Broken Genes And Scrambled Proteins: How Radiation Causes Biological Damage

Broken Genes And Scrambled Proteins: How Radiation Causes Biological Damage

If decades of cheesy sci-fi and pop culture have taught us anything, it’s that radiation is a universally bad thing that invariably causes the genetic mutations that gifted us with everything from Godzilla to Blinky the Three-Eyed Fish. There’s a kernel of truth there, of course. One only needs to look at pictures of what happened to Hiroshima survivors or the first responders at Chernobyl to see extreme examples of what radiation can do to living tissues.

But as is usually the case, a closer look at examples a little further away from the extremes can be instructive, and tell us a little more about how radiation, both ionizing and non-ionizing, can cause damage to biochemical structures and processes. Doing so reveals that, while DNA is certainly in the crosshairs for damage by radiation, it’s not the only target — proteins, carbohydrates, and even the lipids that form the membranes within cells are subject to radiation damage, both directly and indirectly. And the mechanisms underlying all of this end up revealing a lot about how life evolved, as well as being interesting in their own right.

A Radical Proposal

Strangely enough, the main target for ionizing radiation in the cell isn’t any of the usual suspects like DNA or protein, but something quite unexpected: water. It makes sense when you think about it; on average, 70% of each cell is made up of water molecules, so it’s by far the largest target in terms of volume. Water absorbs most of the energy transferred to cells by radiation, whether in the form of photons — gamma rays, X-rays, cosmic rays, and ultraviolet light — or particles — alpha rays and beta rays, speeding neutrons, etc. And the changes that this energy transfer induces in water molecules can be responsible for dramatic biological effects.

\bf H_2O \xrightarrow\it \texthv H_2O^+ + e^-

When a water molecule is struck by an ionizing event, it leaves behind a positively charged species and a free electron. Both of these are quite reactive, and set off a cascade of reactions that can result in the production of free radicals, which are basically molecules that have an unpaired electron. The primary free radical that results from the ionization of water is the hydroxyl radical, which is one hydrogen and the oxygen from the original water molecule, with an unpaired electron on the oxygen. Hydroxyl radicals and related products of ionizing events are known collectively as reactive oxygen species, or ROS.

Thanks to that unpaired electron, hydroxyl radicals are so reactive that they’re virtually guaranteed to react with something within the diameter of only two water molecules from the ionization event, a very small distance indeed. That’s pretty bad news, because what the hydroxyl really wants is to hook up with a proton so it can be plain old water again, and it doesn’t care where it gets that proton from. That can spell doom for something like DNA, which is mainly composed of the five-carbon sugar deoxyribose; when a hydroxyl radical pulls a proton off this sugar, it leaves a lesion on the backbone of the DNA double helix that makes it prone to breakage.

No matter what the target is, biological damage that results from radiation-induced oxidative stress is called indirect damage, since the energy of the original radiation is transferred through the intermediary of free radicals. It’s estimated that 70% to 80% of radiation damage is indirect damage, which again makes sense because of the amount of water in a cell.

Holes In Bones

Biological macromolecules can also incur direct damage from radiation, and depending on the target, the results can be catastrophic. This can result in much of the same kind of damage that oxidative stress reactions cause, except without the limitation imposed by the narrow window of opportunity that hydroxyl radicals have to act. What’s more, because of the way DNA is packed in cells — each cell in your body has over a meter of DNA; to pack it all in, it’s wound tightly around proteins called histones — it’s likely that an incident photon of ionizing radiation can cause more than one lesion on a small stretch of DNA. This is compounded by the actual structure of DNA — despite the simplified cartoons, DNA isn’t a ladder, but rather a double helix with opposite strands actually in very close proximity to each other — which makes it highly likely that direct radiation will result in a double-strand break in DNA. The information-containing bases inside the double helix are also subject to direct radiation damage.

While DNA gets a lot of attention, it isn’t the only potential target for direct damage from radiation, nor is it necessarily the most important one. Proteins are also subject to damage, sometimes visibly so. Recent experiments have actually shown the physical track of high-energy X-rays as they passed through samples of bone, showing up as a series of tiny holes where the radiation destroyed collagen, a tough, fibrous protein found in structural tissues. The damage caused by the X-rays is thought to have been amplified to some degree by the mineral crystals of calcium and phosphorus in the bone, resulting in damage beyond the original path of the radiation. Although non-structural proteins, like enzymes, were not studied here, it can be assumed that they’d suffer the same kind of damage from direct radiation, with the same kind of amplification being possible.

Direct radiation damage to a piece of fish bone. The sample on the right was demineralized, so the larger holes on the left suggest calcium and phosphorus crystals present in intact bone somehow amplify the damage. Source: Sauer, K., Zizak, I., Forien, JB. et al. Primary radiation damage in bone evolves via collagen destruction by photoelectrons and secondary emission self-absorption. Nat Commun 13, 7829 (2022).

Bind-ed By The Light

It’s not just ionizing radiation that causes direct damage to biological macromolecules. As anyone who has ever had a sunburn knows, ultraviolet light can cause quite a lot of damage too. While DNA is actually quite efficient at protecting itself from UV damage — most of the energy in UV is just converted to heat by DNA — some of the UV slips through to the information-coding bases inside the double helix. Here it can form what’s known as pyrimidine dimers, where adjacent pyrimidine bases — thymine (T) and cytosine (C) — become bonded together covalently. This happens when light in the UV-B range strikes the carbon-carbon double bonds in the ring structure of the pyrimidine bases. The result is that the two adjacent bases are joined together through a four-carbon ring, called a cyclobutane ring:

Thymine dimers are formed when two adjacent “T” bases are bound together by UV-B light. This puts a kink in the sugar-phosphate backbone of that section of DNA.

When a dimer forms, it introduces a conformational “kink” in the DNA backbone, designated by the “R — R” in the diagram. Normally, thymine (T) on one strand of the DNA double helix binds with adenine (A) on the other strand, but the formation of a dimer leaves those A residues unmatched. The whole thing is a messy situation that presents a number of challenges to the cell.

First is the problem of DNA replication. Normally, an enzyme called DNA polymerase rides along the length of a DNA strand, unzips it, and makes an exact copy of both strands. The kink induced by a thymine dimer makes it hard for DNA polymerase to move down the strand, potentially slowing down replication or even stopping completely at the lesion. Luckily there are variants of DNA polymerase that have evolved to deal with thymine dimers; unfortunately, they tend to be a bit error-prone, stuffing any old base in the growing DNA strand rather that the pair of adenines it should. This results in changes to the genetic code in the new strands of DNA, which can be a very bad thing indeed.

There’s also a problem with transcription, which creates the messenger RNA (mRNA) template that’s used to direct protein synthesis. The enzyme that directs this is called RNA polymerase, which can also stall at the kink produced by thymine dimers. This can result in truncated mRNA templates, with potentially disastrous results if they end up being transcribed into partial-length proteins. There’s a lot that can go wrong with a cell thanks to a little UV light.

The Repair Squad

Ironically, though, the fact that thymine dimers can form so easily — some estimates are that 50 to 100 thymine dimers form every second human skin is exposed to sunlight, a tanning bed, or even the UV light needed to cure nail polish, it seems — may have been the evolutionary pressure needed to build the biochemical machinery needed to fix these lesions. A whole host of DNA repair enzymes, called photolyases, have evolved to fix thymine dimers and other radiation-induced damage to DNA, especially in plants, which are obviously constantly challenged by ultraviolet light. Photolyases are interesting because they’re literally solar-powered — they contain an “antenna complex” consisting of cofactors that can absorb light at the blue end of the spectrum and in turn transfer electrons into the dimers to break them apart.

Photolyases are evolutionarily ancient; they can be found in almost every organism stretching back to the earliest bacteria. Humans and most other mammals have evolved an additional repair pathway, called nucleotide excision repair, to deal with thymine dimers; essentially, it recognizes the backbone kink and enzymatically clips a section on either side out of the DNA strand, which is immediately filled in by a team of enzymes.

It’s easy to say that nothing good can come from either ionizing or non-ionizing radiation acting on biological tissue; just looking at the tracks left in bone by X-rays certainly supports that. But radiation damage, especially to DNA, is a double edge sword. Yes, most lesions that aren’t repaired can potentially cause problems, up to causing lethal cancers. But the damage caused by radiation has also been a major driver of the mutations that power evolution, and as such is pretty much responsible for what life has become over the last couple of billion years.

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