previous day's activities and sleep). How even my 'healthy' food choices raised my blood sugar (and that's OK) One of the most eye-opening parts of my testing was seeing how some of my favorite healthy staples played out on the glucose graph. A great example of this was my favorite pressed juice. I had a pressed juice in the morning that contained pineapple, beets, carrots, ginger, cucumber and lemon. It's nutrient-dense, but it also spiked my glucose above what's considered my healthy range for about 6 minutes (a small window and still considered optimal for my age and overall metabolic health). This was enough to make me rethink how and when I consume fruit-heavy beverages. The next day, I experimented with having a fruit smoothie instead of juice. I made a homemade smoothie with berries, banana, plant-based protein powder, peanut butter, soy milk and oats. This smoothie kept my glucose completely in range (zero minutes above my personal threshold). The added protein and fiber from the fruit, oatmeal, peanut butter and protein powder helped slow the absorption of natural sugars into my bloodstream. Nasha Addarich Martínez/CNET What I learned: Even natural fruit juices can cause glucose spikes, especially when consumed on an empty stomach and without any protein or fiber. Smoothies that include protein, fat and fiber can help keep spikes at bay and help stabilize your energy levels. Balance your meals with protein, fats and fiber Nasha Addarich Martínez/CNET Later that week, I had sushi rolls with a side of edamame for dinner. To my surprise, my glucose levels stayed within range the whole time. Oura Advisor (Oura's AI coach) even pointed out that this food combination offered protein and fiber, which likely contributed to the steady glucose levels. This moment was really encouraging for me. It made me realize that I don't need to drastically change what I eat. By just being more intentional about how I pair my foods, I can drastically improve the impact they have on my blood glucose. Pairing your foods with healthy fats like avocados, nuts, seeds and olive oil can also slow digestion and therefore the absorption of sugars. Fitton explains that this is primarily due to what happens in our digestive tract, even before the nutrients get to our bloodstream. Protein, fiber and healthy fats work in their own way to slow the absorption of simple carbohydrates into the bloodstream, making a slower, more gradual release of sugars into the blood. These factors turn what could be a glucose spike into a steady rise that your body can clear gradually. "The biggest area of concern when managing our blood sugar levels is limiting refined carbohydrates. When you do choose a refined-carb item (a plain cracker, white flour tortilla, cookies, etc.), try to pair it instead of eating it solo: add cheese, nut butter or a handful of edamame to blunt the glucose rise, and choose a higher-fiber version of your carbohydrate source when possible (for example, whole-grain crackers) so the carbs come packaged with their own speed limit," Fitton says. Cake and a walk equal steady blood sugar? 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Nasha Addarich Martínez/CNET Taking a walk after meals has long been recommended by experts for metabolic health, but seeing the effect in real time made it click for me. I do think that having the cake after having a balanced meal with protein and fiber also contributed to my steady levels of blood sugar. Sometimes, it's not about completely eliminating our favorite treats or carbs, but more so about timing, food pairing and movement. 3 ways I learned to flatten my glucose curve without sacrificing my favorite meals Before using the glucose sensor with Oura, I assumed blood sugar spikes were mostly about foods and how they impact your body. I also thought the only way to manage them was to cut carbs or drastically change my diet. But over these two weeks, I experienced firsthand how and when I eat (and move) matter just as much as what I eat. I learned that these three strategies helped keep my glucose levels in check. Pair carbs and sweets with protein, fiber and healthy fats When I had a berry smoothie with protein powder and soy milk, my glucose levels stayed steady. In contrast, when I had a fruit smoothie earlier that week, my blood sugar levels spiked and crashed more quickly. Takeaway: Carbs on their own, especially refined and processed carbs, can spike blood sugar quickly, but adding protein or fat slows digestion and leads to a more gentle spike. Food pairing examples: Apples and peanut butter, toast with avocado, rice with beans or another it out (especially after sweets) When I had cake as a snack, I was sure my graph would spike dramatically, but it didn't because of my walk (and eating a balanced meal before). A simple walk, even just 10 to 15 minutes, can help offset blood sugar spikes. This small but simple habit helps me now enjoy treats without the crash later. Timing your food matters I also noticed that when I ate higher-carb foods earlier in the day, my body processed them better than when I had them later at night. Breakfast smoothies and bowls kept my levels stable, while the same smoothie after 9 p.m. caused more spikes. "When it comes to blood sugar management, we see that in the morning our body usually has a spike in cortisol (a stress hormone) that can actually help our body take up sugar very quickly and quickly manage blood sugar. Eating in the morning will also calm the cortisol response, reducing the stress on your body. If you wait too long to eat, excess cortisol can create inflammation and also produce larger glucose spikes when you do eat," explained Fitton. Fitton further explained that, conversely, in the evening, the sugar management systems in our bodies start powering down and are not as good at helping blood sugar get into the cells. So it is important to try not to eat too late; otherwise, you'll probably see blood sugar go up and stay up for longer. That doesn't mean you can't eat carbs or treats at night, but eating them earlier in the day when insulin sensitivity tends to be higher can make a real difference.
