Episode Transcript
[00:00:00] Speaker A: Foreign.
[00:00:14] Speaker B: Welcome to Base by base, the papercast that brings genomics to you wherever you are. Our mission, as always, is to take a deep dive into new research, extracting the most important nuggets of knowledge and surprising facts so you, our curious listener, can become well informed quickly and without the overwhelm.
[00:00:31] Speaker A: And today, we're embarking on a truly fascinating journey. We're going deep into the delicate, precarious balance our cells must constantly maintain to keep their genetic codes stable. Imagine a tightrope walker, right, suspended high above a chasm. That's kind of our cell trying to prevent catastrophic damage on one side while allowing just enough flexibility, you know, for adaptation on the other. This cellular tyro back is absolutely critical, especially when that balance goes, well, disastrously awry in something as complex and cunning as cancer.
[00:01:01] Speaker B: And here's where the intrigue really begins. What if the very tools cancer cells use to survive and evolve aren't just random chance, but part of a carefully managed strategy? We're talking about a primate specific protein, one we initially thought had a pretty straightforward, almost mundane job of simply silencing ancient jumping genes. But this protein, it turns out, plays an entirely different, far more critical, almost secret agent like role in how cancer cells adapt, evolve and resist our treatments. It's a surprising finding that fundamentally shifts how we think about genomic stability and, well, cancer's own cutting intelligence.
So let's start with a provocative what if cancer cells aren't simply uncontrollably mutating, haphazardly changing their genetic code in a chaotic, free for all? What if instead they are actually cleverly controlling their own mutations? Think about it. A cell might need some mutations to adapt and evolve, right? To become resistant to a drug, for instance. But too many mutations, too much genomic chaos, can lead to its own demise. So how on earth does a cancer cell walk that incredibly fine tightrope, inducing just enough change to survive, but not so much that it self destructs? What's your initial take on this cellular conundrum?
[00:02:10] Speaker A: That question gets right to the heart of a fundamental aspect of cellular survival and disturbingly, cancer's resilience. Our cells are in a constant, ancient battle against tiny disruptive genetic elements we call jumping genes or transposable elements. The most common of these line ones, or L1s, are almost like biological saboteurs, capable of inserting themselves into new places in our DNA and causing chaos. This isn't just a modern problem. It's an age old biological conflict that has shaped our evolution. And what today's Deep dive reveals is that this ancient battle has unexpected, incredibly modern implications, particularly in the context of cancer. And yes, as you hinted, it involves a protein unique to primates, including us.
[00:02:50] Speaker B: It truly sparks so much curiosity. We had this picture of certain proteins acting as rigid gatekeepers, you know, silencing these genomic troublemakers. But if that's not their only job, I mean, how could a protein previously understood to primarily silence these jumping genes suddenly become a key player in cancer's ability to adapt and resist treatment? What does it really mean when we say a tumor fine tunes its own instability?
Does it imply a level of genomic control we hadn't fully appreciated? That's what we're here to uncover, to peek behind the curtain of cancer's surprising adaptive strategies. Before we delve deeper into the specifics of how this is all happening, we want to take a moment to give special recognition to the brilliant minds behind this groundbreaking work.
[00:03:35] Speaker A: Yes, absolutely. Today we celebrate the groundbreaking work of Romain Faure, Didier Trono and their team at Ecole Polytechnique Federal de Lausanne in Switzerland. Their meticulous research has significantly advanced our understanding of how cancer cells manipulate genome stability through a unique primate specific protein.
[00:03:52] Speaker B: Absolutely. It's a testament to the collaborative nature of science pushing the boundaries of what we know. We also want to give a shout out to Nexco analytics for their contribution to this research. It truly takes a village of dedicated scientists to uncover these hidden truths. Okay, so to really appreciate what this primate specific protein XEONF93, is doing, we first need to understand the gen landscape it operates within. Imagine our genome as a vast ancient library, and within it, these genetic remnants, transposable elements or tes. We often call them jumping genes because they can literally cut and paste themselves, or copy and paste into new locations a particular type. The line ones or L1s, are astonishingly prevalent. I mean, making up a staggering 60% of our DNA.
[00:04:39] Speaker A: That's incredible, isn't it?
[00:04:40] Speaker B: Yeah. While most of these are usually inactive, carefully locked down by our cellular defenses, they can, under certain conditions, become de. Represse, rest, essentially waking up. And when they do, they can cause significant DNA damage and trigger inflammation within the cell, disrupting its delicate balance.
[00:04:54] Speaker A: That's right. And this isn't just a static problem that our genome deals with. It's an ongoing biological arms race that has been playing out over millions of years. Think of it as a constant evolutionary cat and mouse game. Host organisms like us evolve sophisticated molecular weapons to repress these L1s, preventing them from jumping around and Causing trouble. But then the L1s in turn, evolved to escape these cellular defenses, Finding new ways to activate. A major class of these molecular Weapons are called Krab zinc finger proteins, or KZFPs. These are DNA binding proteins in vertebrates that act as transcriptional repressors, Essentially silencing these unwanted jumping genes.
And ZNF93, the star of our deep dive today, Is a crucial primate specific kzfp.
It's a relatively new weapon in our primate lineage's arsenal, emerging about 20 million years ago. Wow, 20 million years. Yeah. Specifically to repress certain L1 subfamilies like L1PA6, L1, PA5, and L1PA4. It's a biological innovation unique to us that allowed us to better control these genomic troublemakers.
[00:05:56] Speaker B: And this is where the cancer paradox becomes truly fascinating. In cancer cells, these transposable elements can become de repressed, Causing a lot of replication stress and DNA damage. You'd think cancer cells, already unstable, would be overwhelmed.
But here's the twist. Cancer cells don't necessarily want too much chaos. They need to survive and proliferate. Right?
[00:06:17] Speaker A: Exactly.
[00:06:17] Speaker B: And uncontrolled damage can kill them. So what often happens is that these stressed cancer cells Upregulate their repressors, like our KZFPs, to silence these jumping genes. Again, this action helps them mitigate that replication stress, which is a major barrier to uncontrolled growth, and ultimately allows them to continue proliferating. It's a critical, often counterintuitive adaptive strategy for cancer cell survival and growth. But how does ZNF particular fit into the strategy?
[00:06:43] Speaker A: Precisely. This paper directly addresses that key problem.
How do these L1 targeting key ZFPs, and specifically ZNF93, influence this complex process of genomic stability in cancer? The researchers wanted to know if there was more to ZNF93 story than simply being an L1 bouncer. You know? Yeah. Did it have another, perhaps even more central role in helping cancer cells navigate this tightrope of controlled instability?
Uncovering ZNF93's hidden role required some serious scientific detective work. Could you walk us through how the researchers began to peer back the layers of this mystery? Well, they started broadly with an initial genome wide screen. They wanted to identify all the KZFPs that were binding to the most dangerous endonuclease proficient L1 elements, though still capable of causing damage. By analyzing the binding profiles and focusing on the youngest, most active L1 subgroups, they identified about 15 KZFPs that were significantly enriched at these potentially disruptive L1 sites, it was like casting a wide net, sort of to find all the usual suspects.
[00:07:42] Speaker B: And then, with an ingenious next step, they connected these potential repressors to cancer itself. They dove into the vast archives of the cancer genome atlas, or TCGA huge, analyzing extensive expression data from 23 different cancer subtypes. This allowed them to correlate the expression levels of these KZFPs with a well established 167 gene signature that acts as a strong indicator of cell proliferation.
Essentially, they asked which of these repressors are consistently on when cancer cells are actively and aggressively growing.
[00:08:13] Speaker A: Right. And to confirm their hypotheses and drill down into ZNF93's specific role, they moved to rigorous experimental validation. Employing a sophisticated array of techniques. They used various cancer cell lines, Leukemia, lymphoma, colorectal cancer, and also control cell lines that naturally don't express ZNF93, like HeLa and HTT116 cells. This was crucial for confirming the specificity of ZNF93's effects, making sure what they observed wasn't just some general cellular response.
[00:08:40] Speaker B: And their genetic manipulations were incredibly Precise. To understand ZNF93's function, they used RNA interference, specifically SHRNA, to deplete ZNF93, essentially knocking it down in these cancer cell lines. Then they meticulously observed the consequences on crucial cellular processes. Cell proliferation, DNA synthesis, and key stress markers like EDU incorporation, PCHK 12 and.
[00:09:04] Speaker A: GOH, exactly that directly impact gene regulation.
[00:09:07] Speaker B: And finally, to understand how ZNF93 physically interacts with other proteins, they employed CO immunoprecipitation, or COIP.
They even engineered a mutated version of ZNF93. That was a clever move, right? To disentangle its mechanism, specifically looking at its interaction with its known CO repressor, TRM28.
[00:09:27] Speaker A: Absolutely, the comprehensive use of multiple cell lines and these sophisticated genetic and molecular manipulations Truly underscores the rigor of their approach to it ensured their findings were robust and specific to ZNF93 itself, not just an artifact of a single experiment.
[00:09:41] Speaker B: So after all that meticulous detective work, what hidden layers did the researchers peel back? What surprising discoveries awaited them regarding ZNF93's true role? The plot, as they say, thickens considerably.
[00:09:52] Speaker A: Well, their initial findings confirmed ZNF93's strong link to cancer. They observed it was consistently upregulated in cancer cells and showed the most pronounced correlation with cell proliferation across 14 out of the 23 cancer subtyp examined. Furthermore, it was robustly upregulated during processes involving rapid cell division like mitogenic T cell activation, Firmly linking its expression to fundamental cell growth.
[00:10:19] Speaker B: So that strongly suggested ZNF93 was acting as a critical guardian of proliferation. And indeed, when they depleted ZNF93 in various cancer cell lines, the results were dramatic.
[00:10:30] Speaker A: Very dramatic.
[00:10:30] Speaker B: A significant reduction in proliferation, a surge in replication, stress, activation of DNA damage responses, and even triggered inflammation. This clearly highlighted ZNF93's critical protective role in cancer cell growth and survival.
[00:10:43] Speaker A: Now, here's the first major twist. The moment their initial hypotheses took an unexpected turn. Given ZNF93's known role as an L1 repressor, they anticipated that depleting it would unleash those ancient jumping genes causing chaos.
[00:10:56] Speaker B: Made sense at the time, it did.
[00:10:59] Speaker A: But unexpectedly, ZNF93 depletion only modestly de repressed L1s. And even more strikingly, there was no detectable increase in the genotoxic L1 encoded protein ORF2P.
[00:11:11] Speaker B: Wow. No increase at all.
[00:11:12] Speaker A: None detectable. This wasn't just a minor finding. It was a seismic shift in their understanding. It meant ZNF93 are supposed to L1 bouncer had a hidden agenda. A much more direct and powerful lever for cancer survival than they ever suspected. This insight immediately redirected the entire investigation.
[00:11:28] Speaker B: So if ZNF93 wasn't just about L1s, what was its critical role? The researchers are left with a puzzle. They had stripped away one layer, only to find something far more profound beneath. And this, our curious listener, is where the story takes its truly unexpected turn. Revealing ZNF93's secret, devastatingly effective mission. They discovered ZNF93 is a critical regulator of APOB3B.
[00:11:50] Speaker A: APOB3B? Yeah.
[00:11:51] Speaker B: This is a potent mutagenic enzyme that's widely linked to driving mutations in cancer. What they found was quite dramatic. ZNF93 depletion dramatically increased APOBC3B expression guyrocketed while ZNF93 over expression reduced it. It's like ZNF93 has a direct powerful switch for this dangerous mutagen.
[00:12:11] Speaker A: And the surprises kept coming. They also found that ZNF93 represses APOBC3D largely through mechanisms independent of its usual CO repressor, TRM28.
[00:12:20] Speaker B: Independent how?
[00:12:22] Speaker A: Well, remember how we mentioned that mutated ZNF93. Even a version of ZNF93 that couldn't bind Trime28 still repressed APOB3B, albeit slightly less efficiently. This points to a completely novel regulatory pathway for ZNF93, one we hadn't seen before for this class of proteins.
[00:12:39] Speaker B: So this new independent pathway, what does it do?
[00:12:41] Speaker A: They showed that XENF93 actually protects proliferating cells from APOB3B induced replication stress. XENF93 overexpression allowed cells to recover faster from genotoxic stress caused by agents like hydroxyurea, mirroring the protective effects of reducing APOBC3B itself.
[00:12:58] Speaker B: It's like ZNF93 is the conductor of a powerful orchestra. And APOB C3B is a sometimes destructive instrument. ZNF93 doesn't silence the entire orchestra, you know, the L1s. Instead, it fine tunes the volume of APOB3B, ensuring it plays its part without causing too much havoc or bringing down the whole performance.
[00:13:14] Speaker A: This study therefore profoundly positions ZNF93 as a pivotal guardian of genome stability. Performing a dual role, it not only represses those ancient L1 jumping genes, but critically, it also acts as a rheostat for the mutagenic enzyme APOB3B. This means ZNF93 help cells navigate that incredibly tricky balance of allowing some mutations for adaptation, while preventing catastrophic DNA damage that would lead to cell death.
[00:13:41] Speaker B: So why does all this matter for you, our listener? Whether you're a scientist, a student, or just intensely curious about the cutting edge of biology, what are the huge implications here for cancer?
[00:13:51] Speaker A: Well, APOB3B is widely known as a major driver of mutations in cancer, pushing tumor evolution, making cancer cells more aggressive and drug resistant. But as we heard, too much of APOB3B's activity can actually overwhelm the cell, leading to its own demise. It's a double edged sword for the cancer cell. So the high correlation of ZNF93 with cell proliferation in most cancers suggests that tumors actively exploit ZNF93 to manage APOB3B levels. This isn't random. It's an incredibly adaptive, almost ruthless strategy for survival. Imagine a highly skilled, ruthless gambler who knows exactly how much risk to take to win big, but not so much as to go bankrupt.
[00:14:33] Speaker B: That's a good analogy.
[00:14:34] Speaker A: Cancer cells through ZNF93 are essentially choosing their mutations, strategically maintaining enough genomic instability to adapt without crossing the line into self destruction.
[00:14:44] Speaker B: That's a truly chilling image of cancer's cunning. But this raises an important question.
What about situations where ZNF93 doesn't follow this pattern where its expression is not correlated with proliferation. Are there exceptions to this rule?
[00:14:57] Speaker A: That's a great question. And the researchers found a fascinating exception in cervical squamous cell carcinoma, or CESC, especially in HPV positive cases.
[00:15:04] Speaker B: HPV positive.
[00:15:05] Speaker A: Okay. In these instances, ZNF93 is actually downregulated, while APOBC3B expression is high.
[00:15:10] Speaker B: The opposite Exactly.
[00:15:12] Speaker A: This highlights the complexity of cancer. Tumors might adapt ZNF93 expression based on specific conditions, like a viral infection, where APOB3B also has an antiviral role. It's a fascinating example of context dependent regulation showing cancer's ability to bend the rules when circumstances demand it.
[00:15:31] Speaker B: So if cancer cells are manipulating the ZNF93APOBC3B axis to their advantage, does that mean ZNF93 could be a potential therapeutic target, A new vulnerability we could exploit?
[00:15:43] Speaker A: Absolutely. Understanding precisely how cancer cells exploit the ZNF93APOBC freeb axis could indeed lead to entirely new therapeutic strategies. For instance, ZNF93 has already been linked to resistance to certain genotoxic therapies like ET743.
[00:15:58] Speaker B: Oh, interesting.
[00:15:59] Speaker A: Yeah. So if we could find a way to either block CNF93's action, or perhaps modulate this specific ZNF93APB3B pathway, it could potentially resensitize resistant cancer cells to treatment, making them vulnerable once more. The challenge, of course, would be to do so selectively without harming healthy cells.
[00:16:16] Speaker B: Always the challenge. So what are the next critical steps for researchers building on this powerful discovery? Where do they go from here?
[00:16:22] Speaker A: Future work really needs to unravel those Tim28 independent mechanisms that ZNF93 uses to repress APOB3B.
How does it do it without its usual partner? Is it steric hindrance, maybe? Or a competition with other transcription factors for binding sites?
We just don't know.
[00:16:41] Speaker B: Yet more mysteries to solve.
[00:16:42] Speaker A: Always. And while L1D repression wasn't the primary driver of the specific phenotypes observed here, the Precise impact of ZNF93's L1 control in other cellular contexts still needs further exploration.
Science always leaves us with more questions than answers, which is, you know, the exciting part.
[00:16:59] Speaker B: This primate specific axis, unique to our lineage, is a truly fascinating example of how even fundamental biological processes, like maintaining genome stability can have these lineage specific layers of reg.
It profoundly emphasizes the unique aspects of human biology and how understanding them is key to tackling diseases like cancer that plague us. It's a constant reminder that Sometimes the most surprising discoveries come from looking closer at what we thought we already understood.
[00:17:24] Speaker A: The central insight here is truly profound. ZNF93, a protein unique to primates, plays a dual and crucial role in maintaining genome stability.
It represses ancient jumping genes and critically acts as a rheostat for the mutagenic enzyme APOB3 bio.
This helps cancer cells navigate the tightrope between accumulating beneficial mutations and succumbing to catastrophic DNA damage.
[00:17:49] Speaker B: So cancer cells are not just randomly accumulating mutations, they are actively subverting this ZNF93APOB3B regulatory access to their advantage, fine tuning their genomic instability to adapt, evolve and resist our current treatments.
What does this profound revelation mean for our approach to cancer, considering not just what goes wrong, but how how these incredibly adaptive cells manage the inherent chaos within their own genomes?
Thank you for joining us on this deep dive into the fascinating world of genome regulation and cancer adaptation. It's a complex, yet incredibly vital area of research that continues to reveal cancer's hidden strategies.
[00:18:25] Speaker A: It's truly incredible how uncovering these intricate cellular mechanisms can shift our fundamental understanding of disease and open doors to entirely new therapeutic avenues.
[00:18:35] Speaker B: This episode was based on an Open Access article Under the Science CCBY 4.0 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 five star rating. If you'd like to support our work, use the donation link in the description. Thanks for listening and join us next time as we explore more science base by base.
