[No idea what DNA is? Don't worry, skip the first paragraph and continue with the second!] In our latest research contribution (read here), we showed that a new DNA modification identified in our lab about a year ago is altered in some cancer patients. We discovered the responsible enzyme as well as the mutations, which corrupt its functionality. A comparison of the cancer patients with and without the mutated enzyme show other biochemical differences, which strongly proposed to individualize current cancer treatment for this subgroup of patients. And if you are lost reading this, here is a more down to earth explanation:
Each cell has DNA which contains the information about all our proteins. You should imagine the DNA as a long book with four letters A, C, G and T. Although this sounds like a rather abstract model, it is more realistic than one might think. The DNA is a huge biochemical molecule built by many smaller molecules. The most important part of DNA is a chain of millions of one out of four molecules. These four molecules – you can guess – are called Adenine, Cytosine, Guanine and Thymine. They correspond to our letters. Other molecules read them as if they would be letters. Depending on the order of the letters, enzymes can build all the different proteins in our cells. The region, which describes a protein, is called a gene. However, all cells contain the same DNA but a liver cell is obviously rather different from a brain cell. Both cells produce different proteins. This is done by regulating which genes of the DNA are used to produce proteins. And who tells which genes should be used? The DNA itself. The DNA contains so-called regulatory regions, which tell other enzymes whether certain genes should be used to produce proteins or not. That’s the basic biochemistry in our cells. And one more step and we can talk about our research.
Some years ago, researchers realized that often the letter C is modified to an mC. This biochemical modification is important as it can change the regulation of our genes. Hence, some people talk about five instead of four letters in the DNA. The group I joined in Boston discovered just before my arrival that C is sometimes further modified to an hmC in embryonic cells (also published in Nature, click here). This was the starting point of a lot of research to understand the function of hmC and how hmC itself is regulated. The result of these efforts are now published in our new article:
Based on a suggestion of the first article, we analyzed an enzyme called Tet2. We could show that Tet is indeed involved in the modification of C / mC to hmC. How do we know this? We found that the function of Tet2 can be disrupted by mutations. The disrupted enzyme is dysfunctional and cells with the disrupted version of the enzyme have much less hmC than normal cells. Investigating the mutations of Tet2 in more detail, we realized that a subgroup of cancer patients have exactly these disrupting mutations. Using tissue samples of these patients (and, of course, control patients), we discovered that tissues from patients with dysfunctional Tet2 have less hmC than the controls. Hence, our findings of mutated Tet2 and altered DNA modifications is not just a special lab case but specifically occurs in a subgroup of one of the most terrifying diseases in the world.
Next, we analyzed the tissues in more detail. In addition to the difference in hmCs, they also differ from control patients by having less mC than C. This is rather strange because cancer patients usually have much more mC than C. In fact, cancer drugs try to reduce the abundance of mC to C in cancer patients. This is current clinical practice. However, for these special patients with mutated Tet2 and, hence, less hmC and less mC, this might be the totally wrong treatment. Besides the biochemical insights in the regulation of hmCs, this is our main finding.
