This episode examines a PNAS study showing that the BRCA1 pseudogene BRCA1P1 produces circular RNAs that suppress antiviral innate immunity in human cancers; depleting BRCA1P1 activates interferon-stimulated genes, increases apoptosis and chemosensitivity, and enhances immune clearance in preclinical models.
0:00Welcome to Base by Base, the papercast that brings genomics to you, wherever you are. Thanks for listening, and don't forget to follow and rate us in your podcast app. So I want you to picture something for a second.
0:10Picture a massive industrial junkyard, just, you know, acres and acres of discarded, rusted, broken machine parts scattered absolutely everywhere. Right, it's a total wasteland. Exactly. And let's say you're part of a local security force, and you have to patrol the perimeter of this junkyard every single day.
0:29To you, it's just this graveyard of useless scrap metal. to see here. Right. But imagine finding out that an enemy has been quietly sneaking into that exact junkyard, picking up those supposedly dead, useless pieces of machinery and secretly welding them together.
0:46Wow. Yeah, and they're using them to build this impenetrable cloaking shield, a shield that makes them completely invisible to your security patrols. I mean, you've basically been walking right past the enemy every day because they are hiding behind your own trash.
0:58It's a great analogy, really. Because that exact phenomenon, you know, hiding in plain sight using discarded material is literally playing out inside the human body right now at a microscopic level. It's kind of terrifying when you think about it.
1:11It really is. I mean, our cells possess these incredibly effective antiviral defense mechanisms. When a normal cell detects a threat. It trips a wire, right? It sounds this biological alarm that rallies the body's defenses to just destroy the invader.
1:27Right. The innate immune system. Exactly. And the important thing here is that that same alarm system can recognize and destroy cancer. But some tumors have learned how to survive by basically hijacking that cellular junkyard you just mentioned.
1:40Wait, so they're using the junk to hide? Yeah, they use ancient broken pieces of DNA to completely muffle that alarm and remain totally invisible to the immune system. So that brings us to the big question for this deep dive.
1:52How could turning off a broken piece of DNA suddenly make a tumor visible to the immune system again? Today, we celebrate the work of Eugene Hana, Alofun Maleo, Iolapade, and their colleagues at the University of Chicago, who have advanced our understanding of how non-coding pseudo genes regulate immune responses in cancer.
2:12And we are going to be exploring the mechanics of their discovery by looking at their paper. Regulation of antiviral and anti-tumor immunity by the BRCA1 pseudogene in human cancers, published in PNAS on May 4, 2026.
2:27Because honestly, this research completely upends the traditional view of what these discarded pieces of the genome are actually doing. It really changes everything. It does. It opens up an entirely new way of thinking about cancer vulnerabilities.
2:39Okay, so to really understand the sheer scale of this, I think we need to talk about what a pseudo-G actually is, like if you look at the human genome, you see the genes that make proteins, right, the building blocks of our biology.
2:49Right, the stuff doing the obvious work. Exactly. But then you see these massive stretches of genetic code that seem to be doing, well, absolutely nothing. Yeah, and historically, the scientific community just kind of wrote them off.
3:02I mean, we have approximately 14,729 of these pseudogenes in the human genome. Almost 15,000. Yeah. And to put that number into perspective, that is roughly the same amount as our actual functional protein coating genes.
3:18That's wild. Half of our genetic real estate is just occupied by these relics, exactly. They're essentially copies of functional genes that over 1000000s of years of evolution, just accumulated mutations.
3:29So they're broken? Pretty much. Maybe they sustain damage to their starting blocks, you know, preventing the cellular machinery from reading them. Or maybe their internal sequences just became too scrambled to produce a working protein.
3:40And because they didn't make proteins. The assumption was always that they just weren't driving biology. They were just, you know, evolutionary baggage. This junk DNA. But the star of our deep dive today proves they are anything but baggage.
3:50So we are focusing on a very specific pseudo gene called BRCA1P1. And, you know, you hear BRCA1 and you naturally think of the highly fair is highly functional tumor suppressor gene. Right, the one critically tied to breast and ovarian cancer risk.
4:06Exactly. But BRCO1P1 is like the strange cousin that sits right next door to it. It's a fusion pseudogene. Meaning it's this genetic chimera made up of discarded pieces from BRCA1, combined with leftover sequences from an entirely different gene called RPLP1.
4:22And our PLP one normally deals with cellular ribosomes. But the evolutionary origin of this chimera is, well, I think it's one of the most fascinating aspects of the biology here. Oh, totally. Because BRCA one P1 is uniquely specific to higher primates.
4:37Which means... Humans have it. Jimpanzees have it, but it does not exist in rodents. Mice do not have the pseudogene. Chicken zone have it. So it's a relatively recent addition, evolutionarily speaking.
4:47Exactly. Sometime during the evolution of primates, this unique fusion event occurred, creating this very specific sequence. And because of a localized mutation, it doesn't encode a protein. It simply exists as a long non-coding RNA, just a long string of genetic code floating inside the nucleus of human cancer cells.
5:07Right, a string of code that the tumor is using to completely shut down the host's antiviral innate immune response. But uh, let's back up for a second. You mentioned earlier that cells use an antiviral system to fight cancer.
5:19Why is the body using a system designed for viruses to fight a tumor that seems counterintuitive? It does seem that way, but the antiviral innate immune response functions as a broad, intrinsic defense network.
5:32It is not just about fighting off a cold, you know? It is about sensing severe cellular distress of any kind. Oh, okay. When the system is activated, It triggers the release of cytokines. You can take cytokines like molecular distress flares.
5:46Okay, distress flares. like that. Yeah. And it signals cytotoxic immune cells, the body specialized cellular assassins, basically, to converge on the area. And most crucially, it triggers apoptosis. Which is programmed cell death, right?
5:58Exactly. A damaged or infected cell essentially sacrifices itself. It falls on its own sword to protect the rest of the organism. Now, cancer is a state of severe cellular damage, so a tumor really should trigger this system.
6:10But it doesn't. Right. The great mystery in oncology has always been figuring out the exact mechanisms tumors use to silence that distress flare. And the researchers here suspected this primate specific ghost gene, BRCA1P1 was the silencer.
6:27But proving that creates an enormous methodological headache, right? Because how do you silence the ghost gene to study it without accidentally breaking the functional, incredibly important BRCA one gene that sits immediately next to it?
6:40Exactly. You can't just throw a general wrench into the DNA. The precision required is, it's on the scale of targeting a single typo in a massive library. Wow, so how did they pull that off? Well, they deployed 2 separate highly targeted methods.
6:53The 1st involved, these engineered molecules called LNA Gapmer, anti-sense oligomucleotides, or ASOs for short. They designed these synthetic strands of nucleic acids to physically bind to one specific mutant junction of the BRCA1P1 RNA. Basically, they scanned the sequence and found a spot that exists only in the pseudo gene, but not in the parent BRCA1 gene. So it functions like a chemical barcode scanner.
7:19That's a brilliant way to conceptualize it, actually. Yeah, like the molecules float through the cell, constantly scanning the RNA. If they encounter the functional BRCA one gene, the barcode doesn't match, so they just ignore it.
7:31Right. They leave it alone. But the moment they read the unique mutant junction of the pseudogene, the barcode matches, and they trigger a mechanism that shreds that specific RNA. Spot on. And to ensure their findings weren't just some weird side effect of the ASOs, they also utilized CRISPR cast 9 genome editing.
7:49Oh, of course. Heavy artillery. Right. They use CRISPR as a secondary validation to physically cut the pseudogene out of the cellular DNA entirely. And they didn't just try this barcode scanning and cutting on one isolated cell type.
8:01Right. They went broad. Very broad. They targeted and depleted BRCA one P1 across 26 different cell lines, spanning 13 different types of human cancers. Breast, colon, lung, brain, blood cancers, you name it.
8:15Okay, so they have the tools to destroy the pseudogene. But before they actually observed what happened to the tumors, they did some biomolecular sleuthing, didn't they, to figure out the actual physical shape of this ghost gene?
8:26Yes. And the shape turned out to be the absolute key to its power. The researchers used an enzyme known as RNA's R to test the structural integrity of the BRCA1P1 transcripts. RNA's R. What does that do exactly?
8:40So RNA's R is an exonucleus. That means it is an enzyme that degrades RNA, but it requires a free end to start cutting. It has to grab onto the end of an RNA strand and then it just chews it up piece by piece.
8:52Wait, so if I'm picturing this correctly, normal linear RNA is like a fragile piece of string. Right. And the Arnazar enzyme acts like a pair of scissors. As long as it can find one of the ends of the string, it can snip the whole thing down into nothing.
9:05But if the tumor somehow ties the ends of that string together to make a seamless loop or ring. The scissors have no starting point. The ring becomes highly durable. That structural difference dictates the entire survival strategy of the tumor.
9:18It's wild. When the researchers exposed the cellular RNA to the RNA's R enzyme, all the normal linear RNA was rapidly destroyed, but a staggering 70 to 80% of the BRCA1 P1 transcripts actually survived the enzyme bath.
9:3470 to 80%. huge. It is. And they survive because they're a circular RNAs or cirque RNAs. They are covalently closed loops with no free ends. In the chaotic enzyme filled environment of a cell, These loops just don't degrade easily.
9:49So they act as highly stable, long-lasting shield. Precisely. The tumor isn't just producing a transient silencer. It is manufacturing durable structural armor to maintain a constant suppression of the immune arm.
10:00Wow. But testing a durable loop in a Petri dish is only step one. I mean, to prove this actually works, you have to move into complex living systems. And this brings us back to that evolutionary quirk you mentioned earlier.
10:11Right. If mice don't naturally have this pseudogene, you can't just inject a standard lab mass with cancer and study this mechanism. Right. The evolutionary gap required highly advanced preclinical modeling.
10:23The researchers had to use 2 distinct testing grounds. First, they use patient derived organoids or PDOs from individuals with triple negative breast cancer. Organoids are like mini organs, right? Basically.
10:36They are miniaturized, three-dimensional structures grown from a patient's actual tumor biopsies. They retain the complex architecture and the exact genetic landscape of the original human tumor, which provides a far more accurate testing environment than, you know, just flat cells growing on plastic.
10:53Right. And for the in vivo testing, the actual living organism testing, they use something called a humanized mouse model. Specifically, humanized NCG B2MKO mice. That is a mouthful. It really is. But basically to bypass the evolutionary gap, the researchers utilize these specialized mice that are engineered with severe immune deficiencies, preventing them from rejecting foreign tissue.
11:16Okay, so there are a blank slate. Exactly. They then ingrafted these mice with human peripheral, blood, mononuclear cells. So they essentially gave the mouse, a functioning human immune system. Oh wow.
11:29Yeah. And once the human immune system was established, they introduced human breast cancer cells. That way, they could observe how a human immune system reacts to a human tumor, when the BRCA one P1 suitor gene is either active or destroyed.
11:42That is incredibly clever. Okay, so they have the humanized mice. They have the 3D organoids, and they deploy those ASO barcode scanners to strip away the circular RNA shield. When they actually pulled the trigger on these cancer cells, what happened?
11:56The data revealed a pan cancer phenomenon. First, they observe that BRCA1P1 is expressed at significantly higher levels in tumor cells compared to normal healthy cells. Which makes sense if they're using it as a shield.
12:08Right. But the true shock wave occurred when they actually depleted the pseudogene, stripping away that circular RNA caused an explosive spike in the expression of antiviral genes and inflammatory side economy.
12:19The distress flares. Exactly. In lung cancer cells, specifically the A549 cell line, the expression of a critical distress cytokine called TNF skyrocketed nearly 16 fold. 16 fold. So the tumor is suddenly blaring a siren into the cellular environment.
12:35It goes from being completely invisible to like the brightest object in the room. And this wasn't isolated to lung cancer either. They record a varying, but consistent massive spikes in other antiviral genes, like IFIH1 and numerous interferons across colon, breast, and other cancer cell wines.
12:52Okay, so if the tumor is suddenly screaming its presence to the immune system, what happens to the cancer cells themselves? Well, the cancer cells rapidly underwent apoptosis. The self-destruct sequence was initiated.
13:03Furthermore, the surviving cancer cells became highly sensitive to standard chemotherapy, specifically Docs Rubison. That's amazing. But the most vital finding, I mean, the detail that makes this a viable therapeutic target rather than just a cool biological curiosity, is that depleting this pseudogene had 0 toxic effect on normal, healthy, non-malignant cells.
13:22Wait, none. None. The vulnerability exists entirely within the malignant tissue. That is the holy grail of cancer research, right? Killing the cancer without hurting the patient. And the results in the preclinical models reflect that lack of toxicity, don't they?
13:36Yes, absolutely. Like when they applied this to the patient derived organoids. The 3D mini tumors knocking down the pseudogene reduced the viability of the tumor cells by 53 to 76%. I mean, the tumor simply could not survive without their shield.
13:52And the humanized mice provided the ultimate confirmation of the mechanism, knocking out the pseudogene led to a profound reduction in overall tumor volume. But what was happening inside the tumor micro environment was even more revealing.
14:04What did they see? The researchers observed a massive influx of the body's own immune cells, migrating straight into the tumor. They recorded a significant infiltration of CD3, CD4 and CD8T cells. The specialized soldiers of the immune system.
14:19Exactly. They were finally seeing their target. And they also saw a massive influx of CD 86 positive macrophages, right? Yes. Macrophages Act is the immune system's heavy cleanup crew. When the cytokines are released, the macrophages receive the signal to move into the tumor and literally consume the cancer cells in a process called phagocytosis.
14:41So the tumor is destroyed from the inside out, completely dismantled by the host's own biology. It's incredible to witness. It really is. But, hold on, I'm stuck on something here. I want to look at the physical mechanics of this.
14:52You keep calling it a BRCA one pseudogene. But the normal functional BRCA one parent gene is famous because it repairs damaged DNA. Like if it breaks, DNA damage accumulates and cancer wrist rises. So how did we jump from DNA repair and maintenance over to a switch for the innate immune system?
15:10It feels like we leaped across 2 entirely different biological disciplines? It's a completely natural assumption to make, given the nomenclature? Because it shares a name, you assume it shares a function.
15:19But the beauty of this discovery is that BRCA one P1 operates entirely independently of BRCA one mutation status. It does not fix DNA. It has nothing to do with DNA repair whatsoever. Yeah. Because of that unique evolutionary fusion with the ribosomal elements we talked about, and because it forms that highly durable circular RNA, its physical shape allows it to perform a completely different job.
15:42The CircarNA acts as a physical tether that binds to a specific protein called RLA. Okay, what is the significance of RLA in this context? So, RLA is a crucial subunit of a protein complex called NFG. An NFK functions as a master transcription factor.
15:58You can think of it as the primary on off switch for the innate immune system. Okay, I follow. Under normal, healthy cellular conditions. If a cell detects severe distress, NFK travels directly into the nucleus, binds to the DNA, and turns on all those antiviral inflammatory and apoprototic genes we discussed.
16:16It is literally the finger that flips the alarm switch. So a transcription factor physically has to travel to the DNA to turn the genes on. Is the tumor using the BRCA1P1 circular RNA to grab onto that finger and hold it back?
16:29That is the exact mechanism. The circular RNA binds physically to the real LA subunit of NEK. It acts like a molecular trap, trapping the transcription factor and holding it in an active state. Wow. The cancer cell should be triggering an alarm, but the machinery required to flip the switch is physically restrained by the pseudogene loop.
16:48When the researchers use the barcode scanners to shred the loop, they are dissolving the trap. And when the track dissolves, NFE is suddenly released, it floods into the nucleus, binds to the DNA, and starts frantically turning on the antiviral genes.
17:03I mean, that completely explains the explosive 16 fold spike in the TNF cytokine. It does. And it explains the rush of T cells and macrophages into the humanized mice. The brinks are off, and the immune system just goes into overdrive.
17:18The logic of the mechanism is incredibly elegant, and it opens up immense clinical possibilities, because these circular RNAs are highly stable in the body, meaning they could serve as excellent non-invasive biomarkers for early cancer detection.
17:30Oh, like a liquid biopsy. Exactly. If we can detect these specific loops in a blood draw, we might spot the tumor shield before we even spot the tumor itself. And clearly they represent potent drug targets.
17:41However, the path from this discovery to a functional clinical treatment has, you know, significant hurdles. The primary hurdle being the delivery vehicle, right? We have the barcode scanners, the ASOs.
17:53But getting a synthetic nucleic acid to survive the human bloodstream and penetrate deep into a solid tumor inside a living patient is incredibly difficult. Delivery is the ultimate bottleneck in RNA therapeutics.
18:06The research is clearly outlined that the next crucial steps require advanced ASO chemistry. We need to engineer these therapeutic molecules so they do not degrade in the bloodstream before reaching their target.
18:18Right. The papers suggest developing advanced cancer targeted nanoparticles, or perhaps leveraging the unique metabolism of cancer cells to shutter these ASOs directly into the solid tumors. The efficacy in the lab is undeniable, but we need specialized delivery vehicles to achieve that same unmasking effect in human patients.
18:35So we have the map, and we have the target. Now we just have to build the transport. That's exactly it It's the classic difficult leap from bench to bedside. But even with the delivery challenges ahead, the paradigm shift in how we view the non-coding genome is just staggering.
18:49It forces a complete reevaluation of the genetic graveyard. We can no longer just look at the 14,000 protein coating genes. We have to scrutinize the spaces in between. You know, the discarded parts that tumors are actively weaponizing.
19:02Let's distill all of this down into our take home message. If you remember one core concept from our deep dive today. Let it be this. Pseudo genes are not dead evolutionary baggage. They're not a junkyard of useless, harmless parts.
19:17They are highly stable, active regulators of human biology. Exactly. Tumors are exploiting primate specific loops of circular RNA to physically trap the immune systems alarm switch. But by deploying targeted barcode scanners to strip away the BRCA1P1 shield.
19:33We can unmask a tumor, reactivate the body's intrinsic antiviral defense system, and signal the immune system's cleanup crew to destroy the cancer from the inside out. It reviews a vulnerability. We simply didn't know existed.
19:44Hidden within code we used to ignore, which leaves us with a massive lingering question. What does this mean for the 1000s of other ghost genes hiding in our DNA, waiting to be turned against the diseases that hijack them?
19:58This episode was based on an open access article under the CCBY4.0 license. You can find a direct link to the paper and the license in our episode description. If you enjoyed this, follow or subscribe in your podcast app and leave a 5 star rating.
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