Wednesday, 24 August 2011

DNA Repair just doesn’t give me the same Buzz

Ask any graduate student and they might tell you caffeine is a lifeline. Ask a health enthusiast and they might tell you it’s a poison. Ask a physician and between sips they might advise you that it’s fine in moderation. If you decide to ask the researchers behind a recent paper in the Proceedings of the National Academy of Sciences, however, they’ll let you know that caffeine can help prevent skin cancer. As a bonus, they’ll even tell you why. In my post last week I started what I intend to be an ongoing discussion on enzymes: what they are, what they do, and how they affect every facet of life. The last post was a (very) general introduction. Some posts will dig into the nuts and bolts of the chemical reactions enzymes help along and how the heck they do it. Some posts, like this one, will discuss the broader roles of enzymes in biology. So grab your coffee cup and sunscreen (just in case) as we talk about some counterintuitive caffeine consequences.

            Before we can talk about what role enzymes play in cancer, we need a very brief description of how cancer works. Cancer occurs in pretty much all life forms that exist, like us, as groups of cells. This is in contrast to single-celled organisms like bacteria and yeasts. Cancer is basically uncontrolled growth of specific cells. All the cells in our body usually divide to form new cells, thus growing the tissue, at specific rates and under specific circumstances. Cancer happens when the cells divide very rapidly without obeying the rules, so to speak, of when they are supposed to replicate. One of the reasons that normal cell division is so regulated is to make sure that the new cells coming out of cell division are healthy and have accurate copies of the parent-cell DNA. When replication is happening too quickly, there is no time for the cell “quality control” mechanisms to check that everything is honky dory, and the result can be new cells with mistakes in the genetic code. These aberrant cells not only have functional problems due to the mutations, but will also go on to divide rapidly, causing a cascade of rapidly dividing, unhealthy cells that form the tumors associated with cancer.  So what is the trigger for this cascade? What causes that initial cell to start dividing too fast? As I mentioned, normal cell division is closely regulated, and if something causes a problem in one of the tools the cell uses to regulate division, the regulation system can go out the window. The genes coding for these regulatory tools are often called oncogenes (basically “cancer genes”) as mutations in these genes are likely to cause cancer.

            There are many things coming at us every day that can cause DNA damage. These range from UV-rays to charbroiled steak to chemicals we make inside our own cells or mistakes by our cellular DNA-manipulation machinery. In fact, lots of DNA damage is done every day inside each one of us, so why are we still up and walking around? Enter the enzyme. Not one enzyme, in fact, but an arsenal of enzymes, each with a specific job to do in DNA-maintenance. In thinking of enzymes in your body, you can think of each one having a very specific skill, like trades-people working to build a house. The plumber doesn’t put in the electrical work and only the floor guy puts in the tile. With enzymes it goes even further, so that in laying floor tiles you’d have one guy to lay the grout, one guy to pick up the tile, another to position it, another to press it down, another to wipe it clean, etc.  In talking of DNA, there is a set of enzymes for making the DNA, specific sets of enzymes to repair specific types of DNA damage, and specific sets of enzymes to detect specific types of damage at specific times and signal to the DNA-repair enzymes to get to work.

            Before we get too jittery, lets talk about how caffeine affects this process. We all have an enzyme called ATR that is involved in a couple things we’ve talked about. This enzyme is a kinase, meaning that it catalyzes transfer of a phosphate group from one molecule onto another. This might seem a bit inconsequential in the context of something as huge as cancer. This one transfer reaction, however, is a recognizable signal in the cell and is passed along and amplified. Eventually it triggers the action of enzymes tasked with repairing certain types of DNA damage, including that caused by UV-rays. The enzyme ATR also happens to be part of the division regulation “tools” that we talked about. It’s a kinase that performs its role as part of a cell division checkpoint, a time when activities in the cell determine if it will go on to divide, or kill itself in a process called apoptosis.

Caffeine binds to ATR and stops it from doing its job. This means that when some kinds of DNA-damage is detected, ATR does nothing (instead of transferring that all-important phosphate), the DNA is not repaired, and instead of replicating, the cell dies. Wait a second, this sounds like a bad thing; how does this prevent cancer? The problem with DNA repair enzymes is that for certain types of DNA damage, there is no way for them to ensure that the DNA is put back together exactly like it was before the damage. Sometimes these enzymes can only physically fix the break and hope that the sequence is repaired by luck, or that it was in a spot that didn’t matter much anyway. If this type of repair happens in an unlucky spot, like an oncogene, the repair makes DNA that looks physically okay, but the resultant mutation can have cancerous consequences. In these cases, NOT repairing the DNA effectively causes cellular suicide before the very first cancer cell can form.

Enzymes have a role in everything our bodies do, from detecting signals and passing messages, to constructing and repairing cellular components. Everything is controlled in a delicate balance, and often this control is itself achieved by enzymes. As this example illustrates, turning an enzyme “off” is an important component of cellular control mechanisms. Although our bodies have many built-in off switches, outside chemicals can also interact with our enzymes with ultimate results that can be difficult to predict. So next time you’re chowing down you can look at your food and ask, “Hey, what enzyme are you hooking up with?”

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