Rosa Rubicondior: Incompetent Design - How Sunlight Turns Off Cancer Protection in Skin

Schematic of the role of YTHDF2 in regulating U6 snRNA decay and interaction with TLR3 to control UVB-induced inflammation and tumorigenesis.

Seungwon Yang, Yan-Hong Cui, Haixia Li, et al.(2025), Fig.7 P

New study reveals how controlling sunburn-triggered inflammation may prevent skin cancer - UChicago Medicine

Researchers at the University of Chicago have uncovered how prolonged exposure to ultraviolet (UV) radiation can lead to skin cancer by disabling a vital protective mechanism in skin cells. They have just published their findings, open access, in Nature Communications.

This protective mechanism relies on a protein called YTHDF2, which plays a key role in regulating RNA metabolism and maintaining cellular health. Sunlight degrades this protein, removing that safeguard and allowing damage to accumulate.

For advocates of Intelligent Design (ID) creationism, this research presents several awkward questions—questions they will either ignore or attribute to ‘sin’.

First, why is this protection needed at all? If life were intentionally and intelligently designed, why would RNA metabolism require an additional, failure-prone layer of regulation to keep cells functioning? Why not design it to be robust in the first place?

Second, why create a system so fragile that sunlight—an unavoidable feature of life on Earth—can disable it? Designing a repair mechanism that breaks down precisely when it is needed most hardly inspires confidence in the designer’s competence.

And then there is the broader problem: ID creationism equates its designer with the supposedly omniscient and omnipotent god of the Bible or Qur’an. If that is true, why design a mechanism that predictably causes cancer? Was this an act of malevolence or oversight?

If YTHDF2 were flawless and impervious to degradation, Discovery Institute fellow William A. Dembski would no doubt present it as an example of “complex specified information,” a supposed indicator of intelligent purpose. But its vulnerability raises uncomfortable possibilities: Is this an unsuccessful attempt to patch over earlier design flaws in RNA metabolism? A sign of competing designers beyond the control of ID’s putative omnipotent creator? Or evidence that the designer is actively introducing harm and suffering?

The answer, of course, is that this problem arises because the human body is not the product of intelligent design at all, but of a long evolutionary process that modifies existing processes and structures to produce workable—though often imperfect—solutions. Evolution favours whatever improves short-term reproductive success, even if it introduces compromises and sub-optimal outcomes that undermine long-term survival and health. These sub-optimal systems then drive the evolution of an additional layers of complexity to minimise the results of failure.

Like other organism's the human body is full of these examples of evolutionary compromises and sub-optimal solutions that cause diseases and health problems that illustrate the difference between an intelligently designed system and an evolved system. Looked at in detail, the human body is evidence against intelligent design and strongly supports the Theory of Evolution, as I show in my book, The Body of Evidence: How the Human Body Refutes Intelligent Design.

UV Damage, YTHDF2, and the Global Burden of Skin Cancer. How UV Radiation Damages Skin

DNA lesions: UVB creates thymine dimers that distort DNA and cause mutations.
Oxidative stress: UVA generates reactive oxygen species that damage DNA, proteins, and membranes.
Immune suppression: UV exposure weakens the skin’s local immune response, reducing its ability to clear damaged cells.
Protein degradation: UV light can degrade key regulatory proteins—including YTHDF2—undermining normal repair mechanisms.
Outcome: Accumulated cellular damage increases the risk of melanoma, basal cell carcinoma, and squamous cell carcinoma.

What Is YTHDF2?

Full name: YTH N6-methyladenosine RNA binding protein 2
Role in cells:

Controls the stability and degradation of methylated RNA
Maintains normal gene expression
Regulates stress responses

Importance:

Loss of YTHDF2 disrupts inflammation control and heightens mutation risk
UV-induced degradation of this protein weakens the skin’s protective pathways

The Global Burden of Skin Cancer

Most common cancer worldwide: Skin cancers outnumber all other cancers combined.
WHO estimates:

2–3 million non-melanoma skin cancers annually
~132,000 melanomas

Major risk factor: Excessive UV exposure remains the dominant avoidable cause.
High-risk groups:

Fair-skinned individuals
People with heavy sun exposure
Users of tanning beds

Prevention:

Seek shade and wear protective clothing
Use broad-spectrum sunscreen
Avoid tanning devices
Conduct regular skin checks

The University of Chicago work is summarised in a UChicago Medicine news item by Chandrika Abburi, PhD.

New study reveals how controlling sunburn-triggered inflammation may prevent skin cancer
Sunlight is vital for human health as it helps the body produce essential nutrients, such as vitamin D. However, too much sun exposure can significantly increase the risk of skin cancer.
In a new study published in Nature Communications, researchers at the University of Chicago have discovered how prolonged exposure to ultraviolet (UV) radiation can trigger inflammation in skin cells through degradation of a key protein called YTHDF2. This protein acts as a gatekeeper in preventing normal skin cells from becoming cancerous. The finding reveals that YTHDF2 plays a crucial role in regulating RNA metabolism to keep cells in a healthy state and opens the door to developing potential new approaches to skin cancer prevention and treatment.

Uncontrolled inflammation triggers skin cancer
Each year, nearly 5.4 million people in the United States are diagnosed with skin cancer, with more than 90% of cases attributed to excessive UV exposure. UV rays can damage DNA and cause oxidative stress and inflammation in skin cells — leading to redness, pain and blistering, commonly known as sunburn.

We’re interested in understanding how inflammation caused by UV exposure contributes to the development of skin cancer.

Professor Yu-Ying He, PhD, Corresponding author
Department of Medicine
Section of Dermatology
University of Chicago, Chicago, IL, USA.

RNA or ribonucleic acid is an essential molecule that helps convert genetic information into proteins. A special class known as non-coding RNAs regulates gene expression without producing proteins. These molecules typically function in either the nucleus, where a cell’s DNA is stored or the cytoplasm, where most cellular activity occurs.

Low levels of YTHDF2 turn normal skin cells cancerous

He’s laboratory studies how environmental stressors, such as UV radiation or arsenic in drinking water, affect molecular pathways and damage cellular systems, leading to cancer. Through screening various enzymes, the researchers found that UV exposure causes a marked decrease in levels of YTHDF2, a “reader” protein that specifically binds to RNA sequences marked with a chemical tag known as N6-methyladenosine (m⁶A).

When we removed YTHDF2 from skin cells, we saw that UV-triggered inflammation was much worse. This suggests that the YTHDF2 protein plays a key role in suppressing inflammatory responses.

Professor Yu-Ying He.

Although inflammation is essential for fighting off infections, it also plays a major role in causing life-threatening diseases, including cancer. However, the molecular mechanisms that regulate this response, especially after UV damage, are not well understood.

YTHDF2 in regulation of non-coding RNA interactions
Using multi-omics analysis and additional cellular assays, the research team found that YTHDF2 binds to a specific non-coding RNA known as U6, which is modified by m⁶A and classified as a small nuclear RNA (snRNA). Under UV stress, cancer cells showed increased levels of U6 snRNA, and these modified RNAs were found to interact with toll-like receptor 3 (TLR3), an immune sensor known to activate inflammatory pathways linked to cancer.

Surprisingly, these interactions occurred within endosomes, where cellular compartments are typically involved in recycling materials, not where U6 snRNA is usually located.
We spent a lot of time figuring out how these non-coding RNAs get to the endosome, since that’s not where they usually reside. For the first time, we showed that a protein called SDT2 transports U6 into the endosome, and YTHDF2 travels with it.

Professor Yu-Ying He.

Once both YTHDF2 and m⁶A-modified U6 RNA arrive at the endosome, YTHDF2 blocks the RNA from activating TLR3. However, when YTHDF2 is absent — such as after UV damage, the RNA freely binds to TLR3, triggering harmful inflammation.

Our study uncovers a new layer of biological regulation, a surveillance system through YTHDF2 that helps protect the body from excessive inflammation and inflammatory damage.

Professor Yu-Ying He.

The findings could open the door to new strategies for preventing or treating UV-induced skin cancer by targeting the RNA-protein interactions that regulate inflammation.

Additional authors include Seungwon Yang, Yan-Hong Cui, Haixia Li, Jiangbo Wei, Gayoung Park, Ming Sun, Michelle Verghese, Emma Wilkinson, Teresa Nam, Linnea Louise Lungstrom, Xiaolong Cui, Tae Young Ryu, Jing Chen, Marc Bissonnette, and Chuan He from the University of Chicago.

Publication:
Yang, S., Cui, YH., Li, H. et al.
YTHDF2 regulates self non-coding RNA metabolism to control inflammation and tumorigenesis. Nat Commun 16, 9946 (2025). https://doi.org/10.1038/s41467-025-64898-7

Abstract
The role of m⁶A RNA methylation of self non-coding RNA remains poorly understood. Here we show that m⁶A-methylated self U6 snRNA is recognized by YTHDF2 to reduce its stability and prevent its binding to Toll-like receptor 3 (TLR3), leading to decreased inflammatory responses in human and mouse cells and mouse models. At the molecular level, endosomal U6 snRNA binds to the LRR21 domain in TLR3, independent of m⁶A methylation, to activate inflammatory gene expression, a mechanism that is distinct from that of the best known synthetic TLR3 agonist poly I:C. Both U6 snRNA and YTHDF2 are localized to endosomes via the transmembrane protein SIDT2, where YTHDF2 functions to prevent the U6-TLR3 interaction. We further show that UVB exposure inhibits YTHDF2 by inducing its dephosphorylation and autophagic protein degradation in human keratinocytes and mouse skin. Skin-specific deletion of Ythdf2 in mice enhanced the UVB-induced skin inflammatory response and promoted tumor initiation. Taken together, our findings demonstrate that YTHDF2 plays a crucial role in controlling inflammation by inhibiting m⁶A U6-mediated TLR3 activation, suggesting that YTHDF2 and m⁶A U6 are potential therapeutic targets for preventing and treating inflammation and tumorigenesis.

Introduction
N⁶-methyladenosine (m⁶A) RNA methylation is the most prevalent internal modification that occurs in messenger RNA (mRNA) and long non-coding RNA (lncRNA) of most eukaryotes^1,2,3,4. m⁶A mRNA methylation regulates several aspects of RNA metabolism, including RNA decay, nuclear processing, translation, transcription, and RNA-protein interactions^1,3,4,5,6,7. At the molecular level, m⁶A RNA modification is installed by writer complexes composed of factors including METTL3, METTL14, WTAP, and KIAA1429, or METTL16, and is removed by erasers FTO or ALKBH5¹. m⁶A is recognized by m⁶A-binding proteins including YTHDF1-3, YTHDC1, YTHDC1-2, and IGF2BP1-3, also known as m⁶A readers, to regulate RNA fate^1,8. Among the m⁶A writers, METTL16 is monomeric, and is distinct from METTL3/METTL14, which is an obligate heterodimer⁹. The METTL16 ortholog mett-10 in C. elegans has been shown to deposit m⁶A on SAM synthase to inhibit its proper splicing¹⁰. Recent studies have demonstrated critical roles for METTL16 in the pathogenesis of leukemia and liver cancer in both m⁶A-dependent and -independent mechanisms^11,12. However, the function of METTL16 remains incompletely understood.

One m⁶A-modified non-coding RNA is the small nuclear RNA (snRNA) U6¹³. U6 snRNA is a non-coding RNA best known for its role in splicing. U6 interacts with three snRNAs, pre-mRNA substrates, and more than 25 protein partners to form the catalytic core of the spliceosome during splicing¹³. Although commonly used as an internal standard to quantify the level of miRNA, U6 snRNA was recently recognized as a highly variably expressed gene in various human tissues including carcinoma tissues¹⁴. Notably, U6 snRNA levels are significantly higher in human carcinoma tissue than in the corresponding normal tissue^14,15. Newly synthesized U6 appears transiently in the cytoplasm and undergoes maturation where it is accompanied by U6-associated proteins known as small nuclear ribonucleoprotein complexes, snRNPs, before returning to the nucleus^13,16. Among the U6 snRNPs, loss of LSM6 or LSM7 induces a cytosolic accumulation of U6 snRNA¹⁷. Recently, U6 has been shown to be m⁶A-modified by METTL16 at A43^18,19. In Schizosaccharomyces pombe, loss of the Mettl16 ortholog Mtl16 alters global splicing²⁰. In contrast, in mouse embryos, Mettl16 deletion had little effect on global splicing²¹. These contrasting functions suggest species-specific roles for METTL16 in splicing. Altogether, the functional role of m⁶A methylation on U6 snRNA in mammals as well as its reader remains unknown.

Emerging evidence has demonstrated that inflammation, originally recognized for its pivotal role in pathogen defense, also plays critical roles in a number of diseases including cancer²² and autoimmune diseases²³, both of which can be induced or triggered by environmental factors such as UV radiation^24,25. However, the molecular mechanisms that regulate inflammation remain incompletely understood. Here we show that YTHDF2 recognizes m⁶A-modified U6 snRNA to regulate U6 stability and binds to TLR3 in the context of inflammation and tumorigenesis, highlighting the crucial role of YTHDF2 and U6 m⁶A methylation in controlling inflammation.

Yang, S., Cui, YH., Li, H. et al.
YTHDF2 regulates self non-coding RNA metabolism to control inflammation and tumorigenesis. Nat Commun 16, 9946 (2025). https://doi.org/10.1038/s41467-025-64898-7

Copyright: © 2025 The authors.
Published by Springer Nature Ltd. Open access.
Reprinted under a Creative Commons Attribution 4.0 International license (CC BY 4.0)

For creationists who attempt to incorporate scientific findings into their worldview, this discovery presents a far deeper challenge than a simple anomaly. The vulnerability of YTHDF2 to sunlight is not an isolated curiosity but part of a consistent pattern: biological systems display layers of compromise, fragility, and historical contingency entirely consistent with an evolutionary origin, yet wholly at odds with deliberate engineering. If one insists on attributing these features to a conscious designer, one must then account for why that designer repeatedly builds systems that fail under entirely predictable conditions.

Moreover, this research illustrates yet again that our bodies bear the unmistakable hallmarks of a process that lacks foresight. The degradation of a key protective protein by the very environmental factor it is meant to help defend against is precisely the sort of mismatch we expect from evolution’s incremental tinkering. For creationists, however, it implies either profound incompetence or deliberate malice on the part of their proposed designer—neither of which sits comfortably with claims of omniscience, benevolence, or perfection.

Those creationists who do try to grapple with such findings are forced into increasingly strained explanations: invoking the Fall, shifting responsibility onto human behaviour, or asserting that harmful systems were once “good” before mysteriously degenerating. Yet none of these appeals address the foundational issue: the structural vulnerabilities are built into the biology itself. They are not the symptoms of decay but the inherent consequences of an unguided evolutionary process.

In the end, findings like this one do not merely pose difficulties for creationist arguments—they expose the fundamental incoherence at their core. The science is clear: our bodies are shaped by evolution, with all the limitations, compromises, and imperfections that entails. And the more we learn about how life actually works, the less room there is for the fiction of intelligent design.

These inconveniences leave creationists with only one option if they think clinging to easily falsifiable beliefs is a test of strength - look the other way and say, "Nuh uh!"

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