Photolyase and cancer

Upon arriving at the beach yesterday, I lathered on the sun screen. Being relatively fair-skinned, I’ve learned my lesson in forgetting or not using enough of the stuff, and I wasn’t about to get all burned up. I don’t like eating lobster; I certainly don’t want to look like one.

But that isn’t the only reason I throw the stuff on so heavily. I’m also well aware of the tenacity and, if such a word is appropriate, vulgarity of cancer. Tanning is just a bad idea unless someone really wants to be diseased. It may look good (and not always), but I doubt that has ever brought solace to any cancer patients. Laying out in the sun without protection (as I saw a few people doing all day – it was at least 85 F, not a cloud in the sky) or jumping in one of those tanning cancer tubes is a sure-fire way to cause potentially deadly somatic cell mutations.

The way this works is that UV light slaps into the double helix structure of DNA causing an incorrect fusion in base pairs on the same side of the helix. Imagine – and apologies for the violence of it all – getting punched in the mouth. Instead of your teeth vertically matching as they do now (at least relatively), a couple teeth on the bottom row are now horizontal and facing each other. This calls for a dentist.

Different organisms have different mechanisms (dentists) for correcting damaged DNA. Naked mole rats, for example, have two genes for contact inhibition instead of the single gene virtually all other mammals have. This has resulted in no one ever recording an instance of cancer in the ugly little critters. If humans had this mechanism, cancer probably wouldn’t be nearly the problem it is.

Instead we get a number of repair mechanisms, chief among them base excision, nucleotide excision, and mismatch repair. (The mechanism in naked mole rats doesn’t repair mutated cells; it merely stops them from proliferating.) Unfortunately, the repair fidelity, just like the copying fidelity, of DNA is not perfect. Mistakes are made, mistakes are missed. We get cancer.

Part of our plight arises from something we’ve lost over evolutionary time. Most plants and other animals have a protein called photolyase which specifically seeks out UV damaged DNA.

Researchers at Ohio State University were recently able to observe exactly how photolyases perform their protective duty. The photolyase protein captures energy from visible light and uses it to project a single proton and a single electron towards a dimer in DNA. The two tiny particles then initiate a series of reactions that knock the contorted nucleotides back into place across the ladder, without needing to remove them like normal human proteins do. A proton and electron finally return to the photolyase protein, presumably so it can dash off to fix the next dimer it finds.

In other words, this dentist isn’t very gentle. He just punches your contorted teeth back into position. (Okay, it’s more elegant than that, but I had to finish the analogy.)

The article goes on to speculate as to the potential utilization of this protein in humans.

Given that photolyases were lost in evolution, it was possible that other proteins in the cell that allowed photolyases to do their job were also lost. But mice that were given the gene for the photolyase protein showed remarkable protection from UV damage. This means that in mice, the rest of the cellular infrastructure that photolyases need is still there. Chances are good that it’s there for humans as well.

There are other instances of mice being able to utilize genes not otherwise found in them, almost as if they’ve had them all along. For example, when injected with snippets of DNA for making red photo-pigment, normally dichromatic mice suddenly had trichromatic vision. This indicates an earlier evolved ability to see colors in the mammalian line that was later lost. In all likelihood, the appropriate gene(s) was probably just turned off out of a lack of need, leaving in place much of the cellular machinery needed to utilize red photo-pigment. I suspect the same is true with photolyase. If this can be extended to humans, a significant leap in the fight against many skin cancers may be on the horizon.

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Devil Facial Tumour Disease

Devil Facial Tumour Disease (DFTD) is a particularly nasty tumor currently afflicting Tasmanian devils. It is responsible for the destruction of around 70% of the island population. One step, fortunately, has been made through the discovery of its specific cause.

The research collaboration, led by Australian scientists, has found that DFTD originates from cells called Schwann cells, which protect peripheral nerve fibres.

The results have been published in the journal Science.

Through the discovery, the team has now identified a genetic marker that could be used to accurately diagnose the perplexing cancer, which has seen the devil listed as endangered and facing extinction.

What happens is that these devils – so appropriately named – tear into each others’ faces because, well, that’s what they do. They’re about as nasty as the tumor itself. This then transmits the disease from one animal to the next. The research, in fact, has shown that the tumors all share the same characteristics, thus showing that it’s essentially the same faulty genes that are getting passed around, not new, individual tumors. Once the disease is passed, a massive tumor grows on the face of the unfortunate devil. If it doesn’t die directly from the cancer first, it starves from its inability to eat with a massive growth all over its face.

Associate Professor Greg Woods from the University of Tasmania’s Menzies Research Institute said the Schwann cell find was an important step in the process to further understand the disease.

“Devils develop tumours of all different types and the genetic markers we have identified are useful for telling apart the tumours that occur in DFTD from other kinds of tumours,” Associate Professor Woods said.

The propensity for devils to develop cancer so easily is distressing. They’re like the anti-naked mole rats. I would specifically be interested in learning about the quality of contact inhibition of the devils. My suspicion is that it simply sucks.

Naked mole rats and cancer resistance

Cells have what is called contact inhibition. This means that once they come into contact with each other (or something else), they will cease to grow (or slow growth significantly). However, this is not true of cancer cells. Indeed, it is a hallmark of such cells; they grow and grow and even layer atop each other. Contact inhibition controls cell growth and cancer is, by one general definition, uncontrolled cellular replication.

A recent study led by Vera Gorbunova of the University of Rochester has focused on the naked mole rat and why it has never been observed to develop cancer.

The findings, presented in The Proceedings of the National Academy of Sciences, show that the mole rat’s cells express a gene called p16 that makes the cells “claustrophobic,” stopping the cells’ proliferation when too many of them crowd together, cutting off runaway growth before it can start. The effect of p16 is so pronounced that when researchers mutated the cells to induce a tumor, the cells’ growth barely changed, whereas regular mouse cells became fully cancerous.

This gene is on top of another gene which contributes to restricted growth. Humans (and other animals) only have one, p27, and it gets ‘worked around’ by cancer commonly enough. Cancer in the naked mole rat is theoretically possible, but since it has to breach two barriers to uncontrolled cellular growth, it is unlikely.

As always, there is an excitement with any discovery which could contribute significantly to curbing or stopping many of the major diseases afflicting humanity, but it must be met with temper.

It’s very early to speculate about the implications, but if the effect of p16 can be simulated in humans we might have a way to halt cancer before it starts,” [says Vera Gorbunova].

Might is the key word, and I think Gorbunova’s caution is appropriate. Cancer is a bit of a devil, to say the least, and every discovery seems to lead to a more complicated understanding of how it works. We’ll see what this research turns out to really mean.